Advances in drug discovery

Pfizer just can't seem to win with Champix/Chantix as another label change approaches

2011-06-17T21:06:00.001+01:00

Pretty much since its launch it seems that Pfizer has been having problems with Chantix (also known as Champix outside of the US).

Launched towards the end of 2006 as the new smoking cessation drug, worldwide sale of Chantix/Champix peaked at about $280 million per quarter worldwide. Then the problems started. First, cases of neuropsychiatric adverse events began to emerge leading to a label modification warning of possible depression and suicidal ideation. These warnings were later converted to a fully blown boxed warning.

Paralleling the label changes was a slump in sales. Between Q1 2008 and Q1 2009 quarterly worldwide sales had fallen by $100 million. Pfizer's response was two-fold. Firstly, to start focusing more on the emerging markets - China and India for example where the rate of smoking is massive - approaching 50% in adult males. Secondly, Pfizer began targeting those patients at greatest risk from the effects of smoking. This included patients with COPD, those going into surgery (smoking delays wound healing) and also those with cardiovascular disease.

A good strategy on the face of things and this was borne out by data suggesting that smoking cessation with the use of Chantix improved lung function in COPD patients. Now however Pfizer has been hit again following reports that Chantix may increase the risk of heart attack in smokers.

The FDA has notified the public and physicians alike that Chantix may be associated with a small, increased risk of heart attack. This safety information will be added to the Warnings and Precautions section of the Chantix physician labeling.

The warning follows an FDA review of a randomized clinical trial of 700 smokers with cardiovascular disease who were treated with Chantix or placebo. In this trial, Chantix was effective in helping patients quit smoking and remain abstinent from smoking for as long as one year. Cardiovascular adverse events were infrequent overall, however, certain events, including heart attack, were reported more frequently in patients treated with Chantix than in patients treated with placebo.

Two questions are prompted by the most recent turn of events. What effect will this new warning have on Chantix sales and how will Pfizer respond.

As far as sales are concerned, two points must be considered. Can sales drop any more in response to adverse event fears, and secondly, patients at risk of cardiovascular disease comprise just a portion of individuals attempting to stop smoking. That is not to say that we will not see a spill over effect where otherwise healthy smokers are put off Chantix as a result of data in cardiovascular patients.

When the first series of neuropsychiatric warning came along Pfizer's reaction was to claim that the adverse events were related to smoking cessation and not to Chantix itself. This question has still not been resolved and Pfizer may well have a point although the damage was done as soon as the label was modified. We would not be surprised if the same defense came out for the cardiovascular risk. There is however one alternative explanation that may have particularly interesting consequences.

One of the most commonly used antiplatelet agents, clopidogrel (branded as Plavix), interacts with nicotine. In short, nicotine enhances the activation of clopidogrel and as a result we are left with a potential paradox.

Individuals at risk of cardiovascular events are advised to stop smoking however there is the possibility that if they are being treated with clopidogrel, smoking cessation could reduce the protection they are receiving. As a result the risk of events such as heart attacks could go up. It will be interesting to look at the data that caused the FDA to issue its warning in greater detail. What proportion of the individuals in the study were receiving clopidogrel? We shall be doing exactly that in our next issue of UpdatesPlus-Nicotinic Receptors and Smoking Cessation ( http://leaddiscovery.co.uk/updatesplus )

Tacrolimus as a new approach to pulmonary artery hypertension?

2011-05-19T19:56:00.002+01:00

I am just sitting here in Dulles airport on the way back from this year's ATS meeting and wanted to share with you a scientific story that has got me quite excited.

Actually I have just been sitting here for rather a long time but that is another story - I am just mentioning this as an excuse for typos etc that may creep in after 24 hours with no sleep.

Just a quick introduction - pulmonary artery hypertension (PAH) is a subset of pulmonary hypertension. PAH is characterized by increased remodelling of the pulmonary artery which takes blood from the right heart to the lung for reoxygenation. The remodeling process results in increased pulmonary artery pressure, right heart enlargement and eventually failure. The disease is rare but often fatal although life expectancy has increased due to a number of advances (prostacyclins, PDE5 inhibitors and endothelin receptor antagonsists).

The reported incidence of PAH is low; 1-5 new cases each year per million people. No one knows exactly what causes PAH - in fact it is an umbrella term for various disease subtypes. It occurs in some HIV patients; metaphetamine users; people with scleroderma; those infected with schistosomiasis (a water bourne parasite). In some patients it is heritable- familial PAH accounts for between 6%-10% and is associated with a defect in a protein called BMPII.

Now onto the exciting part - Stanford researchers have taken a large panel of approved medicines from a broad range of conditions and ran them through an assay of BMPII activity. One molecule lit the assay up - tacrolimus - also known as Prograf or FK506.

Tacrolimus is used in most transplant recipients as an immunosupressant; it prevents the activation of calcineurin and consequent expression of cytokines and their high‐affinity receptors.

In addition to re-expressing BMPII activty, the Stanford group demonstrated that tacrolimus can upregulate the BMPII pathway in cells taken from PAH patients and also correct haematological defect in BMPII KO mice or in a new PAH model induced by SUGEN and hypoxia.

Together these pieces of evidence offer convinging evidence that tacrolimus may just offer hope to some PAH patients - the next step is to test this concept. Tacrolimus has been approved and can therefore be used in patients.

"Viagra to be used for children" - A gripe from LeadDiscovery

2011-05-10T22:29:00.001+01:00

I was just going through a batch of press releases and came across one entitled "Viagra to be used for children" - I am not sure whether to congratulate the authors for headline grabing or go after them with a long stick for incompetent reporting.

The story underlying the headline is quite interesting and also a bit of a master stroke froim Pfizer and so I just wanted to take a few moment to explain.

Pretty much everyone knows what Viagra is by now...a bit of a revolution in its time for the treatment of male erectile dysfunction. Viagra has also been highly profitable for Pfizer. In the Q1 2011 figures released last week Pfizer announced that Viagra generated $470 million worldwideand so it remains a blockbluster and Pfizer's 6th highest earner.

In 2005 the EMA and the FDA approved a product known as Revatio. This drug contains the same molecule as Viagra, sildenafil but is used for the treatment of pulmonary hypertension. This is a serious condition that affects the pulmonary valculature of all age groups. Revatio revenue is respectable, $123 million last quarter, but a fraction of that generated by Viagra.

However, the problem for Pfizer is that the patent on sildenafil is soon due to expire. One common approach to increasing revenue of a drug is to get a 6 month paediatric extension. This is obviously not possible for Viagra however pulmonary hypertension does affect children and gaining approval for Revatio in this indication extend the life of both brands. An extra 6 months of sales represents approximatley $200 million in EU sales, and it is the EMA that has recently extended the exclusivity of sildenafil. This figure will increased dramatically if the FDA follows suit although this is not certain at the moment. The reason for this is complicated and I won't go into now.

There is still something irritating about the headlines coming through the wire - Viagra for children? Facgtually incorrect if you want to be picky...the headline should read Revatio for children but who has heard of Revatio? I guess that it is the point.

If anyone is interested in reading more about pulmonary hypertension drug development we recommend:

Pulmonary Arterial Hypertension clinical community builds order from chaos

As the HCV field continues to move forward all looks rosy for telaprevir but we are not so sure about boceprevir

2011-05-04T23:44:00.002+01:00

Lots of headlines are coming through the newswires now about last week's unanimous decisions by the FDA's advisory panel to approve two new HCV candidates, telaprevir (Vertex/Janssen) and boceprevir (Merck).

On the surface things look pretty good for both compounds, however look below the surface a bit and you will see that telaprevir has come out of last week better off.

Blog continued below

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In addition to blogs we also provide a number of services to the infectious disease drug development community:

- DailyUpdates-Infectious Diseases tracks research, trials and drug development news in infectious disease

- Detailed reports - for example: R&D Trends: Hepatitis C; Epidemiology: Hepatitis C

- UpdatesPlus – Monthly in depth and expert analyses in your area. The linked example is for Nicotinic Receptors but we can cover multiple area.

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...continued

Both protease inhibitors are clearly able to increase cure rate in HCV patients dramatically. Adverse effects don't even look too bad now and physicians should be able to manage them. Two issues are however worth mentioning about the adverse events.

For telaprevir, the main problem has been known for quite a while now - rash. Vertex/Jannsen designed a rash management program for the Phase 3 trials and it has succeeded, at least in part. The incidence of discontinuation of treatment due to rash has progressively fallen - this is due in part to the use of topical agents to reduce rash but also an understanding that discontinuing telaprevir while continuing with background PEG-INF and ribavirin (HCV standard of care) allows rash to resolve while continuing to eradicate the virus.

The current issue about rash is translating the Phase 3 program to a program that is easy to use in the real world. The real challenge is perhaps to enable non-specialist physicians to be able to distinguish minor rash from severe rash and severe rash from a group of very serious skin conditions known as SCAR.

The safety problems faced by boceprevir are however more serious. The major problem is the anaemia that frequently develops in patients. Anaemia is already a problem in HCV treatment due to ribavirin affects - boceprevir makes the problem worse. The problem faced by the regulators is that it is difficult to asses just how bad the problem is; moreover it is difficult to determine the effects of anaemia in patients treated with boceprevir.

Assessing the degree of anaemia is difficult for two reasons. Firstly baseline haemoglobin levels varied in the Phase 3 trials - secondly physicians were able to use erythropoitin (EPO) in the boceprevir studies (this was not allowed in the telaprevir studies). On a related matter, use of EPO creates its own problems - firstly it is associated with adverse events of its own; secondly it has not been approved for use in HCV; and thirdly it is expensive. Alternatives to EPO are ribavirin dose reduction and this is the approach preferred by Merck. However, there is no comparison of ribavirin dose reduction and EPO use. The study looking at this, PROVIDE, is coming and it may be that the FDA will wait until they see the data before approving boceprevir.

PROVIDE is important for a second reason. Pivotal telaprevir studies allowed the enrollment prior null responders; this was not the case for boceprevir studies. Merck has however now tried to get an indication for null responders. As one of the advisory committee members put it, Merck has "tortured the data to death". In effect it has said patients with a <1 log drop in the lead-in phase used in its pivotal studies are the same as those with a<2 log drop at week 12 - the definition of null responders. Patients with a <1 log drop in the lead in phase are able to show pretty good SVR rates (about 40%) if boceprevir is added to the treatment regimen. The advisory panel did not buy this entirely last week and instead Merck may have to rely on PROVIDE. The study included patients who were characterized as "real null patients". Boceprevir was able to eliminate virus in an appreciable number of these patients at the end of treatment in PROVIDE. However we are still at least 12 weeks off of SVR data from the study and again the FDA may wait until it sees this data prior to approval.

So that is the second reason why Merck may have problems. The third reason is that Merck was highly criticized last week for a lack of drug interaction studies. We don't know yet how boceprevir interacts with antidepressant or methadone. It is quite possible that if used in the real world, patients on antidepressants (of which there are many with HCV - PEG-INF actually produces depression as an adverse event) may be at increased risk of suicide if boceprevir is co-administered. In fact the FDA concluded in its review that rates of depression were higher in boceprevir treated arms. Perhaps drug interaction is the reason why. Equally it is possible that ex-drug users will relapse if boceprevir alters the behavior of methadone. Just as serious drug interactions could diminish the concentration of boceprevir increasing the risk of resistance.

A final reason why Merck may have problems is that it the boceprevir treatment regimens are complex. Depending on the patient's characteristics there are about 5 different treatment schedules. As another panel member put it last week - you have to be a Talmudic scholar to use boceprevir.

So all in all, although both agents received unanimous recommendations for approval last week, we would not be surprised if final approval of boceprevir by the FDA is delayed giving telaprevir first to market advantage. Even if both are approved we believe that, at least until Merck releases more data to allay those concerns described above, physicians will prefer telaprevir as the more simple option for treating HCV.

LeadDiscovery has no relationships with any of the companies discussed in this blog

Telaprevir takes a leap towards the HCV market while boceprevir appears to be crawling over the line

2011-04-28T23:15:00.004+01:00

HCV news hot off the press from Maryland: We now have positive opinions on two HCV candidates in two days.

Yesterday boceprevir gained unanimous approval from the FDA's ADCOM panel, today it was the turn of telaprevir. Although both agents gained unanimous approval, telaprevir seems to have come out of the review process more favourably with response guided therapy lauded in both treatment experienced and naive patients. Response guided therapy will likely mean shorter overall treatment with telaprevir (vs boceprevir) in treatment experienced patients (24 weeks vs a likely 32 weeks).

In addition telaprevir appears likely to be approved in null responders, while it remains questionable whether boceprevir will even get an indication for null responders based on currently available data.

So, despite a unanimous approval boceprevir does not, on first glance appear to have come out shining. Some sources even suggest that the PDUFA date may be longer for boceprevir or that it may ever get a CRL due in part to an apparent oversight with respect to drug interaction studies.

Sources:

The patent cliff is set to drive global generic uptake despite tougher market conditions

2011-04-26T23:29:00.001+01:00

According to a new Datamonitor report, branded pharmaceutical companies are set to lose $82bn in sales by the end of 2014 due to the imminent patent cliff. However, this presents a significant opportunity for generics players at a time when the generics market is not only becoming increasingly competitive, but also facing tougher regulations as well as pricing pressures.

Datamonitor's report "Pharmaceutical Key Trends 2011 - Generics Market Overview" indicates that in response to rising healthcare expenditure, aging populations, and the greater use of expensive treatments, governments in developed markets are looking to bolster generic uptake in order to contain costs. Physician prescribing by international non-proprietary name, in addition to automatic substitution and pharmacist incentives, are key tools to drive generic uptake. The use of reference pricing as observed in Germany further drives uptake, with on-patent brands facing generic competition from generic versions of me-too drugs. The European Commission has put forward suggestions to facilitate generic market entry, while the introduction of user fees in the US will serve to expedite generic approvals alongside strategies to speed-up processing of citizen's petitions benefiting generics players.

However, price cuts, high brand loyalty (particularly in Italy, Spain, and Japan), and restrictions on pharmacy chains in France and Germany also present barriers to generics companies. In the US, despite the addition of many new customers and the continued drive to increase generic uptake as a result of the healthcare reform law, generics companies are set to experience further downward pricing pressures and will be forced to operate with ever-decreasing margins, focusing on consolidation and cost-cutting.

In an effort to maximize the opportunities that the patent cliff will bring, while limiting the impact of pricing and growing regulatory pressures, generics producers continue to utilize mergers and acquisitions in order to expand their geographic reach, product portfolio, and manufacturing capabilities.

Generics producers are also increasingly looking to launch generic versions of complex small molecule drugs as well as entering the biosimilars market, exemplified by the FDA issuing a positive opinion for Sandoz/Momenta's generic version of Lovenox (enoxaparin sodium; Sanofi-Aventis) in July 2010.

For generics producers operating in Brazil, Russia, India, and China, the prospects of expanding populations and healthcare coverage are exciting. These markets can, however, be challenging to enter given frequent protectionist policies favoring domestic producers, fierce competition, and pricing regulations. Consequently some generics producers have chosen to use mergers and acquisitions to expand their geographic coverage and facilitate market entry. This is exemplified by Teva's acquisition of Peru-based Corporacion Infarmasa in January 2011, which gave the company wider access to the Latin American market, a key region which is predicted to see strong future sales growth. Similarly, some branded pharmaceutical companies are also looking towards the generics market to drive geographic growth, with Abbott having acquired Indian drugmaker Piramal Healthcare in September 2010.

Related research

Pharmaceutical Key Trends 2011 – Generics Market Overview: Patent cliff set to drive global generic uptake despite tougher market conditions [access report]

Pharmaceutical Key Trends 2011 – Pharmaceutical Industry Infrastructure Overview: Pharma innovates, diversifies and contains cost in order to grow profits [access report]

Pharmaceutical Key Trends 2011 – Biosimilar Market Overview: Biosimilar uptake set to accelerate [access report]

Dual advance to the treatment of Clostridium difficile

2011-04-12T21:58:00.001+01:00

Two recent decisions set to redefine the fight against Clostridium difficile. On April 5th Optimer announced that the FDA's advisory panel had recommended the approval of DIFICID; this followed, the previous day, the FDA's decision to clear Cepheid's diagnostic, Xpert C. difficile/Epi test.

Clostridium difficile infection (CDI), has become a significant medical problem in hospitals, long-term care facilities, and in the community and is estimated to afflict more than 700,000 people each year in the US. Bacterial infection causes colitis, severe diarrhea and, in the most serious cases, death. Patients typically develop CDI from the use of broad-spectrum antibiotics that disrupt normal gastrointestinal flora.

Current therapeutic options for CDI include the off-label use of metronidazole and oral vancomycin, the latter being the only FDA-approved treatment. However, approximately 20% to 30% of CDI patients who initially respond to these treatments experience a clinical recurrence following cessation of the CDI treatment.

Recommending Optimer's DIFICID (fidaxomicin) therefore represents a significant advance. This new antibiotic inhibits the bacterial enzyme RNA polymerase, resulting in the rapid killing of C. difficile. The narrow-spectrum profile of DIFICID eradicates C. difficile selectively with minimal disruption to the normal intestinal flora, while the alternative antibiotics used to treat CDI, metronidazole and vancomycin, have been shown to disrupt the gut flora. DIFICID facilitates the return of normal physiological conditions in the colon which may be responsible for reducing CDI recurrence rates.

In two Phase 3 trials for the treatment of CDI, DIFICID was equally effective in clinical cure when compared to vancomycin. DIFICID also demonstrated statistically significant reduction in recurrences and an increase in global cure rate, defined as cure without recurrence.

Rapid diagnosis is a key part of effective treatment of CDI. Cepheid's Xpert C. difficile test has been available in the United States since July 2009. This test allows for diagnosis within 45 minutes. Last week's FDA clearance relates to Xpert C. difficile/Epi which identifies a specific epidemic strain of C. difficile, known as 027, NAP1 or BI.

C. difficile 027 strain produces high levels of spores which pose significant infection control challenges and may also be associated with more frequent relapses and ultimately higher mortality rates.

Of interest DIFICID has shown good activity against C. difficile 027

D-Day approaches for revolutionary treatments of pancreatic cancer

2011-04-11T22:23:00.004+01:00

The Oncology Drugs Advisory Committee will meet to decide on whether to recommend approval of everolimus (Afinitor) and Sunitinib (Sutent) for the treatment of advanced pancreatic neuroendocrine tumors (PNET).

Pancreatic neuroendocrine tumors (PNET) are a rare subgroup of tumors found in the pancreas. Although pNET is rare, its incidence is rising. It is reported in between 2 million to 4 million people each year, and accounts for 9% of neuroendocrine tumors. PNET can be either functional or non-functional. Patients with functional tumours usually present with syndromes induced by secreted hormones including insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide.

PNET are normally non-functional and have usually already metastasised (to the liver) by the time they are diagnosed explaining why most PNET patients are advanced stage at the time of diagnosis. PNET have a 5-year survival that can range from 97% in benign insulinomas to as low as 30% in non-functional metastatic PNET.

Surgery with curative intent is the mainstay of treatment for localized or loco-regional disease. Surgery as well as other forms of local treatment like transarterial chemoembolization or radiofrequency ablation can also improve prognosis in patients with liver metastases. Unfortunately however patients with pNET have few therapeutic options, and up untill recently no new drug has been approved for the disease for over 25 years.

Sutent became the first new treatment of PNET in December 2010 when it was approved by the EMA.

For further information on PNET see our recently featured report: Pipeline Insight: Cancer Overview Malignant Melanoma, Neuroendocrine Tumors and Thyroid Cancer

If recommended for approval tomorrow, everolimus (Afinitor) and Sunitinib (Sutent) should offer much needed hope to sufferers of this rare cancer. Afinitor probably stands the greatest chance of approval.

Afinitor is an mTOR inhibitor that has already been approved for the treatment of patients with advanced renal cell carcinoma after failure of treatment with Sutent. Pivotal studies reported that progression-free survival (PFS) more than doubled in patients with pNET treated with everolimus (Afinitor) versus placebo with best supportive care.

Novartis was seeking approval of everolimus for treatment of neuroendocrine tumors that are gastrointestinal, lung or pancreatic origin. But the FDA asked Novartis to update its new drug application to to seek approval only for treatment of tumors that begin in the pancreas, according to a press release from the company which was highlighted on today's issue of DailyUpdates-Oncology.

In briefing documents released ahead of Tuesday's advisory committee hearing, FDA reviewers analyzed the Novartis' large, international clinical trial that randomized patients with pNET to everolimus in addition to best supportive care or to placebo and best supportive care.

The final analyses included 274 patients, and found that patients treated with everolimus had a median progression-free survival (PFS) of 11 months, compared with 4.6 months among patients randomized to placebo (P<0.001).

Like Afinitor, Sutent was also able to dramatically increase PFS, doubling it to 11.4 months, versus 5.5 months in the placebo arm. Patients treated with sunitinib had a 71.3% probability of being alive and free of disease at six months, compared with 43.2% of the placebo group. Overall survival had not been reached after a median follow-up of 10-11 months.

Sutent is an oral multi-kinase inhibitor approved for the treatment of advanced/metastatic renal cell carcinoma and unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) after failure of imatinib mesilate treatment. Sutent works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer including VEGFR and PDGFR.

Despite promissing data, the FDA reviewers have expressed major concern that the trial was closed early. The trial was stopped after there were 81 progression-free survival events, which was just 31% of the events that the study design planned for. As a result the reviewers were concerned that the magnitude of PFS is uncertain and hence the benefit:risk assessment may also be uncertain.

Vandetanib is approved in the US for medullary thyroid cancer

2011-04-08T00:06:00.005+01:00

About 44,600 new cases of thyroid cancer were diagnosed in the US last year, with about 1,690 of those resulting in death, according to the US National Cancer Institute. Medullary thyroid cancer is estimated to represent up to 5% of all thyroid cancers, with about 2,200 patients being diagnosed last year with that form of the disease.

Multi-targeted tyrosine kinase inhibitors dominate the thyroid cancer pipeline (see: Pipeline Insight: Cancer Overview Malignant Melanoma, Neuroendocrine Tumors and Thyroid Cancer). There are four late-stage drugs which are forecast to achieve sales of $97m by 2019. It has long been thought likely that at least one of the late-stage drugs will be the first agent approved specifically for medullary thyroid cancer.

Likelihood has now become reality as the FDA has approved orphan drug vandetanib for the treatment of thyroid cancer.

The safety and effectiveness of AstraZeneca's vandetanib were established in a single, 331-patient randomized international Phase III ZETA study designed to measure progression free survival in patients with late-stage medullary thyroid cancer.

The results showed a median PFS of 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. Final progression-free survival in patients treated with vandetanib has yet to be disclosed; moreover, overall survival data re not currently available.

Despite these two issues, vandetanibdoes represent an advance in the treatment of thyroid cancer, but not without a price. Vandetanib's labeling comes with a black-box warning of QT prolongation, torsades de pointes and sudden death. Because of those risks, AstraZeneca was required to implement a risk evaluation and mitigation strategy (REMS) plan for vandetanib,.

While the majority of medullary thyroid cancer cases are sporadic, approximately 20% to 25% are hereditary, caused by inherited mutations in the RET proto-oncogene, which drives the growth of malignant cells. Approximately 25-60% of sporadic MTCs have a somatic mutation of the gene as well.

Vandetanib inhibits RET, as well EGFR and VEGFR, which are involved in cell proliferation and angiogenesis in a number of different tumour types.

Vandetanib is also in Phase II development for the common forms of thyroid cancer (follicular and papillary).

Clopidogrel variability - GIFT data puts the brakes on PON1 as a major factor modifying the response to clopidogrel.

2011-04-05T20:08:00.002+01:00

A presentation of the GIFT sub-study of GRAVITAS, delivered today at ACC in New Orelans has put a dampner on the PON-1 story building around clopidogrel responsiveness.

Clopidogrel is the most widely used antiplatelet agents and is indicated for use in ACS patients as well as the prevention of ischemic events in patients who have suffered a recent myocardial infarction, recent stroke, or with established peripheral arterial disease.

It is well known to the cardiovascular community that the response to clopidogrel is highly variable however the reason for this variability is not clear. Both genetic and baseline factors have been suggested to represent the underlying cause.

For example body weight and diabetes are known to alter the response to clopidogrel. On the other hand, polymorphisms in the gene encoding an enzyme known as CYP2C19 have also gained much attention over the past year or so in the context of clopidogrel variability.

CYP2C19 is a hepatic enzyme that is responsible for the metabolism of many therapeutic agents; one target agent is clopidogrel.

CYP2C19 is responsible for the conversion of clopidogrel to its active metabolite. Polymorphisms in the CYP2C19 gene, and especially the *2 allele result in much reduced clopidogrel activation. Carriers of two *2 alleles (poor metabolizers) show particularly poor activation. Similarly, certain other therapeutic agents that interact with the CYP2C19 enzyme, such as the proton pump inhibitor omeprazole, have also been reported to reduce clopidogrel activation.

Reduced clopidogrel activation has been related to lower antiplatelet activity and increased risk of ischemic events after percutaneous intervention - the procedure by which stents are placed in the coronary vasculature in patients after a myocardial infarction or those at risk of having one.

The fear that the *2 allele of CYP2C19 may limit the activity of clopiodgrel and increase the risk of stent thrombosis as well as other ischemic events in stented patients has recently lead the FDA to impose a box warning on the Plavix (clopidogrel) label. The warning is that "Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with PLAVIX at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function".

Despite the box warning, CYP2C19 genotype and other known factors account for just a very small part of clopidogrel's variability - in fact less than 20%. One of the big questions is what accounts for the rest? Earlier this year Dutch researchers reported in Nature Medicine that paraoxonase-1 (PON-1) is a major determinant of clopidogrel efficacy - in fact variability in the gene encoding this enzyme (another enzyme responsible for the activation of clopidogrel) was suggested to account for nearly all the variability in clopidogrel response.

The finding, stunning as may have been, has been greeted with emotions ranging from doubt to excitement. The finding was discussed on multiple occasions at this year's ACC meeting in New Orleans, the first big cardiology meeting following the PON-1 announcement.

Dr Matthew Price has however just put a damper on the PON-1 story.

GRAVITAS was a study looking at the ability to compensate for the poor response to clopidogrel in some patients by personalizing the dose of clopidogrel used. This study in itself was negative. Data presented last year at AHA reported that increasing the dose of clopidogrel in poor responders had no effect on clinical outcomes. GIFT was a genetic sub-study of GRAVITAS. Data presented from GIFT this morning reports that PON-1 has absolutely no effect on the response to clopidogrel.

So what next? The contradictory nature of the two reports is intriguing and also perplexing. Replication of the Dutch data could have lead to much improved use of clopidogrel. Explanation of the difference is eagerly awaited. One suggestion that we would like to put forward involves geographical differences in the studies. GRAVITAS was a North American study - the study looking at PON-1 recruited largely European individuals. Whether this difference is important remains to be seen.

UK recommendation for Merck's Simponi but it may struggle to make an impact in the rheumatoid arthritis market

2011-03-25T19:52:00.000Z

For further information on the rheumatoid arthritis market:

The National Institute for Health and Clinical Excellence has recommended Simponi for psoriatic arthritis. Based on this, Datamonitor believes that the drug will gain further positive recommendations in other rheumatology indications. However, while Simponi does have dosing advantages over other approved biologics, it is unlikely to make a huge impact on the UK market.

The recommendation of Simponi (golimumab; Merck & Co.) for the treatment of active and progressive psoriatic arthritis (PsA) represents a u-turn by the UK's National Institute for Health and Clinical Excellence (NICE). Having previously issued negative draft guidance, NICE's newfound faith in the drug is based on a review of additional information. This is positive news for Merck & Co., although NICE is yet to issue the final guidance to the NHS (likely due by April 2011).

Simponi represents the fourth tumor necrosis factor (TNF) inhibitor to become available for psoriatic arthritis in the UK, following in the wake of Enbrel (etanercept; Amgen/Pfizer), Remicade (infliximab; Johnson & Johnson/Merck), and Humira (adalimumab; Abbott). However, the recommendation comes with the condition that Simponi should be used in the same way as other TNF inhibitors, namely after patients have failed two prior traditional disease-modifying antirheumatic drugs, administered either individually or in combination. NICE arrived at this conclusion after deeming that there was no clinical evidence to distinguish Simponi from its competition. Furthermore, NICE has demanded that Merck provide the higher 100mg Simponi prefilled syringe at the same price as the 50mg dose. Explaining this, the Appraisal Committee felt that Simponi was not as cost-effective as Enbrel, and that the 50mg dose had acceptable comparability to Remicade and Humira.

NICE is still reviewing Simponi for ankylosing spondylitis (AS) and rheumatoid arthritis (RA), with outcome dates expected in October and June 2011, respectively. The PsA recommendation bodes well for Simponi in these additional indications. Indeed, the potential recommendation in RA may well mirror what happened in PsA.

In October 2010, NICE did not recommend Simponi for the treatment of RA in patients who have had therapy with a TNF inhibitor and for whom rituximab is appropriate, placing it further behind recent entrant and close competitor Cimzia (certolizumab; UCB), which was approved for RA under a cost-sharing scheme in February 2010. While Cimzia was approved ahead of Simponi in the UK for RA, Merck wisely submitted Simponi for RA, PsA, and AS in the EU simultaneously (Cimzia is still in Phase III for PsA and AS). Together with its monthly subcutaneous dosing, this may generate advantages for Simponi in all three indications.

Datamonitor forecasts that, if approved, Simponi could generate RA sales of over $20m by 2019 in the UK. However, opinion leaders have warned that as a new drug Simponi may not be a preferred agent in RA or indeed in PsA, with rheumatologists likely to remain loyal to established, tried and tested brands.

What effect will the availability of HPV vaccines really have on cervical cancer

2011-03-23T22:31:00.005Z

According to Epidemiology: Cervical Cancer, during 2010, it was estimated that 35,898 women will develop cervical cancer in the seven major markets. Of this number 13,170 cases will have been in the US and approximately 18,000 in the EU5.

The good news is that between 2010 and 2020, total cervical cancer incident cases in the seven major markets are expected to decrease slightly by 4%. This change is due to This weak decreasing trend is due to forecast decreases in incidence rates alongside forecasted increases in the most susceptible populations.

One recent advance that should contribute to a gradual fall in the numbers of women suffering cervical cancer is the availability of HPV vaccines.

HPV is the primary cause of cervical cancer and two vaccines have recently been made available to prevent infection with HPV.

Merck and its European marketing partner Sanofi-Pasteur launched Gardasil in the US and Europe in 2006. This was followed in 2007 by GSK's launch of Cervarix in Europe and later in 2010 in the US (see Infectious Diseases Vaccine Market Overview for more on the vaccine market).

The ultimate success of HPV vaccines in reducing the incidence of cervical cancer will be dictated by uptake. It is believed that uptake of about 80% is required for "herd immunity" - in other words 80% of girls in the target age range must be vaccinated to drive the eradication of HPV.

UK Department of Health figures suggested that by 2009, approximately 70% of 12-to-13-year-olds in England had been fully vaccinated. This high uptake is due in part to full state funding of the vaccine. The HPV vaccine is offered free of charge to the target population in Germany, Italy and the UK.

So, good news in some of the largest EU countries but elsewhere in Europe the picture is not as good. In France 65% of the cost is borne by the social security scheme and a recent report in the March issue of the Journal Vaccine by Fagot et al reports that just 33% of girls of the age of 14 years in 2007 and 24% in 2008 were reimbursed for required 3 doses of HPV vaccine.

This low rate of reimbursement is reflected in reports last year of low uptake. According to a Parisian study, reported by Rouzier and Giordanella, HPV vaccine coverage for female adolescents is around 17%, with less than half of girls vaccinated receiving all three doses.

According to the cervical cancer epidemiology report France has one of the lowest incidences of cervical cancer in Europe but based on the current uptake of HPV vaccine this may not continue to be the case.

Ipilimumab continues to push forward expectations for the treatment of melanoma

2011-03-22T22:33:00.000Z

Exciting news has emerged from BMS on its anti-CTLA-4 mAb, ipilimumab. The antibody has met its primary endpoint, overall survival, in a study looking at first line treatment of metastatic melanoma. The level of improvement in overall survival has yet to be disclosed. Data will be presented at ASCO this year.

Ipilimumab is currently under review around the world but for patients with later stage disease that has already been treated. Pivotal data from NCT00094653 reported that ipilimumab improved median overall survival by close to four months in those with previously treated melanoma, compared with an experimental therapeutic cancer vaccine, gp100, which has been extensively tested in the disease. Median overall survival for ipilimumab alone was 10.1 months versus 6.4 months for gp100 alone. A US decision on whether to approve ipilimumab based on these data has been set for March.

If given the go-ahead, ilipimumab could become the first new therapy approved for melanoma in more than a decade in the US. EU approval of the product in this indication is also anticipated for this year.

Currently, most melanoma is diagnosed at an early stage, with surgery proving curative in many patients. For advanced disease, current treatment options are inadequate, with only three approved drugs: interferon alpha-2b in the adjuvant setting, and dacarbazine and interleukin-2 for metastatic disease. Most patients are therefore treated in clinical trials.

Approved products for melanoma confer only mediocre response rates with minimal effects on survival, and high levels of toxicity, thus restricting their use to certain patients. Unmet needs therefore prevail, highlighting the urgent need to develop novel therapeutics offering significant clinical improvements over existing treatment options.

Depending on the final first line data it is inevitable that BMS will file for a first line indication.

The possibility of filing as a first line therapy has led to share prices peaking at an increase of 6% and Credit Suisse analysts raising their expectations for the drug. A proce of $30,000 per patient per year had been placed on ipilimumab but analysts predict that a first line indication could double this figure leading to peak global ipilimumab sales of in excess of $2 billion.

For further reading on the melanoma market see:

Stakeholder Opinions: Melanoma

Melanoma - Drug Pipeline Analysis and Market Forecasts to 2015

Pipeline Report - Neuronal alpha 7 nicotinic receptors: Candidates for the treatment of Alzheimers disease and Schizophrenia

2011-03-21T23:30:00.000Z

To order this order click here

Neuronal nicotinic receptors (nAChR) have been gaining interest over the past decade as a potential target for both therapeutic and, more recently, imaging agents. Various peripheral disorders such as inflammation are now being encompassed by nicotinic receptor drug discovery which has, in the past focused on CNS indications.

The first α7 nAChR agents are nearing the market. This report describes the proof of concept supporting the development of this class specifically for Alzheimer’s disease and schizophrenia.

α7nAChRs are selectively expressed in the brain, particularly in regions implicated in cognitive function and especially Alzheimer’s disease and schizophrenia.

A large body of evidence supports the development of α7nAChR ligands for the treatment of Alzheimer’s disease. Nicotinic agonists may directly block the deleterious effects of αβ42 mediated through α7nAChRs. The efficacy of α7nAChR seen in trials to data is however more likely to reflect the enhancement of physiological cognitive pathways and domains which are compromised during Alzheimer’s such as working memory are stimulated by α7nAChR agonists.

The most popular approach to α7 nAChR drug development for Alzheimer’s disease has been to develop partial agonists although some of these partial agonists may actually be co-agonists. This new concept involves ACh docking in one receptor binding site and the agonist binding the second site. This results in synergy ACh and ACh esterase inhibitors (eg Donepezil).

Schizophrenia is associated with multiple overlapping symptoms including positive symptoms (eg psychoses); negative symptoms (eg flatness) and cognitive disorders. Treatments are only available for positive symptoms even though negative symptoms and cognitive impairment significantly reduce the patient’s quality of life.

Seven domains of cognition are deficient in schizophrenia. These include: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, processing speed, reasoning and problem solving and social cognition. α7 nAChR involvement has been reported for most of these domains supporting the development of this class for CIAS.

A number of pharmacological options exist for the development of α7nAChR ligands for CIAS. Most promising, but underutilized, may be allosteric modulators (PAMs) as this approach can upregulate cholinergic pathways without subjecting the α7 nAChR to continuous stimulation and potential toxicity.

A total of 8 α7 nAChR candidates are currently in the clinic. Of these, 2 Phase 2 candidates are for non-CNS indications (diabetes and asthma; TC-6987 and ASM-024) while Neuroderm’s ND0801 is in Phase 2 development for ADHD. ND0801 appears to be a nicotine formulation. This leaves 4 candidates in Phase 2 and 1 in Phase 1 development for CIAS and/or Alzheimer’s disease. We believe that the Phase 1 candidate, XY 4083 has been terminated with its parent company, Xytis possibly no longer trading.

The 4 Phase 2 candidates are RG3487 (Roche; Alzheimer’s); EVP6124 (En Vivo; Alzheimer’s and CIAS); TC-5619 (Targacept; CIAS as well as ADHD) and AQW051 (Novartis; CIAS). Very little is known about AQW051.

EVP6124 and RG3487 lead the α7 nAChR field. Both are described as co-agonists but RG3487 has additional 5HT3 antagonist activity. A Phase 2b study of RG3487 in Alzheimer’s is due to read out in May 2011 while EVP6124 is in Phase 2b trials for both Alzheimer’s and CIAS. The Alzheimer’s study should read out at around the same time as the RG3487 study in mid-2011; the CIAS study should read out a little earlier. En Vivo could gain first in class status although the company does not have a development partner outside of Asia and this could delay matters.

TC-5619 currently sits a little behind EVP6124, in Phase 2a for CIAS (as well as ADHD); it is not currently competing with RG3487 as the two are being developed for different indications. This may change if Alzheimer’s disease is adopted as a target. Like EVP6124, TC-5619 does not antagonize the 5HT3 receptor. One intriguing difference is that TC-5616 appears to have activity against cognitive decline as well as positive and negative symptoms of CIAS. This has yet to be disclosed for EVP6124 and if this remains the case TC-5619 will have a major advantage. The Phase 2b study of EVP6124 should address this issue.

In the CNS arena, α7nAChR development now seems to be quite mature. All molecules are in Phase 2 with little following up in Phase 1 or from preclinical development. There was at one stage significant activity around the development of PAMs although this has not resulted in clinical success. A number of companies, including some large ones that were interested in the α7nAChR appear now to be less interested. We believe that the next surge of interest will come as the class is developed for non-CNS disorders, a trail being blazed by Targacept and Asmacure.

The α7 nAChR field has resembled a drug discovery graveyard over recent years. We believe that Xytis and CoMentis who were both developing clinical stage candidates are in effect no longer trading although this requires confirmation. A number of notable terminations have also been reported.

Sanofi-aventis was developing α7 nAChR agonist SSR-180711 for the treatment of Alzheimer's disease and CIAS however development was terminated, reportedly due to cataract development. We believe that Sanofi-aventis is however attempting to get back into the clinic.

NeuroSearch entered into a research and license agreement with Abbott in 1999 however this collaboration does not appear to have been productive. α4ß2 agonists have stalled while development of an α7 nAChR agonist was stopped for what we believe to be PK issues.

AstraZeneca started a Phase 2a schizophrenia study of α7 nAChR agonist AZD-0328 in 2008 but development stopped in April 2009.

Pfizer has had moderate success in the α4ß2 field with varenicline despite concerns over neuropsychiatric adverse events. Success around α7 nAChR candidates has been poor with at least three candidates entering the clinic only to be terminated for cardiovascular reasons.

Despite the attrition rate of α7 nAChR molecules and the apparently empty early stage pipeline, of course any of the larger companies that have previously been active in the field could rapidly emerge with a new clinical stage candidate.

Understanding the link between nicotinic receptors and amyloid toxicity in Alzheimer's disease

2011-03-18T22:13:00.003Z

Research around nicotinic receptors has largely focused on cognition. Consequently nicotinic receptor ligands have been developed for various disorders associated with cognitive dysfunction such as schizophrenia, ADHD and Alzheimer's disease.

Involvement of nicotinic receptors in Alzheimer's disease particularly interesting as, in addition to improving cognition through direct effects on nerve pathways, a growing body of data have demonstrated the ability of α7 nicotinic agonists to reduce amyloid toxicity in the brain. Amyloid1-42 has been associated with the development of Alzheimer's.

Exactly how α7 nicotinic agonists impact on the effect of amyloid is unknown. Some believe that agonists prevent amyloid binding to, and excessively activating hippocampal cells. Another hypothesis can be postulated supported by data appearing in the February issue of Neurochemical research. This research suggests that activation of α4β2 nAChR by nicotine decreases BACE1 expression. BACE1 is responsible for the production of Aβ, and this was suggested by the authors to explain why levels are reduced in hippocampal neurons following nicotinic receptor stimulation.

The full paper can be accessed through http://www.leaddiscovery.co.uk/articles/21336821 - if you are involved in the development of nicotinic agents you may also be interested in LeadDiscovery's monthly service UpdatesPlus-Nicotinic receptors - http://www.leaddiscovery.co.uk/updatesplus

Further information about Alzheimer's disease for pharmaceutical personel:

Alzheimer's Disease: Current Treatment Practices and Opportunities, 2010

Repligen reports Phase 3 RG1068 data: Improved MRI imaging of pancreatic and biliary disease expected to reduced ERCP procedures

2011-03-15T06:43:00.006Z

According to a recent report, Medical Imaging Markets: MRI and Ultrasound the market for MRI continues to grow despite the recession. This is due to improvements in MRI cameras and also imaging agents.

One advance which likely to further drive the use of MRI, specifically in the area of pancreobiliary imaging is Repligen's RG1068. Yesterday, the company announced Phase 3 data supporting the use of RG1068 in combination with MRI for the diagnosis of pancreatic and biliary disease.

Diagnosis of pancreatic and biliary disease can be achieved through MRI or ERCP.

ERCP (endoscopic retrograde cholangiopancreatography) is a procedure used to image the pancreas and bile duct. The procedure involves the local introduction of water soluble iodine-based contrast media directly through the biliary and pancreatic ducts under endoscopic guidance. This then allows imaging using X-ray.

ERCP is considered a good test for diagnosis of ampullary cancers, chronic pancreatitis and duct stones. The procedure also has the advantage of being able biopsy and/or treat at the same time as diagnose. Balanced against this advantage however is the risk of adverse events such as hypersensitivity. In addition the procedure is invasive requiring patient sedation and requires considerable clinical experience. Ideally, ERCP should be reserved for those at greatest need.

MRCP offers an alternative to ERCP. Use of MRCP was first reported in 1991. This procedure replaces endoscopic intervention with an MRI and so is less invasive. One disadvantage however is that image quality may not be as good as with ERCP. RG1068 offers the potential to address this situation.

RG1068 is a synthetic version of human secretin, which stimulates the secretion of pancreatic fluid into the pancreatic ducts, thereby filling the ducts with water, which improves the ability to visualize pancreatic abnormalities. The FDA has granted RG1068 Orphan Drug status and Fast Track Designation, and Repligen estimates that there are approximately 300,000 MRI procedures conducted in the U.S. and Europe each year that could directly benefit from the addition of RG1068.

The Phase 3 data evaluated the ability of RG1068 to improve: sensitivity of detection of
abnormalities without a meaningful lose of specificity; and image quality. Both measures were improved. This contrast with an earlier analysis of the data based on which the study failed to meet its end-points. This was due to "flawed analysis due to deficiencies in performance by the contract research organization overseeing the original analysis". The FDA approved the re-read.

If, based on these data, RG1068 is approved the numbers of ERCP procedures conducted are likely to fall as patients in which the procedure is not required are triaged to alternative therapeutic regimens. Although absolute numbers of ERCP procedures may fall, improvements in endoscopy technology means that success in those procedures that are conducted may increase.

According to The World Market for Gastrointestinal Endoscopy Equipment, the GI endoscopy market is expanding due to improved technologies such as robotics. This expansion covers all types of GI diseases and is primarily being driven by the increase in GI cancers. We expect that ERCP will benefit from such advances but will increasingly be used after initial MRI diagnosis.

Edible vaccine for Alzheimer's disease?

2011-03-08T21:46:00.002Z

Just read a really cool report from a Japanese group of researchers who are developing a possible new approach to Alzheimer's disease. Fellow geeks will know that Alzheimer's is caused by an excess of a protein called beta amyloid. One possible way of treating the disease is to develop a vaccine that generates antibodies able to bind beta amyloid. That is exactly what the Japanese group has done but with a twist...they have engineered rice to express beta amyloid. Hey presto, one edible vaccine. It has been tested in preclinical models and found to work. The rice is eaten and anbodies are produce. Next step - can the antibodies cause the removal of beta amyloid and reversal of disease. Geeks like me can read on at http://www.leaddiscovery.co.uk/articles/21307566

Molecular Diagnostics in Infectious Disease Testing

2011-01-26T22:37:00.003Z

New report loaded today - are you interested in infectious disease diagnostics? This 300+ page report will be for you access this report now.

In the current medical diagnostics market, molecular diagnostics in infectious disease testing offers one of the most promising areas for growth and innovation. The confluence of breakthroughs in genomics and proteomics--along with the development of microarray devices to measure analytes in the blood--has led to this revolutionary market development. Specifically, molecular diagnostics offers the power of advanced analytical techniques to diagnose infectious diseases. Whereas before, the detection of many infectious agents was slow and expensive due to reliance upon culturing methods, researchers are now at the cusp of overcoming such limitations via the use of nucleic acid-mediated molecular diagnostics testing.

The purpose of this report is to describe the emerging field of molecular diagnostics in infectious disease testing. The infectious disease space is the most dominant and profitable sector of molecular diagnostics. Topics covered in this study include:

1) the existing and emerging technologies in the field

2) the U.S. and global market size for molecular diagnostic products

3) the profiles of companies that are focusing on the molecular diagnostic sector.

The research examines drivers and restraints for sales growth, market share and technical trends. In addition, an in-depth analysis of the competitive situation of prominent market venders is provided with five-year sales forecasts.

GSK's Avandia survives FDA panel vote but damage may have been done

2010-07-21T18:42:00.000+01:00

The majority of a 33-member FDA advisory panel has voted against the complete market withdrawal of GlaxoSmithKline's Avandia. However, considering the safety concerns surrounding the drug, and with 12 of the panelists voting for withdrawal, Avandia's sales are likely to decline further even if it remains on the market.

The future of GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone) is still unclear after the two-day FDA advisory panel hearing on the safety of the drug.

In the crucial vote on the withdrawal of Avandia, the majority of the expert panel showed strong concern about Avandia's risks by voting for withdrawal (12 votes) or increased restrictions on availability (10 votes). Seven panel members voted for stronger warnings and only three members voted for the drug labeling to remain unchanged. The FDA must now decide on Avandia's future.

The issue facing the panel was the possibility, first raised publicly in 2007, that Avandia may increase the risk of heart attacks and other ischemic events relative to other antidiabetic drugs. In comparison, Takeda's Actos (pioglitazone), a competitor drug in the same class as Avandia, has demonstrated no such risks.

While several meta-analyses and patient outcome studies have shown increased risk of ischemic events in Avandia patients, GlaxoSmithKline argues that clinical trials do not show evidence of cardiovascular risk. Recently, however, the company-sponsored RECORD trial, designed to study Avandia safety, has come under attack for poor methodology and breaches of protocol.

The FDA advisory panel heard a range of evidence and opinion before voting on questions about Avandia's safety and continued use. Majorities on the advisory panel voted that there was sufficient evidence to raise concerns about ischemic cardiovascular risks with Avandia relative to Actos and to other antidiabetic drugs, but decided that evidence was insufficient to find increased risk of overall mortality in each of these comparisons.

The inconclusive nature of the testimony presented was reflected by the fact that, despite having expressed concerns about Avandia's safety, a panel majority voted for the continuation of the TIDE trial comparing Avandia and Actos. Panel members require more evidence for Avandia's safety despite a market presence of 11 years. However, enrolment has been lower than expected in the TIDE trial and it seems likely that the latest FDA panel vote will not improve matters. Indeed, in June, the Indian government halted Avandia trials there because of safety concerns.

The fate of Avandia rests in part on the FDA's action on the advisory panel's mixed recommendations. In the absence of stronger evidence for risk, there may be an incentive to keep Avandia on the market to allow for wider clinician choice, a view expressed in panel discussions. Nevertheless, even if the FDA does not follow the panel's advice to withdraw or restrict prescribing of Avandia, physician and patient concerns about safety and litigation (and the availability of alternative therapies for most patients) are likely to lead to continuing decline in Avandia sales.

Avandia's decline opens the door for further growth by the antidiabetics that have already filled the gap created after the initial Avandia safety scare in 2007, namely class leader Actos and Merck's blockbuster DPP-4 drug Januvia (sitagliptin). With Avandia hit by safety fears and Actos approaching patent expiry in 2011, there is also the possibility for newer drug classes to seize market share, maintaining the attractiveness of type 2 diabetes as a commercial and clinical target.

Related research

Commercial Insight: Cardiovascular and Metabolic Market Overview - Diabetes to the fore as generics hit primary care markets priced $15,200

The Diabetes Market Outlook To 2014: Market dynamics, competitive landscape, emerging therapies $3,835

New data analysis reduces some of the concerns over upcoming Systemic Lupus Erythematosus (SLE) treatment, Benlysta (belimumab)

2010-06-28T23:26:00.002+01:00

Related report: Pipeline Insight: Systemic Lupus Erythematosus - Turning a corner in drug development click here

A gradual improvement has been seen over recent decades in the treatment of Systemic Lupus Erythematosus (SLE) through the use of non-biologics. Emerging data describing Benlysta (belimumab), an anti-BLyS (BAFF) monoclonal antibody developed by Human Genome Science and GSK is increasingly underlining the central role that biologics may play in the next era of lupus treatments.

Data from the pivotal studies, BLISS-52 and BLISS-76 highlighted two recent meetings, EULAR in Rome and LUPUS2010 in Vancouver.

Systemic Lupus Erythematosus (SLE) is a multiorgan autoimmune disease which is particularly common in women. Prevalence varies between different ethnic groups; in African-American women of child-bearing age the prevalence may be as high as 1 in 200 but overall prevalence rates across USA and Europe vary from 14-70/100 000 and the annual incidence is between 3 and 5 new cases per 100 000 population.

The past quarter of a century has seen a remarkable improvement in the treatment of lupus even though there has not been a new drug approval for the disease for at least 50 years. The improvement has come from a better understanding of the disease and the use of pre-existent treatments and as a result 5 year survival rates have improved from 50% to 95%.

Mild to moderate disease is treated with low dose steroids, NSAIDs, methotrexate and antimalarial treatments. More severe disease is treated with higher doses of steroids, cyclophosphamide (Cytoxan) and mycophenolate (Cellcept). Despite the improvements that such treatments have brought, significant needs remain. Notably the treatments carry considerable adverse events, significant mortality remains and, according to a recent survey, up to 30% of sufferers report that they are unemployed as a result of their disease.

To fill the unmet needs a number of companies are developing biologics. The most advanced of these include Benlysta (belimumab), epratuzumab, sifalimumab, atacicept, abatacept and rontalizumab. As described in our recent feature Pipeline Insight: Systemic Lupus Erythematosus - Turning a corner in drug development [learn more about this report here], the pipeline is relatively complex, targeting a variety of different immune proteins and exhibiting a range of profiles. Successful development of the pipeline is however likely to bring significant rewards, not only for patients but also for companies developing lupus candidates.

The commercial potential of biologics is clear. The pipeline insight report described above estimates that 2008 lupus sales were approximately $1.1 billion in the seven major markets. This report forecasts that four late-stage pipeline products could inject $2.9 billion into the market by 2019.

Most clinicians expect Benlysta (belimumab) to reach the market first and are excited about the potential it will offer. Human Genome Sciences and GSK will therefore likely benefit from rapid uptake, with peak sales of $1.9 billion expected by 2013. Market potential will remain for pipeline products through both further patient penetration and patient switching. Critical questions will include: which patients will receive Benlysta (belimumab) and how will the drug be used? Closer inspection of data released from Phase 3 studies offers some clues.

Two Phase 3 studies of Benlysta (belimumab) have been completed forming the basis of IND and MAA filings in June 2010: BLISS-52 and BLISS-76. Both studies randomized patients to three arms (placebo, belimumab 1mg/kg and belimumab 10mg/kg). The primary end-point was a composite measure designed for the study known as the SLE responder index (improvement in SELENA SLEDAI score of 4 points or greater, with no clinically significant BILAG worsening and no clinically significant worsening in Physician’s Global Assessment). The primary end-point was measured at 52 weeks and improved with 10mg/kg belimumab compared to placebo from 44% to 58% in BLISS-52 and 34% to 43% in BLISS-76.

There are two key differences between BLISS-52 and BLISS-76. The former was conducted outside of the US, while BLISS-76 was conducted in the US. Other than the geographical differences, the studies are distinguished by the fact that BLISS-52 continued for 76 weeks, 24 weeks longer than BLISS-56. This difference has given rise to some degree of confusion around Benlysta (belimumab).

Although both trials met their primary end-point with an increase in patient response rates at 52 weeks, significance was lost at week 76 in BLISS-76. Some clinicians believe that non-biological immunosupressants should be used initially in lupus patients with biologics reserved for maintenance therapy. With this paradigm the BLISS-76 data may limit Benlysta (belimumab) use to just 1 year thus reducing the potential revenue for the drug. A recent re-cut of the data presented at LUPUS2010 suggests otherwise however.

A press release from Human Genome Sciences at the time of LUPUS2010 describes a reanalysis of the effect of Benlysta (belimumab) on the SLE Responder Index at 76 weeks iusing different SELENA SLENDAI definitions. Consequently, if an improvement of 5 instead of 4 points on the scale is employed, Benlysta (belimumab) is seen to have a significant effect at 76 weeks – the scores in placebo and 10mg/kg groups were 20% vs 33% at 52 weeks and 22% vs 31% at 76 weeks. In short this reanalysis may dramatically modify how the drug is used.

The next question is which patients would most benefit from Benlysta (belimumab)? One criticism of the BLISS studies is that patients have been recruited on relatively high levels of background therapy. This is a potential problem as it may mask efficacy under a trial setting. However this issue may also have revealed a particular benefit for Benlysta (belimumab). Specifically, a significant number of patients become “stuck” on medium to high levels of steroids and data presented from the BLISS studies suggests that Benlysta (belimumab) is able to reduce steroid use.

At entry into the BLISS-76 study, approximately 46% of patients were receiving steroids at a prednisone-equivalent dose of at least 7.5 mg per day. Among these patients, the percentage of patients who had their average steroid dose reduced from baseline to 7.5 mg per day or less by Week 76 was 25.8% for Benlysta (belimumab) 10 mg/kg, 27.7% for Benlysta (belimumab) 1 mg/kg, and 17.5%% for placebo. Although this was statistically significant for just the lower dose, we believe that clinicians will view Benlysta (belimumab) as being a particularly good steroid sparing strategy while at the same time improving response.

Overall therefore, as Benlysta (belimumab) approaches the market, clinicians are gaining a better understanding on how to use the drug. This understanding will improve as we move closer to approval although it is only after approval and real world experience is gained that matters will really become clear.

Promising data reads out from ADVANCE as first generation oral HCV therapies march on

2010-05-27T22:04:00.002+01:00

Hepatitis C (HCV) represents a major global problem infecting approximately 180 million people around the world. The United States accounts for approximately 3.9 million people with chronic infection. Remarkably 75% of these patients do not even know it. The incidence of infection has now stabilized in the developed world with the exception of certain sub-groups such as intravenous drug users. Consequently those patients who are infected have increasingly chronic disease and this carries significant risks such as increased fibrosis and hepatocellular cancer.

Treatment options for HCV are currently limited to one of two pegylated interferons (Pegasys and PEG-INTRON) and in some geographies, non-pegylated interferon. Standard of care dictates that the interferon of choice should be taken alongside ribavirin for 24 to 48 weeks depending on the HCV genotype. Treatment is arduous, carrying multiple adverse events over an extended period of time; moreover treatment is more often than not unsuccessful and underused. In the US cure rates are approximately 40-45% in genotype 1 patients, falling drastically in patients who have already failed once course of treatment. Genotype 2 and 3 patients fare considerably better however these patients are in the minority, at least in the US and Europe. As if the cure rates in genotype 1 patients was not bad enough, success becomes increasingly common as the disease becomes more chronic.

Against the backdrop of poor response and difficult treatment it is hardly surprising that less than 10% of diagnosed patients are treated. This explains the intense excitement around the new wave of oral antiviral approaching the market. The two main classes of therapeutic agents are the HCV protease inhibitors and polymerase inhibitors. The proteases lead the way by a couple of years and this class is in turn lead by telaprevir (Vertex/Tibotec/Mitsubishi Tanabe) and boceprevir (Merck) which are running neck and neck to reach the market first.

Having passed through its Phase 2 study program, PROVE, Vertex submitted the Phase 3 telaprevir protocol to the FDA in Jan 2008. The program comprises 3 studies: ADVANCE and ILLUMINATE (treatment naïve) and REALIZE (treatment experienced). The aim of the treatment naive studies was to increase cure rate while at the same time reducing the duration of treatment. Consequently, ADVANCE compared 48 weeks standard of care versus two telaprevir based treatment arms. One arm treated patients for 8 weeks with triple therapy prior to stopping telaprevir; the second arm continued triple therapy for 12 weeks. In both cases the intention was to stop all treatment at week 24 although ADVANCE included a novel protocol where treatment duration was personalized. Those patients not clearing virus by week 4 and remaining virus negative until at least week 12 (ie eRVR) received standard of care for 48 weeks.

ADVANCE opened March 13th, completed enrolment in Oct 2008 and a few days ago, Vertex announced top line data. SVR rates (ie undetectable virus for at least 24 weeks after end of treatment) were an impressive 69-75% (depending on how long telaprevir was on board) compared to the usual depressing 44% with standard of care.

Vertex and most analysts are excited. The SVR rates in ADVANCE are slightly greater than the 67-68% reported from PROVE 1 and 2. This has been suggested to reflect improved management of adverse events, notably rash, and reduced drop outs (which were counted as treatment failures). Perhaps a little disappointing, SVR rates were lower than the 81-85% reported in another Phase 2 study, C208, which like ADVANCE incorporated an individualized treatment protocol. This difference has been put down to the relatively large numbers of difficult to treat patients in ADVANCE (eg African Americans; patients with fibrosis etc).

During conference calls around the ADVANCE data release it was commented that 70% of patients achieving SVR were treated for 24 weeks. On the surface this sounds impressive however bearing in mind that patients in the standard of care arm received 48 weeks of treatment by definition, we calculate that ≈50% of telaprevir treated patients were on treatment for 48 weeks. This will be viewed with interest by those at Merck considering that Vertex has consistently messaged that one advantage of telaprevir is its ability to offer high cure rates with short treatment duration.

One particularly remarkable aspect of ADVANCE is that treatment discontinuation rates due to adverse events were just 7% and 8% in the 12 and 8 week telaprevir arms vs 4% in controls. On the surface this is considerably reduced compared to PROVE 1 and 2 rates of 12-21%. Of particular note, rash related discontinuation was reduced from 7% to 1.4% reflecting successful us of the rash management protocols developed for the Phase 3 program.

However, LeadDiscovery urges caution in interpreting the discontinuation rates as figures reflect stopping all treatment. Comments were made during the Vertex calls that discontinuation rates were approximately doubled if patients discontinuing just telaprevir were included. Even against this backdrop of potentially high telaprevir discontinuation rates, SVR rates do not appear to particularly suffer. It remains to be seen however what effect discontinuing just telaprevir has on both SVR rates and also the duration of treatment.

An editorial on HCV would not be complete without mentioning IL28B.

Last year data were published showing that the 30% of patients carrying a particular allele of this gene stood a very good chance of being cured with standard of care. This could be a threat to telaprevir. Would payors allow telaprevir use in patients with this allele? Moreover this story plays right into the arms of Merck and boceprevir, Vertex's chief rival

Firstly Merck claims to have the intellectual rights to IL28B testing; secondly boceprevir studies incorporate a 4 week lead in phase during which patients receive just standard of care. Conceivably, a paradigm could emerge through which patients are tested for IL28B prior to treatment and if they achieve an early antiviral response at 4 weeks (RVR) there is a very good chance that the patients will not require a protease inhibitor. This offers the clinician greater flexibility in treating patients and payors an opportunity to cut costs.

So how is Vertex responding to this? Well, based on comments made it appears that the company will be retrospectively genotyping patients from ADVANCE in order to determine whether patients carrying the good IL28B may achieve cure more rapidly. This is turn opens up the path towards dropping treatment duration below even the 2 weeks evaluated in ADVANCE. The FDA is apparently working with Vertex in order to understand the impact of IL28B genotype on anti-viral activity in STATC regimens. It is unlikely that data will be available for AASLD 2010. This particularly story is sure to run however.

Do you want to learn more about telaprevir? Click here.

Dendreon: landmark cancer vaccine approval but high costs may hinder uptake

2010-05-07T19:32:00.000+01:00

Having been approved by the FDA in castration-resistant prostate cancer (press release), Dendreon's Provenge represents the first therapeutic cancer vaccine to reach the market (click here for related reports). This is a significant step forward: the current standard of care is Taxotere-based chemotherapy, which is associated with significant toxicity. However, it remains to be seen how frequently Provenge is used.

Provenge (sipuleucel-T; Dendreon) is composed of autologous peripheral blood mononuclear cells, including antigen-presenting cells that have been activated during culture with a recombinant human protein, PAP-GM-CSF. PAP-GM-CSF consists of prostatic acid phosphatase (PAP), an antigen expressed on approximately 95% of prostate tumor cells, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. Upon administration, the PAP-activated cells cause activation of T-cells and other immune system components to recognize the target antigen and destroy prostate tumor cells.

Manufacture of Provenge requires collection of antigen-presenting cells from individual patients, via leukapheresis, a blood collection process used to isolate white blood cells. The cells are then transported to the Dendreon manufacturing facility, presumably in cold storage, where co-culture with a PAP-containing recombinant fusion protein occurs. Manufacture of Provenge takes approximately two days, after which the vaccine is delivered to the physician's office for infusion into the patient. This entire process is carried out three times over the course of a four-week period, in order to provide three vaccinations to each patient.

Provenge has had a troubled development history to date. Dendreon initially filed a Biologics License Application (BLA) in January 2007 on the basis of Phase III D9901 study results, which showed an improvement in overall survival but failed to meet its primary endpoint of time to progression. The FDA issued an approvable letter in May 2007, requesting additional clinical data. This was met with controversy from the public; indeed, prostate cancer patient group Care to Live filed a lawsuit against the FDA, demanding that Provenge be approved.

Following this, the FDA stated that it would accept interim or final data from the ongoing Phase III IMPACT study to amend Provenge's BLA. Positive results were announced in April 2009, showing that Provenge conferred a 4.1 month survival benefit over placebo in asymptomatic or minimally symptomatic metastatic CRPC, thus meeting the study's primary endpoint. This made Provenge the first therapeutic cancer vaccine to demonstrate an improvement in overall survival for metastatic CRPC.xx Despite now having received FDA approval in asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (CRPC), it remains to be seen how frequently Provenge will be used in the treatment of this disease. At present, patients are typically treated with standard Taxotere (docetaxel; Sanofi-Aventis)-based chemotherapy. Taxotere is relatively simple in terms of manufacture and use, capable of immediate, 'off the shelf' administration. In comparison, an autologous vaccine like Provenge requires a costly and labor-intensive manufacturing process.

Dendreon has indicated that Provenge will be priced at $31,000 per dose, equating to $93,000 per complete course of treatment. In comparison, Taxotere costs under $3,000 per cycle of therapy, with an average of six cycles of treatment therefore costing around $18,000. Dendreon has stated that Provenge is more cost effective due to the lack of required premedication and supportive care costs compared to Taxotere.

Furthermore, Provenge's favorable toxicity profile may influence physician preference in comparison to Taxotere's adverse side effects, particularly in patients who are asymptomatic. Taxotere is associated with significant toxicity, while Provenge causes only mild grade 1/2 side effects. Provenge is therefore likely to be used in those patients precluded from Taxotere therapy.

Provenge's approval in asymptomatic or minimally asymptomatic patients indicates that the vaccine may be used before Taxotere. Presumably once patients progress and become symptomatic after Provenge, Taxotere will still be required. Given that healthcare systems are becoming increasingly cost-conservative, the high cost of Provenge may hinder its uptake in some patient groups, particularly those that do not qualify for the patient access plan that Dendreon has set up in light of the approval.

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AAN 2010: new treatments address unmet needs in Alzheimer's and epilepsy

2010-04-29T11:35:00.001+01:00

A number of leading drug makers used this year's meeting of the American Academy of Neurology to present new data for promising pipeline candidates. Despite promising results, however, the epilepsy drugs will likely struggle to find their place in the market. Moreover, the positive Phase II data for Baxter’s potential Alzheimer’s therapy Gammagard do not guarantee later success.

Alzheimer's disease: hope remains despite setbacks

There remains an enormous unmet need in the treatment of Alzheimer's disease. For the millions of elderly people worldwide, there are just four drugs available that can only offer a modest symptomatic effect. Even so, these treatments cannot slow or modify the course of this neurodegenerative disease, which is the ultimate goal in Alzheimer's therapy. While it was announced in March 2010 that in a Phase III trial Medivation/Pfizer's Dimebon (latrepirdine) failed to meet any of its clinical endpoints (read our editorial Hope for an Alzheimers breakthrough remains despite Dimebon's failure), there remains hope in the pipeline for Alzheimer's sufferers and their caregivers. One such drug, Baxter's Gammagard (intravenous immune globulin; IGIV), is actively recruiting for a Phase III trial, and at the American Academy of Neurology Annual Meeting (AAN 2010) the company presented new data from the extension phase of its Phase II trial.

Gammagard is a human antibody preparation already launched for the treatment of primary immunodeficiency diseases in the US and Western Europe. The drug is currently being assessed in Phase III clinical trials in patients with mild-to-moderate Alzheimer's disease. At AAN 2010, Baxter presented clinical trial results for the first time measuring function and cognition in patients who received uninterrupted Gammagard for a period of 18 months for mild-to-moderate Alzheimer's disease. After 18 months, patients who received Gammagard continuously averaged approximately 1.36 points higher than patients who initially received placebo on the Alzheimer's disease Cooperative Study-Clinical Global Impression of Change rating (ADCS-CGIC).

While clarifying that the study involved only a very small number of patients, Baxter is clearly encouraged by these data and has stated that it plans to initiate a second, concurrent Phase III study of the drug in this patient population. However, in light of the recent setback with Dimebon and other numerous late-stage trial failures in the last 10 years, Gammagard's prospects should be treated with caution until Q3 2011 when results of the 360-patient Phase III study are expected.

Epilepsy: long-term data for new drugs thehighlights

The second half of 2008 and first half of 2009 saw a flood of generic second-generation anticonvulsants enter the US market as Lamictal (lamotrigine; GlaxoSmithKline), Keppra (levetiracetam; UCB), Depakote IR and ER (valproate semisodium; Abbott) and Topamax (topiramate; Johnson & Johnson) lost patent protection. As the market environment for new and prospective drug candidates becomes increasingly price-sensitive and competitive, both Valeant/GlaxoSmithKline and UCB presented long-term safety and efficacy data for their respective novel anti-epileptic candidates in order to support their positions in the growing treatment arsenal.

Valeant's retigabine is a first-in-class anti-epileptic drug that reduces neuronal excitability by enhancing the activity of neuronal KCNQ (Kv7) potassium channels and through its gamma aminobutyric acid type A (GABA-A) receptor agonistic properties. In August 2008, Valeant entered into an exclusive worldwide collaboration agreement for retigabine with GlaxoSmithKline, and in October 2009 the companies filed a New Drug Application (NDA) in the US and a Marketing Authorization Application (MAA) in Europe for the adjunctive treatment of partial-onset seizures in adults with refractory epilepsy.

The efficacy and safety of retigabine in patients with refractory partial-onset epilepsy was demonstrated in two pivotal Phase III trials, RESTORE 1 and RESTORE 2. At AAN 2010, Valeant provided insight into the maintenance of efficacy and the safety profile of retigabine at doses of 600mg-1,200mg/day, as demonstrated in the long-term open-label extensions of the trials. With 81% of patients transitioning from RESTORE 1 and 92% doing so from RESTORE 2, median percent reduction in 28-day total partial-seizure frequency was 57% and 53%, respectively. Furthermore, safety assessments supported what Valeant called an acceptable safety profile for an adjunctive therapy.

With both US and EU regulatory bodies currently appraising the drug, the inconvenient dosing regimen and reasonably high level of treatment-related side effects will probably deter some treatment-refractory epilepsy patients and their physicians from using retigabine, despite the strong efficacy data demonstrated thus far.

UCB's Vimpat (lacosamide) was the subject of numerous studies and analyses at this year's AAN conference. Indicated as an adjunct therapy for the treatment of partial-onset seizures in adults with epilepsy, Vimpat was approved in the EU in September 2008 and shortly after in October in the US, making it one of the most recent novel entrants to the epilepsy market. Although monotherapy trial data is anticipated by mid-2011, long-term analysis from adjunct trials presented on the conference provides additional support to Vimpat's growing safety and efficacy profile.

Data presented during the meeting focused largely on providing long-term safety/tolerability and efficacy of Vimpat from Phase II-III double-blind and/or open-label extension trials. While one study reported the efficacy of Vimpat in cohorts of patients completing successively longer durations of lacosamide exposure, another indicated that lacosamide improved 50% responder rates and reduced median seizure frequencies by up to 42% and 86% for complex partial seizures and secondarily generalized seizures (the two most commonly reported seizure types), respectively. A third poster provided insight into the drug's long-term safety profile; an important consideration for a drug dosed in such a chronic fashion.

However, with questions previously raised regarding the drug's side-effect profile in comparison to first-line treatments like levetiracetam and lamotrigine, Vimpat is likely to encounter difficulty in taking significant market share from its well-tolerated competitors. Potential future indication expansions in pediatric patients as well as primary generalized tonic-clonic seizures is predicted to hold the key for Vimpat's commercial success in epilepsy.

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Hope for an Alzheimer’s breakthrough remains despite Dimebon's failure

2010-03-05T16:13:00.001Z

On March 3rd we highlighted a press release issued by Medivation/Pfizer announcing that a Phase 3 study of Dimebon in Alzheimer's disease had failed to meet any of its clinical endpoints, despite high hopes of the drug after promising Phase 2 results. This is a significant setback for Dimebon's developers, particularly Medivation, however as recently discussed in our recent feature, Pipeline Insight: Alzheimer's Disease, there remains significant hope for the millions of Alzheimer's sufferers and their caregivers in the pipeline.

On March 3, Medivation and Pfizer announced that its big hope for Alzheimer's disease, Dimebon (latrepirdine; Medivation/Pfizer), failed to achieve clinical benefit over placebo in one of its pivotal Phase 3 trials. In the trial, dubbed the CONNECTION study by the company, investigators were unable to demonstrate that Dimebon significantly slowed the progression of the disease based on any of the five commonly used endpoints. Speaking in a press conference, Medivation's CEO David Hung stated: "The outcome of the trial was unexpected, and is obviously a major disappointment, especially for Alzheimer's patients and their caregivers."

The result certainly comes as a surprise to those tracking the progress of the drug. The CONNECTION data stand in stark contrast with positive Phase 2 results released in 2006, which served to greatly raise expectations of what was purported to be a future blockbuster for Alzheimer's disease. Indeed, on the strength of these data, Dimebonhad previously been forecast to achieve annual sales of around $5 billion in the seven major markets by 2018, placing it as one of the biggest-selling drugs at this time.

Early analysis of the CONNECTION data suggests that the placebo response was greater than that previously seen and that Dimebon showed 'a materially weaker response'. The study results, drawn from 598 participants across the US, Europe and Latin America, contradict those from the preceding Phase 2 trial, which involved 183 patients in Russia. These Phase 2 data were so encouraging that they were published in the July 2008 issue of the Lancet (Doody et al).

However, even before the CONNECTION data were revealed, some experts were skeptical of the outcome of the Russian trial. In its press announcement for the Phase 3 trial, Medivation conceded that the Russian results may have been limited by the small sample size, the involvement of just one geographical location and the use of only one language to communicate disease severity.

In June of 2009 we featured a report Emerging Clinical Trial Locations Eastern Europe which focussed on decision by the the biopharmaceutical industry to reduce costs by conducting clinical trials in what are referred to as the emerging markets. This report analyzed implications and factors which need to be taken into consideration when conducting clinical trials in Eastern Europe. The discord between Phase 2 study data and CONNECTION highlights one negative aspect of off-shoring trials. According to another recent report Global Clinical Trial Business Report & Analysis 2008-2018 the global clinical trials business was worth $50bn in 2008, with a growth of rate of 10%. Broadly we ask what affect CONNECTION will have on this market.

For the moment however it is time to focus on Dimebon. Despite the reservations of Medivation many remained highly encouraged by the Phase 2 data and regarded Dimebon as one of the most promising candidates in late-stage development for Alzheimer's disease. Indeed, Pfizer's decision to in-license the drug at such a high cost is testimony to these high hopes.

Medivation will face a rough patch, though it is not yet over for Dimebon

Medivation has suffered as a result of Dimebon's failure, with its share price plummeting by 68% to $13.04 from an all-time high of $40.49 only the day before the announcement. With future milestone payments and royalties hanging in the balance and no products currently on the market, Medivation has undoubtedly suffered a major blow. However, although the CONNECTION results are certainly a setback, they do not necessarily spell the end for Dimebon. The company is expected to now pin its hopes on additional Alzheimer's trials already underway such as CONCERT and CONTACT as well as Dimebon's secondary indication in Huntington's disease, for which it is currently in Phase 3 development in the HORIZON trial.

If the currently ongoing Phase 3 trials also fail, Pfizer, which signed a collaboration deal with Medivation in September 2008 and has since co-developed the drug, stands to lose most or all of the return on its large investment. The company's initial upfront payment to Medivation was $225m, one of the largest of its type in recent years. Still, the CONNECTION setback is limited somewhat by Pfizer's existing presence in the Alzheimer's marketplace, through its market-leading compound Aricept (donepezil) and the extensive portfolio of pipeline candidates which it inherited following the acquisition of Wyeth.

One positive to come out of the failure is that there will not be significant ramifications for other drugs in development for Alzheimer's disease. We have featured the Alzheimer's pipeline in recent months (see Pipeline Insight: Alzheimer's Disease). The area is characterized by high risk and high reward. At the time of publication Dimebon and Johnson & Johnson/Wyeth's bapineuzumab were forcasted to reach blockbuster status. As discussed in the report, within the current pipeline, Dimebon is unique in its mode of action. The drug is a small molecule mitochondrial permeability transition pore (MPTP) blocker, as well as an NMDA receptor antagonist and cholinesterase inhibitor. Unlike Dimebon, the majority of the other pipeline candidates are targeted towards the hypothesized Alzheimer's disease etiology. Drug developers' focus has shifted from neurotransmitter replacements to biological agents that affect beta-amyloid and tau protein, both hallmarks of the disease. The next eagerly awaited compound for which Phase III results will be announced is likely to be bapineuzumab (Johnson & Johnson/Pfizer), a humanized monoclonal antibody for beta-amyloid. However, given the high attrition rate in the pipeline, expectations will be tempered.

As other markets stall, the high risk/high reward of Alzheimer's is tempting

There remains an enormous unmet need in the treatment of Alzheimer's disease. For the millions of elderly people worldwide, there are just four drugs available to them that can only offer a modest symptomatic effect. Even so, these treatments cannot slow or modify the course of this neurodegenerative disease, which is the ultimate goal in Alzheimer's therapy. However, despite this need, drug developers have struggled to get new agents to market and the pipeline over the past 10 years is littered with late-stage failures. Indeed, excluding reformulations, no new drugs have launched for Alzheimer's disease since Namenda (memantine; Forest/Merz/Lundbeck) arrived in 2002. Since then, around 20 products have failed Phase III trials.

With this in mind, then, the news about Dimebon may not be such a surprise after all. It is, of course, a big disappointment to those in the Alzheimer's community, but the future looks bright. As other core therapy markets become less profitable, both major pharmaceutical and biotech firms are increasingly looking to the huge potential of the untapped Alzheimer's disease market. Investment into Alzheimer's drug R&D continues to grow exponentially and, ultimately, this is the best news for sufferers: it is only a matter of time before an effective therapy arrives.

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Avandia's MammaScreen - Answering the question of how to treat small tumours in breast cancer patients

2010-03-04T12:07:00.004Z

As reported in our recent feature "Breast Cancer - Targeted Therapies, New Cytotoxics and Vaccines" the incidence of breast cancer in the seven major markets is close to 0.5 million, while over 100,000 women will die from the disease. Despite advances in treatment over the past decade, significant unmet needs remain. This level of demand and the large patient potential makes breast cancer a relatively attractive indication for drug developers. Collectively, late-phase pipeline candidates are forecast to achieve $2,230m in sales in 2017 in the seven major pharmaceutical markets.

There are over 100 drugs in clinical development for breast cancer. These are primarily targeted therapies and cytotoxics. Unlike cervical cancer (see our earlier editorial Advaxis lights up the future for cervical cancer ) therapeutic vaccines account for just a small part of clinical development . Importantly, the majority of clinical trials of drugs in late-phase development for breast cancer are in the metastatic setting. This reflects the higher level of unmet need, lower bar to market entry and shorter trial completion time as compared with the adjuvant or neoadjuvant treatment setting.

In addition to developing improved treatments, better diagnostic and prognostic tools are equally required. For example, primary tumor size, in addition to axillary lymph node status, is considered to be one of the most important prognostic factors in breast cancer, with small tumor size being an indicator of good prognosis. However, even small tumors can metastasize. Predicting which patients with small tumors will metastasize represents an unmet need that will likely be addressed by advances in the field of molecular diagnostics.

Another of our featured reports "Molecular Diagnostics in Cancer Testing" describes this rapidly-advancing area. New technologies and applications are being continually added. The technologies that come under the umbrella of molecular diagnostics include first-generation amplification, DNA probes, fluorescent in-situ hybridization (FISH), second-generation biochips and microfluidics, next-generation signal detection, biosensors and molecular labels, and gene expression profiling using microarrays.

Together the global in vitro diagnostics market generated sales of over $40bn in 2008. The market will generate nearly $60bn in 2014. One diagnostic tool described in"Molecular Diagnostics in Cancer Testing" is Agendia's MammaPrint. This prognostic tool was cleared by the FDA in 2007 to predict breast cancer recurrence.

Specifically MammaPrint provides a unique 70-gene signature to identify which early-stage breast cancer patients are at risk of distant recurrence following surgery, independent of Estrogen Receptor status and any prior treatment. Unlike previous generation genomic tests, MammaPrint interrogates all of the critical molecular pathways involved in the breast cancer metastatic cascade. It analyzes 70 critical genes that comprise a definitive gene expression signature and stratifies patients into two distinct groups — low risk or high risk of distant recurrence.

Breast cancers are staged according to the absence (N0) or presence (N1-3) of nodal involvement and the size of tumor. MammaPrint has previously demonstrated prognostic power according to nodal involvement. Today's featured journal article from the Annals of Surgical Oncology report on the prognostic ability of the MammaPrint signature specifically in patients with small invasive tumours. This is particularly important given that the number of patients presenting with such tumors is expanding in parallel with breast cancer screening programs and increased awareness

The study reported by Mook et al took a retrospective look at 964 breast cancer patients, 14% of whom had a pT1ab tumor (primary; 0-1cm), 86% had a pT1c tumor (1-2cm). The majority of patients were node negative. During follow-up 154 patients developed distant metastases. The probability of metastasis-free survival at 10 years was 90% and 86% for pT1ab and pTc patients classified as low risk compared to 76% and 72% classified as high risk. Simply put, the chance of metastasis-free survival at 10 years was increase 2.5-3.5-fold in the low risk group.

Among the 964 patients 57% received no adjuvant systemic therapy while almost all of the others received endocrine- and/or chemotherapy. The prognostic ability of MammaPrint was similar irrespective of therapy.

So what do these data mean? Mammograms have come under significant criticism over the past few years for a number of reasons. Firstly, false-positive results from mammograms expose women to unnecessary biopsies. Secondly, there is the issue of how to medically manage women who have been diagnosed with breast cancer following screening. The issue is particularly troublesome in those individuals with small tumours as treatment guidelines are vague for T1 stage disease. The present study demonstrates the significant benefit of MammaPrint; specifically it can identify those women who are at high risk and may require more aggressive adjuvant chemotherapy and likewise those at lower risk who may gain protection from endocrine therapy without suffering the adverse events of chemotherapy. Mammograms are undeniably useful; we hope that MammaPrint will address some of the criticism screening has attracted and contribute to the overall advance of breast cancer management.

Hope ahead for cervical cancer sufferers as Advaxis therapeutic vaccine shines

2010-02-24T21:59:00.002Z

Advaxis' ADXS11-001 (formerly Lovaxin C) is a therapeutic vaccine in development for cervical cancer and potentially rare forms of head and neck cancer. Despite the launch of HPV vaccines, cervical cancer will remain a significant clinical problem in the developing world as well as in the developed world for the near future. Recent phase 1 data suggests that some advanced cancer patients inoculated with ADX11-001 have survived an astonishing 3 years. In today's blog we discuss these data and the cervical cancer/therapeutic vaccine field in general.

Invasive carcinoma of the cervix is the second most common cancer in women worldwide with over 450,000 new cases and 230,000 deaths annually, most of them occurring in developing countries. Persistent infection with high-oncogenic risk HPV, especially HPV16 and HPV18 are common underlying causes of malignant lesions, accounting for over 70% of Invasive carcinoma of the cervix and over 50% of high-grade precursor lesions.

According to Gynecological Cancers - Niche opportunities in advanced disease the incidence of cervical cancer is set to fall with the advent of prophylactic HPV vaccines. However cervical cancer will remain a problem for many years for two reasons. Firstly, prophylactic vaccines are unlikely to offer significant benefit to those women already infected with HPV. Consequently cervical cancer will continue to be a problem in women who were sexually active prior to the introduction of the vaccine. Secondly, worldwide implementation of such vaccines remains a challenge.

Given that cervical cancer will continue to be a problem it is particularly disappointing that few advances in this area of oncology have been witnessed over recent years. The best hope for women at risk of cervical cancer is early detection. Prognosis for women with early stage disease is good with cure rates of 60%-80% and fortunately there have been advances in diagnostics. For example DailyUpdates reported news from BD Diagnostics 2008 that the FDA had approved its FocalPoint GS imaging system [press release]. In May 2009 that Israeli company Zetiq demonstrated improvements over Pap staining. Pharmacological options remain in a state of relative inertia however.

According NCCN guidelines the first line approach to later stage disease remains radiotherapy with concurrent cisplatin-based chemotherapy. Response rates are quite low (20%-30%) and complete responses rare; overall survival with cisplatin is 6-9 months. Second line treatments are chemotherapeutic and associated with limited efficacy and significant toxicity. There is an obvious need for more targeted therapy that can offer improvements over cisplatin and possibly alternatives/adjuncts to surgery and radiotherapy.

With the exception of SRI International's cytotoxin, tirapazamine and PharmaMar's Zalypsis in (Phase 3 and 2 respectively) little development is being seen in the form of small molecules. Instead most activity is from the biologics sector. YM Bioscience is developing EGFR antibody, nimotuzumab, but by far the greatest efforts are currently being focussed on therapeutic vaccines (see World market for cancer vaccines 2007-2012).

To our knowledge four candidates are currently in the clinic for cervical cancer or the premalignant disease, cervical intraepithelial neoplasias (CIN). Inovio is developing a DNA vaccine targeting E6 and E7 proteins of HPV16 and HPV18, VGX-3100 for the treatment of CIN. This candidate is in Phase 1 development. More advanced is Roche's RG-3484, a modified vaccinia Ankara vaccine expressing E6 and E7 along with IL-2. Phase 2 trials opened last year, again focusing on CIN. A third vaccine is being developed by ISA Pharmaceuticals. In contrast to the Inovio and Roche vaccines this candidate is being developed for both CIN (Phase 2) and cervical cancer (Phase 1).

A recent paper (Radulovic et al, 2009) describes a fourth therapeutic vaccine in development for the treatment of cervical cancer, Advaxis' ADXS11-001 (formerly Lovaxin C). The technology being developed by Advaxis differs from other thereapeutic vaccines as it is the only live bacterial vaccine currently in clinical trials. It is based upon attenuated, bioengineered Listeria monocytogenes that provides very strong stimulation of innate immunity as well as both arms of the adaptive immune system, alters the tumor microenvironment to remove regulatory T cells (Tregs) and Myeloid Derived Suppressor Cells (MDSC) that are sources of immune inhibition, increases the pool of mature immune cells, facilitates migration of immune cells into tumors, and other effects.

Radulovic et al describe data from a Phase 1 study in which the vaccine was administered safely to women with cervical cancer and who had failed surgical, radiation and/or chemotherapeutic intervention. Patients were inoculated twice, at day 1 and day 22; the protocol required administration of antibiotics five days post-inoculation to attenuate the live vaccine. Adverse events were generally flu-like and transient.

The women recruited to the study would normally be expected to have a median survival of only 6 months with a 1 year survival of 5%. In this study, the median survival was doubled and the 1 year survival increased 10-fold. Remarkably, Advaxis recently reported updated data showing that 2 of 13 patients were alive at 3 years.

The data reported in the present study are fascinating, especially given the advance stage of disease and the fact that responses were seen with just two inoculations. Further studies, perhaps with booster vaccinations built into the protocols are awaited with great interest. In addition the promise shown in the present study suggests that evaluation of the vaccine in earlier stage CIN may be worthwhile. LeadDiscovery understands that further trials are planned for this year - one a Phase 2 study of cervical cancer patients; another a study of CIN patients.

Finally, a paper was published by Maxwell et al last year in the journal head and neck linking HPV to a rare head and neck cancer, nasopharyngeal carcinoma. We understand that a further trial is planned evaluating ADXS11-001 in this disease. This is not only of great clinical importance, it may also be of commercial importance. Advaxis failed to gain orphan drug status from the FDA last year on a cervical cancer indication. The company may be able to refile for an orphan indication on this new indication (for further information on head and neck cancer, including pharyngeal cancers read Stakeholder Opinions: Head and Neck Cancer).

Javelin Pharmaceuticals' good fortunes continue - Ereska meets its pain-reduction end point but will it overcome the stigma of adverse events and drug

2010-02-22T22:02:00.004Z

Javelin is one of a few companies that is reformulating existing drugs to address unmet needs in the pain management market. Candidates in development include Dyloject, Ereska and an intranasal morphine formulation known as Rylomine.

Dyloject was initially launched by Javelin in the UK in December 2007 for the treatment of acute pain, including postoperative pain. Dyloject differs from other IV formulations of diclofenac in that it employs a proprietary solubilizing agent that reduces irritation to veins and therefore does not require dilution or slow infusion. Movement towards the market in other geographies has taken longer with the company filing an MAA through the Mutual Recognition Procedure in 2009 and an NDA in December 2009. Last week we announced in DailyUpdates that the FDA had accepted the IND for review and that a PDUFA date had been set for October, 2010.

The NDA acceptance came after further good news for Javelin a few days earlier. On February 11th, 2010 the company announced that an external review of Phase III data for Ereska had found previously negative top-line results for its primary endpoint to be statistically significant. This randomized, placebo-controlled study assessed the safety and analgesic efficacy of repeated doses of Ereska over 6 hours in 259 patients with acute moderate to severe pain following orthopedic surgery. The primary end-point, pain intensity over the 6 hour period was reduced from 78.5 ± 12.4 to 47.3 ± 12.3 units (p=0.046)

While the revised analysis offers renewed hope for the company, doubts over Ereska must remain due to ketamine's association with drug abuse and its well-documented hallucinatory effects. Both factors represent key weaknesses in the market place, despite Ereska's proven efficacy.

Prior to the third-party reassessment of pain score measurements, Javelin Pharmaceuticals reported that Ereska (intranasal ketamine) had narrowly missed the principal goal of a late-stage trial. However, a third-party biostatistics company verified the presence of inconsistencies in the previously disclosed top-line results (based upon data captured by an external vendor). Indeed, the company has benefited from a share increase of around 6% since the announcement of the re-examined data.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been in use for over 25 years as an anesthetic, although is not approved for use as a pain reliever. Nevertheless, low-dose ketamine has been used off-label for the treatment of various pain complexes and the safety and efficacy of ketamine as an anesthetic and analgesic is well documented. According to IMS Health, ketamine achieved total sales of over $8m across the seven major markets (US, Japan, France, Germany, Italy, Spain and the UK) in 2008.

The market research company, Datamonitor believes that an FDA-approved formulation of ketamine for the treatment of moderate to severe pain will provide physicians with an accepted and regulated alternative to off-label use and opioids. Breakthrough pain, which affects approximately 42% of cancer patients across the seven major markets, is typically treated with opioids. In 2008, the opioids market was valued at an estimated $9.6 billion across the seven major markets and is forecast to grow in the future as a result of the launch of rapidly acting fentanyl products. However, opioids are associated with several adverse events and patients who use opioids chronically may display tolerance. For this reason, Datamonitor believes that there is a market for a non-opioid agent to treat breakthrough pain.

That said, pain specialists interviewed for today's featured report, stakeholder insight report into cancer pain, expressed concerns related to potential safety issues despite ketamine's potential as an alternative to opioids. Therefore, Javelin will need to carefully monitor the hallucinatory side effects of ketamine in future trials of Ereska. Pain specialists also proposed that use of ketamine and an opioid such as Actiq (fentanyl citrate; Cephalon) in combination represents an interesting avenue of research.

As the only non-opioid in the current breakthrough pain pipeline, and being of an intranasal formulation, Ereska is well positioned to compete against Cephalon's Actiq and Fentora in this market. However, a substantial challenge for Javelin will be to tackle the negative perception of ketamine as a dangerous drug that is associated with narcotics abuse. In order to overcome this barrier, Javelin would benefit from seeking the marketing resources of a larger company with experience in the narcotic analgesics market.

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Fall out from Merck's announcement that vicriviroc has failed in phase III treatment experienced trials

2010-01-29T20:32:00.004Z

In 2008, antiretroviral sales across the seven major markets totaled $10.7 billion, growing at a CAGR of 12.8% between 2005 and 2008. This expansion is expected to slow down. Despite drivers such as new product launches, earlier treatment initiation, decreasing mortality and an increase in HIV prevalence, a series of patent expiries will impact branded sales from 2011. [See Forecast Insight: HIV - Cross-class fixed dose combinations drive continued growth]

The dynamic nature of the HIV market has been further evidenced by Merck's announcement last week that it will not, for the moment, be submitting an NDA for vicriviroc in treatment-experienced HIV-infected patients. This news came with the disclosure that two Phase III studies in this patient population failed to meet their primary efficacy endpoint.

Results from these studies will be presented at CROI in February.

Cowen and Co had already expected vicriviroc to achieve modest sales, $75 million in 2012, growing to $150 million in 2015. These figures will have to be revised.

Patients were recruited to the two Phase III trials, VICTOR-E3 and VICTOR-E4, only if they had documented resistance to at least two antiretroviral drug classes. Patients were treated with an optimized background regimen (ritonavir boosted protease inhibitor plus at least two active drugs) with or without vicriviroc.

Even with resistance to at least two antiretroviral drug classes, efficacy rates of 90% can nowadays be achieved with antivirals such as Merck's Isentress (raltegravir) or Tibotec/Johnson & Johnson's Prezista (darunavir) and Intelence (etravirine).

This supports Merck's explanation that the trials failed because many patients enrolled had three or more active drugs in their optimized background therapy regimen. Unsurprisingly therefore, this would leave little room for newer agents such as vicriviroc to show any additional benefits. While plausable we can't help but ask why this potential problem wasn't foreseen when the studies were designed and alternatives sought.

Despite the recent disappointment vicriviroc may still join the first in class CCR5 antagonist, Selzentry on the market as it will not be shelved according to Merck.

Merck continues to evaluate vicriviroc in treatment-naïve HIV-infected patients and patient enrollment has now been completed. In fact the experiences of Selzentry would suggest that the treatment-naïve population may represent the best target for vicriviroc.

Selzentry was initially approved for experienced patients, of whom only 50-60% are CCR5 tropic. As a result patients have to be tested prior to treatment to determine whether they are likely responders. The cost of testing presented a hurdle to Selzentry uptake. In contrast, approximately 80% of treatment-naïve patients have CCR5 trophic virus. Even though testing is still required its cost is less likely to represent wasted expense. In light of this, Merck is continuing the development of vicriviroc for treatment-naive patients.

Interestingly, the company is taking a novel approach in this setting by investigating vicriviroc in combination with Bristol-Myers Squibb's Reyataz (atazanavir) and eliminating the traditional nucleoside backbone. Concerns over NRTI toxicity have led to a renewed interest in such regimens, and prescribing two agents instead of the traditional three is also likely to have cost benefits. Moreover, this strategy may be highly effective in countering the threat from developmental fixed-dose combinations such as Gilead's Quad Pill and Gilead and Tibotec/Johnson & Johnson's Truvada/rilpivirine combination.

For further information on the HIV market see:

Roche's new sub cutaneous formulation of Herceptin (trastuzumab) to offer increased benefit to early stage breast cancer patients

2010-01-22T11:23:00.004Z

Herceptin was initially launched in 1999 for the treatment of HER2 positive metastatic breast cancer. Since that time lifecycle management has been stepped up and revenue for this leading monoclonal antibody hit 2.6 billion Swiss francs ($2.5 billion) during H1 2009. LCM activity has included the broadening of breast cancer indications; expansion to evaluate Herceptin as a gastric cancer therapy; and now the reformulation of Herceptin to allow subcutaneous administration.

Having received approval for the treatment of metastatic HER2 positive breast cancer, Roche soon after received expanded EU approval in June 2004 to include use in combination with docetaxel as a first-line therapy in patients who have not yet received chemotherapy. The 2006 approval was granted for the use in early-stage HER2 positive breast cancer following surgery and standard chemotherapy. The FDA granted approval for use in early stage breast cancer in 2008. Recent data reports that at least 80% of women with early stage HER2 positive breast cancer receiving one year of Herceptin were alive free of the disease at 5 years follow-up [press release].

LCM activity has also involved the development of Herceptin for the treatment of stomach cancer, with patients demonstrating improved survival when Herceptin was added to standard chemotherapy in the ToGA trial. This was particularly impressive in HER2 positive gastric cancers. The drug is in pre-registration in Europe for this indication and is expected to be filed soon in the US (for further information see Gastric Cancer - Targeted Therapies Home In On a Neglected Tumor Type)

Improving delivery of oncology therapies has received and will continue to receive considerable attention (see Drug Delivery in Cancer - Technologies markets and companies). In addition to broadening its indications, Roche hopes to draw on optimization through drug delivery development to encourage uptake of a more convenient formulation of Herceptin. This strategy could help to conserve its share of an increasingly competitive market, but may be challenging to implement due to concerns over compliance and financial incentives to prescribe intravenous cancer drugs.

Roche has invested roughly CHF190m ($183m) at two production sites to manufacture devices that will allow patients to self-administer a subcutaneous formulation of Herceptin (trastuzumab; Roche/Genentech/Chugai).

One site will supply the devices for a Phase III study which could support approval of the subcutaneous formulation. In this study, 552 patients with stage I-IIIc breast cancer will receive chemotherapy in combination with either subcutaneous or intravenous Herceptin before surgery, followed by 10 three-weekly infusions of subcutaneous or intravenous Herceptin. The study opened in October 2009 [Press release]

Herceptin's current intravenous formulation requires patients to receive the drug in hospital via a one-hour infusion. The subcutaneous formulation (developed in partnership with Halozyme Therapeutics) would increase convenience, allowing patients to self-administer the drug at home via a five-minute infusion. This is important given that Herceptin is administered for up to a year in early-stage breast cancer. Additionally, this would help to reduce costs associated with patient hospitalization and could improve the drug's side-effect profile by reducing infusion reactions.

Roche will hope that these factors increase brand loyalty and protect Herceptin's market share against potentially fierce competition from GlaxoSmithKline's oral HER-2 inhibitor, Tykerb (lapatinib), which is approved for metastatic breast cancer and is currently in Phase III trials for early-stage HER-2-positive breast cancer. Furthermore, switching patients to a subcutaneous formulation could help insulate against potential competition from biosimilar versions of intravenous Herceptin. As the lucrative monoclonal antibody market approaches maturity, such lifecycle management activities are likely to become increasingly common.

However, Roche could find it challenging to encourage uptake of subcutaneous Herceptin because it will make it more difficult for physicians to ensure patient compliance. Indeed, patient compliance can be a problem for some orally administered anticancer drugs. In the US, financial incentives for oncologists to prescribe intravenous drugs could further restrict uptake of the subcutaneous formulation. The ongoing Phase III study may therefore have to show that the more convenient subcutaneous formulation also has superior efficacy in order to drive appreciable uptake.

For further information on antibody therapeutics in oncology see Monoclonal Antibodies in Cancer Therapy 2009-2024

Until phase 3 data emerges, HCV PI share splits are pure guess work

2010-01-19T20:53:00.001Z

Market research has been published reporting that 50% of US gastroenterlogists would treat HCV non-responders with telaprevir and concludes that this protease inhibitor will gain 70% of the market share.

I would treat any forecasts on how telaprevir and boceprevir will shape up against one another with respect to market share as pure guess work until phase 3 data is disclosed.

Sure, telaprevir has so far shown better efficacy in non-responders based on Phase 2 data. It is therefore hardly surprising that clinicians will favour telaprevir at this moment in this population. This could however change very rapidly as we progress through this year

in reference to:

"U.S. gastroenterologists will treat a larger proportion of treatment non-responder hepatitis C patients with Vertex/Tibotec/ Mitsubishi Tanabe’s telaprevir than Merck’s boceprevir"
- Vital Biopharmaceutical Insights and Analytics - Decision Resources (view on Google Sidewiki)

New treatment opportunities on the way for ADHD? AstraZeneca commits to further development of nicotinic agonist AZD3480

2009-07-08T20:38:00.002+01:00

Good news today for Targacept with the announcement that AstraZeneca is continuing to support the development of nicotinic agonist, AZD3480 (TC-1734) for ADHD (see DailyUpdates). This is particularly welcome for Targacept not only because it comes with a milestone payment of $10 million but also because AZD3480 has previously failed two Phase 2b studies (Sirocco for Alzheimers disease; and HALO for CIAS). The fate of AZD3480 has been looking up since May when it was announced that it had met its primary end-point in a Phase 2a ADHD study (see UpdatesPlus, May 2009). The degree of improvement was reportedly similar to that expected with a stimulant but the adverse event profile was unremarkable. Of interest we have previously suggested that AstraZeneca may be evaluating the possibility of using AZD3480 as an add on to its antidepressant, Seroquel. Also significant is the announcement that AstraZeneca will continue development of AZD1446 (TC-6683) for Alzheimer’s disease. AZD3480 had shown some activity against secondary end-points in Sirocco but it looks like it will remain a back-up for Alzheimers disease with AZD1446 becoming the lead for this indication. Read more about the implications of today's news as well as all other significant activity in the nicotinics field in the July issue of UpdatesPlus due out in the next few weeks. To reserve your copy at a 10% discount contact us now

Stelara is likely to benefit from the fall of Raptiva however topicals continue to dominate

2009-04-15T21:01:00.003+01:00

Psoriasis is a disease of the skin that affects millions of individuals worldwide. The therapeutic landscape for psoriasis is dominated by genericized and/or nonprescription topical therapy in terms of volume. In terms of value, however, the moderate to severe psoriasis market is bolstered by the use of biologics, first approved for use in psoriasis in 2003. Recent research into prescriber trends suggests that while biologics have made a significant impact in the treatment of psoriasis, topical therapies have not been displaced, especially in patients with milder disease; moreover the future may see moves towards improved phototherapy rather than greater uptake of biologics.

According to the 180 dermatologists interviewed as part of our recent feature Psoriasis - Biologics are yet to make topical treatments obsolete, psoriasis presentation and diagnosis patterns have remained constant over the past five years, indicating an essentially unchanged point of view among psoriasis sufferers. Psoriasis epidemiology is remarkable in that 54% of psoriasis sufferers are undiagnosed and this is because 80% of affected individuals have symptoms that are so mild that they never present to a physician. Even those patients that are diagnosed are not diagnosed immediately probably reflecting, at least in part the mild nature of the disease in many individuals. Of those patients that are diagnosed 36% of patients are estimated to be suffering from mild psoriasis, 38% from moderate psoriasis and 26% from severe psoriasis. Given that biologics are only indicated for moderate to severe disease it is clear why topical therapies dominate the market in terms of volume.

In stark contrast to the consistent epidemiological picture of psoriasis, treatment trends in psoriasis have shifted, reflecting payers’ and prescribers’ evolving priorities in terms of psoriasis. One ongoing trend is the choice of topical versus biologic therapy, a trend that is dependent on geography. Absence of approved biologic therapy in Japan leads to higher use of traditional systemic agents in this market. Elsewhere however the approval of biologics for the treatment of psoriasis has seen growth in this area, albeit of a hetrogenous and regionally varied nature. In the UK where biologics are available, NICE recommends that this class should only be continued if clinical improvement is demonstrated within 12 to 16 weeks. Elsewhere in Europe the estimated use of biologic therapy varies from market to market. Of course, the situation in the US is highly influenced by insurance companies seeking to control costs.

So what is the biologic of choice in psoriasis patients? On average, 41% European physicians surveyed in the abovementioned report prefer Raptiva (efalizumab) at first line, and 20% prefer Remicade (infliximab), despite this drug’s intravenous method of administration. EU physicians may have preferred Raptiva in 2008 because it had the longest history of use in psoriasis, but its recent withdrawal from the EU for safety reasons will create a significant space for other therapies, particularly Stelara (ustekinumab), approved in the EU in January 2009.

As highlighted in yesterday’s issue of DailyUpdates, Raptiva will be phased out of the US market over the next 3 months (press release). Genentech's decision was based on the association of Raptiva with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease of the central nervous system. The Raptiva prescribing information was updated in October 2008 to include a boxed warning on the risk of serious infections, including PML, in patients receiving Raptiva. There have been three cases of diagnosed PML in patients receiving Raptiva.

According to the National Institutes of Health (NIH), between 5.8 and 7.5 million Americans have psoriasis. Of these more than 3 million are believed to have moderate to severe disease and would have been candidates for Raptiva treatment. However, Genentech estimates that just 2,000 patients in the United States may currently be receiving Raptiva for chronic plaque psoriasis. Raptiva has been therefore occupied a very small market share reflected in the fact that it has been generating sales worth just $105 million. Instead, among US dermatologists, 60% prefer Enbrel (etanercept) at first line, followed by 26% of physicians preferring Humira (adalimumab). Physicians in the US and the EU rated Stelara highly in terms of disease modification, maintenance of efficacy and dosing frequency. Clearly therefore there is considerable potential for Stelara to capture a significant portion of the market however, payers’ enthusiasm for Stelara will be crucial to the drug’s success.

While systemic therapies have revolutionized the management of moderate-to severe psoriasis, topical treatment remains the foundation of psoriasis therapy. In mild psoriasis, physicians from all countries surveyed report that at least 82% received topical therapy alone. In the US and Europe, topical therapy usage declines with increasing disease severity. In Japan, lack of biologic therapy appears to sustain high usage of topical therapy across all disease severities. Phototherapy is a treatment option for patients with moderate to severe psoriasis who have not responded to topical therapies. This is particularly the case is Germany where physicians estimate that phototherapy should be used by 54% of patients. The mean percentage of patients recommended to use phototherapy in the four other European countries is 26%; nearer to the US figure of 17% and the Japanese figure of 20%. According to US opinion leaders, technological advances in home phototherapy units, in combination with the expense and safety signals associated with biologic therapy, may inspire renewed interest in phototherapy among payers and prescribers in coming years.

The psoriasis market thus continues to evolve. As some biologics such as Raptiva fall others, most prominently Stelera will rise...at least for the moment. The use of topical agents continues however to dominate treatment choices in patients with mild disease and therefore the psoriasis arena as a whole. Commercial success in the psoriasis market will continue to demand a clear understanding not only of regional trends but also unmet needs including improved biologics for severe disease and cheap and safe alternatives to topical treatment for mildly affected patients

For further details on the psoriasis market see:

Psoriasis - Anti-TNF's lead another indication
Psoriasis - Biologics are yet to make topical treatments obsolete
The World Dermatological Market Outlook, 2009-2023

The dynamic opioid analgesic segment continues to evolve – reformulation advances rapid acting and long duration analgesics

2009-04-07T19:01:00.002+01:00

The treatment of pain continues to suffer significant unmet needs. One of the oldest classes of analgesics, the opioids, remains a large and dynamic one which has changed significantly over the past few years.

As described in today’s featured report, Forecast Insight: Opioids, the market value for opioids was reportedly worth $8.4 billion across the 7 major markets in 2007. Growth has continued at a CAGR of 4% and is expected to grow at this rate through to 2018 at which time the market is expected to be worth $11.9 billion. This is remarkable given current market pressures including price competition, generic availability, negative stigma, and the US Risk Evaluation and Mitigation Strategy.

One drug development concept central to the opioid class is reformulation. The development of new combination therapies and delivery forms is a relatively inexpensive development process thereby presenting accessible strategies to mid- and small sized drug delivery and development companies. The attractiveness of the class is amplified by the large patient base and comparatively low market entry barriers

Reformulation of established opioids offers a useful means of treating breakthrough pain (by developing formulation with a fast onset of action) or chronic pain (by developing extended release formulations).

OxyContin, Duragesic, Kadian, Avinza and Opana are all extended-release reformulations of opioids. Duragesic has suffered from product recalls as well as generic incursion and hence a decline in revenue. Generic equivalents of Duragesic have also suffered product recalls and so OxyContin is expected to enjoy a majority market share this year with sales of $3 billion expected across the 7 major markets.

Activity in the development of extended release formulations continues however and there is a current emphasis on reducing abuse potential, frequently through the incorporation of naltrexone, an opioid receptor antagonist. The launch of several oxycodone controlled release-based opioids with anti-abuse potential will erode OxyContin’s market share in the mid-term. Despite this it is unlikely that any individual anti-abuse opioid brands will gain blockbuster revenues. This reflects unclear demand from frontline stakeholders such as prescribers and patients, and the flood of brands set to enter the market. Moreover the development of anti-abuse opioids appears to be a US-specific trend in the pipeline.

Despite the fragmented nature of anti-abuse opioids, King Pharmaceutical’s anti-abuse opioid franchise does however look set to reach blockbuster levels with combined sales of Remoxy (oxycodone controlled-release), Embeda (morphine extended release and naltrexone) and the immediate-release opioid Acurox (oxycodone and niacin) forecast to generate around $1 billion per annum by 2018

Overall the long-acting opioids market is expected to grow from $5.0 billion in 2007 to $6.1 billion in 2018 across the 7 major markets.

Reformulations enabling rapid onset of analgesia have, like extended release formulation, also gained significant attention. In particular this is to satisfy the demand for improved treatments of breakthrough pain. Actiq and Fentora are fentanyl formulations with transmucosal and buccal routes of action respectively. Choices open to physician and patient are likely to grow as dissolvable and spray formulations advance through the pipeline.

While the current market for short- and rapid acting opioids is quite low ($771m in 2007), growth is expected with sales expected to reach $1.7 billion by 2018 in the 7 major markets, representing the strongest growth rate among the opioid market. This reflects new product entries in addition to an expected increase in Fentora sales should it receive approval for non-cancer pain. The FDA issued a complete response letter for this submission in September 2008.

Unlike the anti-abuse long-acting opioids, short- and rapid-acting opioids are being developed across all three major market regions (US, 5EU and Japan). Cephalon’s Fentora is expected to remain the market leading brand in the US, however experienced local marketing partners such as Meda (Onsolis, buccal fentanyl) and Nycomed (Instanyl, intranasal fentanyl) are expected to provide significantly more competition to Cephalon in what will become an increasingly fragmented European market

All in all the opioid market remains dynamic. Hopefully development will feed through to improved treatments of pain. This editorial is based on new data reported in our current feature: Forecast Insight: Opioids - Saturation limits the commercial potential of individual brands

Other recent market research and pipeline reports:

Kicking the habit: Nicotine Dependence - where are we now and where are we going?

2009-04-06T20:21:00.005+01:00

Although the dangers of tobacco use have been recognized for almost half a century, nicotine dependence continues to represent a serious global health problem. According to the World Health Organization (WHO), there are currently an estimated 1.3 billion smokers in the world and at the current rate; this figure is expected to rise to 1.7 billion by 2025.

The current nicotine dependence market consists of a wide range of over-the-counter products including various formulations of nicotine replacement therapies, yet only two specific prescription drugs are approved for this indication— Chantix/Champix and bupropion.

The unmet needs and commercial potential surrounding the smoking cessation market are reflected in a new report featured by LeadDiscovery: Pipeline and Commercial Insight: Nicotine Dependence - Chantix issues overshadow vaccine potential

Other recent products:

Approximately 150 million people in the seven major markets are estimated to be current tobacco smokers. As a result of numerous anti-smoking campaigns and strict public bans, smoking prevalence rates in the US and UK have decreased steadily over the past decade. In contrast, with smoking remaining less stigmatized and far less regulated in Germany and Japan, rates have notably remained higher.

Chantix/Champix was launched in the US and Europe in 2006 and appeared to be not only revolutionizing the smoking cessation market but also fast growing into one of Pfizer's most successful products. Recent problems have however emerged with reports of suicidal ideation leading to a label modification reflecting this risk. In addition Chantix/Champix has been related to various and diverse accidents resulting in the FAA banning the use of Chantix by airline pilots. Overall US sales figures have fallen by approximately 50%. Combating negative publicity, Pfizer has been attempting to reinstate prescriber and patient confidence in Chantix by establishing a favourable risk-benefit ratio and emphasizing the requirement for improved patient screening and follow-up. While these efforts may reverse US sales trends, there remains a massive opportunity in the developing world. Remarkably, 60% of Russian and Chinese men smoke compared to 23% in the US and UK.

Those smoking cessation products that have been launched have succeeded because marketing efforts have paralleled government initiatives. This will continue to be the case and of note a new antismoking drive has been launched in India and this should offer an environment that companies such as Pfizer and GSK could harness. In addition Pfizer, in particular, has made a point of identifying those individuals most likely to want to stop smoking and targeting marketing towards this group. Of interest a study has recently opened in Asia aimed at identifying the characteristics of individuals seeking help in the cessation of smoking. Studies such as these should help break into emerging markets.

While Champix/Chantix and bupropion are both relatively successful in the short term, only a minority of individuals achieve permanent abstinence after an initial quit attempt. This represents one of the major unmet needs of currently available treatments. This problem exists in part because of sub-optimal treatments and also because the duration of existing therapies may be too short. This in turn relates at least in part to cost. Improving overall reimbursement/cost barriers should therefore have a significant impact on the success of future quit attempts;

So what is the future? Two relatively advanced smoking cessation vaccines are in the pipeline and both are being positioned as maintenance treatments. In other words they will hopefully be able to prevent relapse and should therefore stand side by side with current options that aid cessation. The smoking cessation market has grown 84.5% from 2004 to reach $1.35 billion in 2008 across the 7 major markets. If vaccines enter the market, the authors of Pipeline and Commercial Insight: Nicotine Dependence - Chantix issues overshadow vaccine potential anticipate the market growing to over $3.81 billion in 2018.

Nabi Biopharmaceuticals’ NicVAX is in line to become the first nicotine vaccine to enter the market. Assuming Nabi will secure a suitable development partner, NicVAX is expected to generate yearly 7 major market sales of almost $1.1 billion by 2018. Development of Cytos and Novartis’s nicotine vaccine NIC-002 is behind NicVAX’s. However, Novartis’ sales and marketing experience in the central nervous system and vaccines sectors bodes well for the launch of NIC-002 and yearly sales could reach $1.0 billion in the 7 major markets by 2018.

Whether a vaccine enters the market remains to be seen as both candidates have suffered development problems (for further analysis of these issues see LeadDiscovery’s recent issues of UpdatesPlus Nicotinic Receptors).

Lower Back pain: New therapeutic opportunities open up for a “new” indication

2009-04-03T16:56:00.004+01:00

An estimated 129 million adults suffer from back pain across the seven major markets.

Despite the size of this group of conditions, back pain remains an unmet clinical need characterized in equal measures by developmental challenges and market potential. No therapeutic agents have been specifically indicated for back pain and until recently the regulatory bodies have not even viewed the condition as a specific indication.

Our latest feature “Back Pain - Gain competitive edge by targeting subpopulations” sets out to examine key issues and unmet needs in the diagnosis and management of back pain. The report provides a thorough review of etiology, epidemiology, diagnosis and current treatment options. The report also explores potential commercial opportunities for companies intending to either penetrate, or increase, their share in this competitive market. Analysis is supported by interviews conducted with key opinion leaders in the US and Europe.

For free sample pages contact leaddisc@leaddiscovery.co.uk

Recently published reports in pain:

Custom analyses of the pain market and pipeline are available on request

The most important unmet need in the treatment of back pain to emerge from opinion leader interviews is for more targeted treatments. Therefore, the challenge to researchers is to provide evidence of which treatment, if any, is of most benefit for subgroups of patients with back pain. In order for this unmet need to be addressed, greater investment in basic science research is required to further our understanding of pain mechanisms.

Broadly speaking however back pain can be split into acute and chronic pain. Two areas of chronic pain under investigation are neuropathic back pain and breakthrough chronic back pain. Targeting back pain subpopulations represents a viable strategy and neuropathic back pain which affects an estimated 18 million adults across the seven major markets represents one such lucrative subpopulation.

Although targeting back pain subpopulations is viable, of the numerous companies are targeting neuropathic pain indications, to date no one product has a specific label for neuropathic back pain. Moreover, few pipeline drugs appear to be to be in development for this condition. This may in part be due to the regulatory bodies failing to recognize neuropathic back pain in its own right; it may also be due to the complexity of diagnosis.

Cephalon has tried and so far failed in breakthrough back pain with the FDA issuing a complete response letter relating to Fentora and its risk management program. Lilly has demonstrated that Duloxetine reduces back pain in individuals with depression. More directly, efficacy has also been reported in a Phase 3 chronic back pain trial with pain scores reduced by 2.4 points from baseline compared to 1.4 points on a standard 10-point rating scale. This effect was significant. Whether Lilly intends to file for a back pain label remains to be seen.

Most recently, Newron announced just this week that it has randomized the first patients to treatment in SERENA, its first phase IIb/III study of ralfinamide in patients with moderate neuropathic low back pain. Newron's ralfinamide now has the potential to become the first drug approved for the treatment of neuropathic low back pain. Ralfinamide is believed to mediate analgesic and anti-inflammatory effects through the modulation of ion channels implicated in pain and the inhibition of substance P.

A small Phase II study has previously shown that 33% of neuropathic low back pain patients demonstrated a 50% improvement following treatment with ralfinamide compared to 10% in a placebo group.

SERENA is one of potentially two large studies that will evaluate the safety and efficacy of ralfinamide compared to placebo. The study is a 12-week randomized trial being conducted in Europe and Asia that will randomize approximately 400 patients with chronic neuropathic low back pain. The primary efficacy measure of the trial will be based on the 11-point Likert Pain Scale. Secondary efficacy measures will include patients’ self ratings of the Visual Analogue Scale as well as responder rates. Patients who complete the 12 weeks of treatment will be eligible to enter a double-blind 40 week extension

Newron is anticipating SERENA data in H1 2010 and in the meantime is expecting to partner, presumably to conduct a similar study in the US and to passage through registration.

During the development of Ralfinamide various health authorities agreed that neuropathic low back pain would be treated as a specific indication. This and the headway being made by Newron suggest that other companies in the pain arena will also focus on back pain. This should hopefully result in new, and much needed treatments becoming available to patients by around 2011.

A tour around tuberculosis: The problem and its solution

2009-04-02T15:54:00.005+01:00

Tuberculosis (TB) infects nearly 15 million people worldwide and causes the death of 1.7 million each year. Individuals, especially in Southern Africa are commonly co-infected with TB and HIV, a combination with very poor prognosis. Having been largely ignored until recently TB is currently receiving significant attention from both NGOs and also industry. The latter is evaluating new vaccines as well as second line treatments of TB. The pharmaceutical sector has been playing a significant part in the combat of HIV infection in the developing world for the past decade; it is now expected to follow suit in the related area of TB

For a detailed analysis of opportunities and development in the field of TB see our brand new feature Tuberculosis - Development pipeline shows signs of life or read on

Incidence

TB is a major cause of illness and death worldwide, especially in Asia and Africa. Globally, 14.4 million prevalent cases of TB, 9.2 million new cases and 1.7 million deaths from TB occurred in 2006. India and China have the highest incidence of TB worldwide; Asia and the Western Pacific account for 55% of global cases of TB

Sub-Saharan Africa also has a high incidence of TB accounting for 31% of global infection. In this region coinfection with HIV represents a massive problem. TB infection is found in over 50% of all new cases of HIV infection in Southern Africa and this results in a dramatic worsening of prognosis.

The seven major markets accounted for relatively small fractions of global cases and incidence has
been declining sharply in these countries over the last few decades and this has been accompanied by a fall in commercial incentives for pharmaceutical companies to invest in antituberculosis drug research, which has resulted in a paucity of new drugs.

Growing intent to treat supported by NGO efforts

Large pharma has however been showing an increasing appetite to treat developing world prominent disease and in particular companies have been lowering the cost of HIV treatment. This has been accompanied by significant efforts from NGOs and consequently two landmark documents in global TB control were launched in 2006: the Stop TB Strategy and the Global Plan to Stop TB.

The primary NGO aims are to increase detection and to improve treatment and a central component of these strategies is known as DOTS (directly observed treatment, short course). To ensure thorough treatment, it is often recommended that the patient takes his or her pills in the presence of someone who can supervise the therapy. In addition to implementing uptake of DOTS, major efforts are underway to increase TB detection and treatment

Detection
Despite the enormous global burden of TB, case detection rates are low, posing serious hurdles for TB control. The definitive diagnosis of TB requires identification of the mycobacterial pathogen in a patient’s secretions or tissues. Identification of the organism is necessary for drug susceptibility testing which further guides selection of treatment regimens. Conventional TB diagnosis continues to rely on tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Furthermore conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In industrialized countries, newer technologies such as interferon gamma release assays for the diagnosis of latent infection and nucleic acid amplification tests and liquid culture for diagnosis of active TB disease are being increasingly used. However such tests have not been implemented in high-burden developing countries to any significant degree, mainly because the level of sophistication and cost that has, to date, made their routine application unfeasible.

Vaccines
The current TB vaccine, bacillus Calmette-Guerin (BCG) is a live vaccine that protects against severe childhood forms of disease. It also confers protection against leprosy. However it does not prevent the
reactivation of latent TB, the main source of mycobacterial spread in the community. Given the limitations of the current BCG vaccination, several novel vaccines and strategies are being investigated for both prevention and treatment of TB.

Replacement of BCG with a more effective vaccine that provides lasting protection, a new vaccine for adolescents/adults that prevents adult pulmonary TB, and an immunotherapeutic vaccine could each provide improved approaches. Given the wide use of the BCG vaccine, particularly in the developing world, a prime-boost strategy using a new TB vaccine candidate to boost the BCG vaccine is considered the best way to test and introduce new TB vaccines into endemic countries.
Public-private partnerships have been the strongest force driving TB Vaccine development. For example the Aeras Global TB Vaccine Foundation which receives NGO funding currently works on six candidate vaccines. Aeras is developing these through collaborations with companies like Crucell, GlaxoSmithKline, Sanofi Pasteur and several others. The vaccine candidates include BCG strains that have been genetically manipulated to express immunodominant antigens (recombinant BCG) and several non-living vaccines

Treatment

Although the current tuberculosis treatment regimens are highly effective they are far from ideal. Many of the drugs used have side effects and even with the optimal combination of the available drugs, the duration of treatment required for curing patients cannot be reduced below six months. As a result these regimens are associated with high rates of non-adherence leading to drug resistance and increased morality. The rise in multi drug resistant and extensively drug resistant strains has also
caused concern, particularly in the developing world. Conventional short course antibiotic therapy has remained the mainstay of treatment for tuberculosis for several decades.

In 2007 the global TB antibiotics market was worth approximately $300 million with a CAGR of 2.2% from 2004-2007. Given the low incidence of TB in the seven major markets, they accounted for approximately 40% of total sales, the balance was accounted by the rest of world which includes the majority of the high burden countries.

The classes of anti-tuberculosis drugs have traditionally been divided into first and second-line drugs, with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin being the primary first-line drugs. The most frequently recommended and effective combination is isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months followed by isoniazid and rifampicin for 4 months.

Currently second line therapy represents the area with the greatest commercial opportunity since many second line drugs have greater toxicity and in the case of XDR-TB, they are simply ineffective. Newer drugs that can substantially reduce the duration of therapy and have activity against multi drug resistant and extensively drug resistant TB strains have a strong chance of gaining commercial success. Currently the products that are being investigated include the fluoroquinolones gatifloxacin and moxifloxacin, Tibotec/Johnson & Johnson’s TMC207, Chiron Pathogenesis/TB Alliance’s PA824, Otsuka Pharmaceuticals’ OPC-67683 and Sequella’s SQ-109.

Related reports:

Biotech strategies to avoid falling prey to cash rich pharma

2009-01-23T18:40:00.002Z

The Big Pharma market has over the last decade increased its dependence on the biotechnology sector to help replenish its dwindling product pipelines. This along with relatively easy financing had enabled, until recently, biotech companies to partner their products at quite advanced stages of development. This in turn allowed them to wield significant power.

With the onset of the credit crunch the tables have however turned and the sector has witnessed the start of a period of licensing and M&A activity...but on Big Pharma’s terms. How can biotech companies respond?

Biotech’s position has become destabilized and as a result some companies may be forced into negotiating deals (both licensing and M&A) that would not have been dreamed of until recently.

On average non-profitable public US biotechs have 1.7 years of cash remaining. To avoid being snapped up by Big Pharma, biotechs have two options: cutting costs to reduce high cash-burn rates, or accessing quick cash from external sources.

Accessing external financing is becoming increasingly difficult especially in the face of dwindling share prices. The capital raised by US biotech firms has declined from over $2.1 billion in Q4 2007, to under $700m in Q4 2008. Also no IPOs have occurred in the US Biotech industry since Q1 2008.

While raising quick cash from traditional sources represents a problem the options are to go to plan B: reducing burn rate; or to explore new funding opportunities...and thankfully there are some.

New funding opportunities include: obtaining government support, identifying novel investor strategies, and grants and donations. These opportunities are there but will likely only be available to the strongest companies. Others will have to contend with reducing costs further until the only options left are acquisition or in the worst case scenario, winding down the company.

Source: Biotech Financing in the Credit Crisis: Strategies for a radically altered landscape

Published December 2008 - $3800 (Contact us for biotech discounts or for free pages)

Narcolepsy - a small market capable of launching blockbuster therapeutics

2009-01-22T18:10:00.002Z

Although representing a total market of just $230 million narcolepsy offers an entry point for blockbuster products

Still a small market, sales of narcolepsy therapeutics have increased by approximately six-fold over the last 4 years, reaching $230m in 2007. This rapid expansion is mainly due to
better awareness of the disorder, and the significant penetration of two approved treatments,
Provigil (modafinil, Cephalon) and Xyrem (sodium oxybate, Jazz Pharma).

Yet narcolepsy driven sales belies the bigger picture for products such as Provigil.

Cephalon’s Provigil has become the clear narcolepsy market leader with 2007 indication-specific sales of $166 million. Despite this modest revenue stream the total brand sales were $852 million in 2007. One of the reasons for this is Cephalon’s label expansion efforts.

Provigil’s label now includes obstructive sleep apnea/hypopnea syndrome and shift work sleep
disorder,

The main threat to Provigil comes from generic incursion expected from 2012 and also Xyrem. Cephalon has attempted to throw down barriers to generic incursion largely through the development of Nuvigil, a reformulation of modafinil. On the other hand threats from Xyrem have been minimized by its black box warning. This is despite the fact that Xyrem has the advantage of being approved for both major symptoms: excessive daytime sleepiness and cataplexy.

Consequantly, Xyrem’s sales are substantially lower than that of Provigil at only $42.3m across the seven major markets in 2007.

So there is room for novel compounds within the narcolepsy market – primary those with improved efficacy and safety. Developers should not be put off by the relatively low value of this market. Targeting narcolepsy as a primary indication and then expanding represents a strategy proven by Provigil.

Read more about the narcolepsy market and how it offers a stepping stone to much greater sales in our new feature "Narcolepsy - Entry-point to a lucrative fatigue-associated market" or request sample pages from the report by contacting leaddisc@leaddiscovery.co.uk

Sarcoma treatment - where are we now

2009-01-22T12:25:00.002Z

Incidence of sarcomas estimated to have to have hit 36,000 in 2008 in the seven major markets - Treatment of GIST represents a success story in oncology while significant unmet needs remain for other sarcomas

Sarcomas are a diverse group of rare connective tissue tumors representing only 1% of all adult and 15% of all childhood cancers, the development of metastatic disease is a major clinical problem particularly for soft tissue sarcomas.

Treatment depends mainly on the sarcoma subtype. For example, advanced gastrointestinal stromal tumors (GIST) are primarily managed using molecular-targeted therapies, whereas other soft tissue sarcoma subtypes and bone sarcomas are managed using conventional chemotherapy with surgery and/or radiotherapy.

In a just released report on the current state and future of sarcoma treatment it was concluded that better classification and understanding of disease mechanisms may facilitate a shift towards the use of more novel molecular-targeted therapies.

The treatment of GIST represents one of the success stories in modern day oncology.

The identification of specific mutations that are key drivers of GIST has permitted the use of two effective small molecule tyrosine kinase inhibitors: Gleevec/Glivec (imatinib; Novartis) and Sutent (sunitinib; Pfizer).

Nevertheless, the development of tyrosine kinase-resistance in Gleevec-treated GIST patients has created opportunity for more novel molecular-targeted therapies to enter the market. These include Novartis’s second-generation Tasigna (nilotinib) for third line GIST, Genentech/Roche/Chugai’s Avastin (bevacizumab) for first-line GIST and Infinity/MedImmune’s Hsp90 inhibitor retaspimycin for third-line GIST.

As the manufacturer of the current standard first line GIST drug Gleevec, Novartis is perfectly positioned to ensure a potentially smooth and high impact entry of Tasigna into the third-line GIST market.

Improved treatments of unresectable, metastatic bone and soft tissue sarcomas (excluding GIST) represents a key unmet need. Limited therapeutic advances have been made in the treatment of this oncology sub-class. One such agent in Phase III development for metastatic soft tissue and bone sarcomas is ARIAD/Merck & Co’s oral mTOR (mammalian target of rapamycin) inhibitor deforolimus, which has the potential to improve the currently unchanged survival of metastatic sarcoma patients.

Read more about current options, unmet needs and pipeline candidates in sarcoma here

Antipsychotics Market Insight and Analysis 2008

2008-06-05T22:39:00.002+01:00

Schizophrenia is a chronic, severe, and disabling brain disease. Approximately 1% of the population develops schizophrenia during their lifetime and more than 2 million Americans suffer from the illness in a given year.

Schizophrenia is charecterized by hallucinations and delusions, as well as cognitive symptoms such as the inability to focus attention. Treatment of diminished cognition represents an unmet need in the field of schizophrenia and one that LeadDiscovery has been focussing on in UpdatesPlus-Nicotinic Receptors.

Nicotinic receptor modulators represent an exciting emmerging therapeutic class. In particular alpha7 nicotinic receptor modulators have shown promise in the treatment of Alzheimer's disease and cognitive impairment associated with schizophrenia. There are currently 8 candidates from this class in the clinic and many more in preclinical development. Today's edition of DailyUpdates-Psychiatric Diseases focuses on a new candidate, Pfizer's PHA-709829. Acker and colleagues report that this compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model. Further analysis of this paper will appear in the next edition of UpdatesPlus.

Today's edition of DailyUpdates also features a new reports on the more well known aspect of schizophrenia, psychosis. The report Antipsychotics Market Insight and Analysis 2008 forecasts the future antipsychotics market. Revenue from the sale of antipsychotics was $18.1 in 2006 and is expected to reach $18.6bn by 2007. But what will it be in 2012?

This in-depth market analysis examines prospects for antipsychotic drugs right through to 2012, including sales forecasts for leading products. The antipsychotics market will face decreasing growth throughout the forecast period, due to the patent expiry of leading blockbuster drugs. Safety concerns over the current antipsychotics along with high prices, will also contribute to decreased growth in this market.

The antipsychotics market currently contains four blockbuster drugs; Zyprexa, Risperdal, Seroquel and Abilify. This report predicts that a fifth drug will also reach blockbuster status by 2008. The authors also highlight pipeline developments and important contemporary issues, especially commercial drivers and restraints.

According to the National Alliance for Research on Schizophrenia and Depression, approximately 22.1 per cent of American adults (approximately 64 million people) suffer from a diagnosable mental illness in any given year. Of these, it is estimated that over 2 million suffer from schizophrenia. Similarly, approximately 18.8 million people have a depressive disorder, with approximately 2.3 to 3 million suffering from bipolar disorder.

The Antipsychotic Drugs Market Insight and Analysis 2008 examines the market critically through a comprehensive review of available information. Sources include primary research unavailable elsewhere, in-house and industrial databases, commercial news, published reports, economic research and consultation with experts. The report applies financial forecasting, qualitative analyses and the assessment of unmet needs to provide a comprehensive market report with detailed analysis and informed opinion.

In particular, The Antipsychotics Market concentrates on the following essential aspects of the market:

Discussion of the current pharmaceutical market
Forecast of the worldwide pharmaceutical market from 2007-2012
Drivers and restraints facing the antipsychotics market
Opportunities and threats facing the antipsychotics market
Growth of the antipsychotic drugs market between 2007-2012
Commercial prospects for the market-leading drugs, with sales forecasts from 2007-2012
The potential of generics manufacturers to penetrate this market
Pipeline developments with blockbuster potential
Currently marketed drugs with blockbuster potential
Discussion of unmet therapeutic needs and relative advantages of products

For similar reports visit PharmaReport - Psychiatric, Addictive & Sleep Disorders

Transgenic plants offer hope for type 1 diabetes.

2008-05-05T07:38:00.002+01:00

As reported in Autoimmune Market Outlook to 2012 autoimmune related disorders continue to maintain prominence within the global disease burden, having achieved a worldwide market growth of 9.4% over the 2002-06 period.

The autoimmune arena represents a key opportunity for drug development companies, with the potential for success largely attributable to substantial unmet demand, a significant patient population and the medical proclivity for long term treatments.

Type 1 diabetes is one high priority autoimmune disease as well as one of the most common chronic diseases in children and adolescents; about 151,000 American below the age of 20 years have diabetes and while a growing number of these individuals have type 2 diabetes the majority have type 1 disease. Diabetes often leads to long term complications, a problem that increases with duration of disease and so type 1 diabetes remains a particular concern. While good glucose control through injectable insulin is able to reduce the onset of complications in later life new strategies that can reverse the disease represent the holy grail of diabetology.

Interleukin-13 (IL-13) is a pleiotropic regulatory cytokine with the potential for treating several human diseases, including type 1 diabetes. However thus far, conventional expression systems for recombinant IL-13 production have proven difficult and are limited by efficiency. In an article from Plant Biotechnology Journal, soon to be highlighted on DailyUpdates, Wang et al report on the use of transgenic plants as a means of producing human IL-13 (hIL-13).

Transgenic plants represent an exciting opportunity in the emerging arena of biologics (see Transgenic Animals and Plants in Pharmaceutical Research and Manufacturing). With the mapping of the human genome and the concomitant explosion of proteomics, a steady stream of biopharmaceuticals have been launched. As the rate of regulatory approval for biopharmaceuticals increases, the number of products reaching the market will impose unprecedented demands on the industry’s biomanufacturing capacity. Whether or not this will create a biomanufacturing bottleneck is a hotly debated issue in the industry. One issue that is not debatable, though, is the high cost of manufacturing biopharmaceuticals. While biopharmaceuticals produced in bacterial or mammalian cell culture bioreactor facilities have proven to be very effective therapeutic agents, they are also among the most expensive drugs produced, and there is doubt that the current pricing models are sustainable regardless of these agents’ efficacy.

One way to address these concerns is through the use of transgenic plants to manufacture biopharmaceuticals.

Wang and colleagues have taken this approach producing DNA constructs containing hIL-13 cDNA that were introduced into tobacco plants. hIL-13 protein efficiently accumulated in transgenic plants with an expression level as high as 0.15% of total soluble protein in leaves. Multiple forms of plant-derived recombinant hIL-13 resulted from differential N-linked glycosylation. Of significant interest, plant rhIL-13 was highly resistant to proteolysis. In particular, resistance to gastric and intestinal fluid digestion was suggested.

These exciting findings suggest that not only can plants be harnessed to produce IL-13 at high levels reducing production costs, but also that the protein produced may be active orally removing the need for injection, a route of administration expected for such a molecule

Further development of this research is eagerly awaited as are studies establishing IL-13 as a therapeutic option for the treatment of type 1 diabetes

A hopeful future for Parkinson's disease patients

2008-03-12T18:00:00.004Z

As discussed in our recent feature Parkinson's Disease Market analysis and forecasts Parkinson's disease is the second most common neurological disorder, affecting approximately 4.1m people worldwide.

Parkinson's disease is a neurodegenerative disorders characterized by the progressive loss of dopaminergic neurons and hence pharmacotherapy centers on bringing dopaminergic activity back to normal. The range of options open to Parkinson's disease patients is however changing.

Treatment of Parkinson's disease currently includes the use of levodopa, COMP inhibitors and dopamine agonists

Levodopa - the Gold Standard: Since its introduction in the 1960s, levodopa has been considered the gold standard drug therapy for Parkinson's disease. Levodopa is a precursor to dopamine that, when given to people with Parkinson's, is converted into dopamine by nerve cells in the brain. The increase in dopamine may reverse many of the disabling symptoms of Parkinson's disease.

Treatment with dopamine itself isn't possible, because dopamine doesn't cross the body's blood-brain barrier. Levodopa, on the other hand, does cross this barrier, but only a small amount actually reaches the brain. Today levodopa is generally combined with carbidopa that targets levodopa to the brain (by limiting its activation in the periphery) increasing the therapeutic index.

During early treatment, side effects from carbidopa-levodopa therapy are usually not a major problem. However, the drug works less evenly and predictably as the disease progresses. As a result, some people may experience involuntary movements (dyskinesia), primarily when the medication is having its peak effects. The length of time for which each dose is effective may begin to shorten (wearing-off effect), leading to more frequent doses.

Another problem that may develop with long-term carbidopa-levodopa usage, the on-off effect, may cause Parkinson's-related movement problems to appear and disappear suddenly and unpredictably. Other side effects may include hallucinations and a drop in blood pressure when standing (orthostatic hypotension). Some people may experience nausea with carbidopa-levodopa therapy.

COMT inhibitors as adjuncts to levodopa: Catechol-O-methyltransferase (COMT) inhibitors are often used alongside levodopa. COMT inhibitors prolong the effect of carbidopa-levodopa therapy by blocking an enzyme that breaks down dopamine. Tolcapone (Tasmar) is a potent COMT inhibitor that easily crosses the blood-brain barrier. But because Tasmar has been linked to liver damage and liver failure, the drug is normally used only in people who aren't responding to other therapies. Entacapone is a COMT inhibitor that shares some of the properties of tolcapone but doesn't cross into the brain. It may help manage fluctuations in the response to carbidopa-levodopa in people with Parkinson's disease. Entacapone doesn't cause liver problems and is now combined with carbidopa and levodopa in a medication called Stalevo.

Dopamine agonists as important components of the Parkinson's disease arsenal: Although carbidopa-levodopa typically allows people with Parkinson's disease to extend the time they are able to lead relatively normal lives and in many cases is effective for a number of years other treatment options are required. Dopamine agonists are used both as adjuncts to carbidopa-levodopa therapy. Bromocriptine and Permax suffered problems with adverse effects in the past however other dopamine agonists such as romocriptine (Parlodel), apomorphine (Apokyn), pramipexole (Mirapex) and ropinirole (Requip) are all still used.

Selegiline as a strategy for delaying carbidopa-levodopa initiation: Selegiline (Eldepryl) is another commonly used therapeutic. This product is an MAO-B inhibitor that limits the breakdown of both naturally occurring dopamine and dopamine formed from levodopa. Selegiline may delay the need for carbidopa-levodopa for about a year, and when taken with carbidopa-levodopa, may enhance the drug's effectiveness.

Parkinson's disease represents a multi-billion dollar market for the pharmaceutical sector: In 2006, the global sales of Parkinson's disease therapeutics were $3.1bn up by 11% from $2.5bn in 2005. Revenues of approved Parkinson's disease drugs across the major markets (US, Japan, France, Germany, Italy, Spain and the UK) totaled over $2.2bn in 2006, with revenues expected to exceed $4.6bn by 2012.

While it may seem distasteful to some talking about a disease as distressing as Parkinson's in terms of dollars, the size of the Parkinson's disease market is driving pharmaceutical activity which will hopefully improve options available to patients. We are currently seeing a climate of change in this market. A number of key drugs are approaching the end of their patent life while other new products are about to enter the market.

The future of Parkinson's disease: The leading therapeutics expected to change the Parkinson's disease market dynamics will include GSK's Requip Once-daily ER, UCB-Schwarz's Neupro and Teva/Lundbeck’s Azilect. Requip ER received an approvable letter from the FDA in Dec. 2007, while at about the same time UCB filed for Neupro. Other key compounds predicted for success include Kyowa Hakko’s Istradefylline, Merck-Serono/Newron’s Safinamide.

The new wave of Gene/cell Therapy compounds that have revealed positive initial clinical data, thus Neurotrophic growth factors (NGF), either to be injected directly into the brain are also tipped for potential market success. Ceregene’s Neuturine, Neurologix’ GAD (glutamic acid decarboxylase) amongst other similar drugs, will add to the present Parkinson's disease therapeutics that will expand revenue growth in the long-term.

More information on Parkinson's disease: LeadDiscovery currently lists over twenty in depth reports on various aspects of Parkinson's Disease (click here) plus over 200 journal articles (click here). To keep track of all activity in the Parkinson's Disease arena subscribe to DailyUpdates-Neurodegenerative Diseases [see todays edition here]

The Return of Drug Discovery

2008-03-11T21:54:00.004Z

The more observant amongst you will notice that this is the first offering from Advances in Drug Discovery for a while.....in fact one year. This is not to say that there has been a lack of advances over the past 12 months. Quite the opposite and our silence has been due to the efforts that we have been placing on redesigning our main site, LeadDiscovery to better cover drug discovery.

Just a few words on what we have been up to before we continue from where we stopped this time last year.

DailyUpdates, our alert service now highlights key research and breaking news across 12 different therapeutics channels. The service is now a key intelligence tool across the pharmasphere. DailyUpdates is now supported by a monthly service, UpdatesPlus which takes a deep dive into R&D activity providing detailed analysis on selected indications or drug classes. Our portfolio of PharmaReports, in depth pharmaceutical market research and pipeline analysis reports, has expanded with over 1,000 reports now on offer. All in all we now offer insight into drug discovery at increasing levels of detail....so if you need to track a particular area of drug discovery let us help you, we can!

Anyway enough of us and onto the blog.

Todays edition of DailyUpdates covers nearly 50 key journal articles published over the past couple of weeks, a selection of trials and all the most important news. One of the journal articles that we would like to highlight here looks at the therapeutic potential of AT-101 which is featured in a paper highlighted on DailyUpdates-Oncology.

Cottoning onto apoptosis...

Ascenta Therapeutics' AT-101 is an enantiomer of gossypol, a natural product of cotton. The molecule is an orally active inhibitor of the Bcl-2 family of anti-apoptotic proteins and is in Phase 2 cancer trials in a number of oncology indications.

Apoptosis, or programmed cell death represents a pathway targeted by multiple oncology therapeutic candidates. The Bcl-2 proteins (Bcl-2 stands for B-cell lymphoma) comprise the best known anti-apoptotic group. Proteins from this family are frequently over-expressed in cancer making the cells resistant to death signaled by natural or therapeutic stimuli. There are at least five well characterized members of the Bcl-2 family: those most implicated in cancer progression and resistance to conventional therapies are Bcl-2, Bcl-X_L and Mcl-1. Over-expression of anti-apoptotic members of the Bcl-2 family are observed in the majority of Non-Hodgkin's lymphomas (NHLs) , contributing to intrinsic and acquired drug resistance. Since AT-101, inhibits each of these proteins there is strong proof of concept to support the development of AT-101 as a treatment of NHL.

NHL is the most common hematological malignancy and is comprised of around 30 different disease subtypes. Each of these present with a distinct set histological, genetic and clinical characteristics. Treatment options in NHL include chemotherapy, targeted therapies, stem cell transplantation and radiotherapy (see our recent feature Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success?)

Rituxan-based regimens constitute the mainstay of first-line treatment options in several NHL subtypes. There is however a lack of consensus over the treatment of relapsed and refractory disease in most NHL subtypes. Refractory patients are poorly served by currently available treatment options. Consequantly the NHL late-phase pipeline is relatively active, with 10 Phase IIII drugs and 46 Phase II drugs.

In their upcoming paper in the journal Blood, Paolluzi et al characterize AT-101, one of these phase II candidates in B cell lymphoma. The IC50 for AT-101 was reported to be between 1 and 10 microM for a diverse panel of B-cell lymphomas. In a mouse model of drug resistant B-cell lymphoma, 35 mg/kg/day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide and rituximab in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

These data support the open-label, phase II trial of 52 NHL patients comparing rituximab with AT-101 and rituximab which commenced in the US in 2006.

LeadDiscovery currently featured 24 market research reports analyzing various aspects of NHL (click here for listing) and nearly 300 journal article selected for their importance to drug discovery (click here for listing). Interested readers can view our entire oncology portfolio here

Advances in the treatment of urge incontinence...Novel Approaches to Ventricular Fibrilation

2006-07-28T18:31:00.002+01:00

Todays Headlines from across the DailyUpdates network

Breaking News (from DailyUpdates-Genitourinary Tract Disorders): Advances in the treatment of urge incontinence: BioXell’s lead molecule, Elocalcitol, is a vitamin D3 analogue that is able to prevent proliferation of both prostate and bladder tissue induced by various growth factors. Elocalcitol entered Phase IIa evaluation for the treatment of BPH in April 2003 and was found to arrest prostate growth in 92% of patients. A Phase IIb trial is currently being conducted. One of the problems associated with BPH is overactive bladder, a symptom that results from bladder hypertrophy. Thus Elocalcitol represents a promising treatment for BPH as it has the potential to reduce both prostate growth and resultant bladder hypertrophy. As well as being caused by BPH, overactive bladder can also result from the aging process or various neurological conditions and the potential market for Elocalcitol may cross multiple subtypes of overactive bladder. This market is large with 68 million people being diagnosed in the 7 principal pharmaceutical markets in 2005 (see our recent feature Dry Overactive Bladder). A segment of this patient group go on to suffer Urge Urinary Incontinence which produces a greater loss of quality of life and incurs greater costs. Over $1 billion spent on drug treatments for overactive bladder although the main approach to treating the condition involves anti-muscarinic agents despite associated tolerability issues which limit compliance. Today’s featured press release from BioXell announces plans to proceed with a Phase IIb trial of Elocalcitol in overactive bladder. The new study follows the successful completion of a Phase IIa trial of Elocalcitol in 114 women with OAB, announced in May [Source:BioXell]

Featured Journal Article (from DailyUpdates-Cardiovascular Disease): Novel Approaches to Ventricular Fibrilation: Ventricular fibrillation causes more than 70% of out-of-hospital cardiac arrests and is responsible for 220,000 deaths each year in the

. Our recent report Ventricular & Atrial Fibrillation report includes a detailed analysis of the causes and current treatments of this arrhythmia. The primary objectives in ventricular fibrillation patients are to restore sinus rhythm rapidly and to reduce the chance of future episodes. Electrical defibrillation remains the cornerstone in acute treatment of ventricular fibrillation. The report discusses the potassium channel, Kir6.2 and the gap junction, connexin43 as molecular targets of future pharmacological therapeutics. The peptide rotigaptide (ZP123) targets the latter by increasing junction permeability and has recently been advanced into phase 2 trials by Wyeth following its in licensing from Zealand Pharma. Today’s featured journal article reports mechanistic data for rotigaptide and in particular demonstrates that it suppressed dephosphorylation of connexin43 Ser297 and Ser368 following ischemia. These data suggest that small molecule phosphatase inhibitors could offer alternate approaches to increasing connexin43 gap junction permeability thereby offering new approaches to cardiac arrhythmia J Mol Cell Cardiol. 2006 Jun;40(6):790-8. Epub 2006 May 5.

Breakthroughs in cardiovascular diseases

2006-07-25T16:44:00.002+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Cardiovascular Diseases): Promising approach to acute limb ischemia As highlighted in our recent feature Acute Limb Ischemia (ALI) this condition is associated with high mortality especially in individuals with diabetes. Treatment options are limited and amputation is unfortunately the primary clinical approach to patients presenting with ALI. More conservative approaches represent a clearly unmet area, especially since hemorrhage represents a real risk in ALI patients treated with thrombolytics. Moreover, streptase (which is no longer available) was the only approved agent for the use in the periphery. A number of next generation thrombolytics are however under development in an attempt to reduce the risk of hemorrhage. The number of patients with ALI is difficult to determine with the commonly quoted figure of 40,000 in the

being very conservative; the ALI market thus represents a lucrative and largely under-exploited area. Today’s featured study represents one novel candidate approach to ALI. Kusumanto and colleagues report that intramuscular administration of phVEGF(165) (vascular endothelial growth factor gene-carrying plasmid) improved hemodynamic performance and reduced skin ulcers and pain in diabetic patients with ALI. Although the primary end-point of reduced amputation was not met, larger studies are warranted especially given the lack of adverse effects Hum Gene Ther. 2006 May 2; [Epub ahead of print]

Featured News Item (from DailyUpdates-Cardiovascular Diseases): Cardiome reports promising data on atrial fibrillation candidate In April, 2006 we highlighted Cardiome Pharma's announcement that the company's co-development partner, Astellas Pharma, had submitted an NDA to the FDA seeking approval to market the intravenous formulation of RSD1235, an investigational new drug for the acute conversion of atrial fibrillation. LeadDiscovery's brand new report on emerging pharmacological approaches to atrial and ventricular fibrillation (click here) concludes that RSD1235 is one of the most promising new candidates for patients with atrial fibrillation. The NDA is based on a 5-year clinical development program for RSD1235. RSD1235 is also being investigated as a chronic-use oral drug for the maintenance of normal heart rhythm following termination of AF. Phase I data concerning this indication were released by Cardiome on May 5^th, 2006). A Phase 2a pilot study for oral RSD1235 was initiated in December 2005 and interim results from this study have now been released. The data show that RSD1235 is well-tolerated and give the first indications of efficacy. Just as important, during the 28 days of oral dosing, serious adverse events occurred at a similar rate in placebo and RSD1235 treated patients, while, contrasting with other antiarrhythmics no cases of drug-related Torsades de Pointes were observed [source: Cardiome]

Involvement of GSK-3 in inflammation...FDA approves the use of Symbicort as a maintenance treatment of asthma

2006-07-24T14:54:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Immunology and Inflammatory Diseases): Involvement of GSK-3 in inflammation [Licensing Option] Glycogen synthase kinase-3 beta (GSK-3b) is a serine threonine kinase with a broad array of cellular targets, such as cytoskeletal proteins and transcription factors. Since the mid-1990s there has been a near exponential rise in the level of GSK-3 related research and the therapeutic potential of GSK-3 inhibitors has become a major area of pharmaceutical interest. Initial targets of GSK-3 inhibitors were metabolic disorder, neurodegenerative diseases and potential psychiatric conditions. Today’s featured research suggests a role for GSK-3b in the control of inflammation. Previous research has implicated GSK-3b in NFkappaB pathways which in turn regulate the expression of inflammatory genes. Now researchers from Dr Reddy’s Laboratories in the US have reported direct evidence to show that GSK-3b is a negative regulator of cytokine expression by endothelial cells. In vivo studies reported that transfection of animals with GSK-3b reduces inflammation suggesting a novel approach to various conditions; on the other hand it reveals potential risks for the development of GSK-3 inhibitors. This is particularly the case for candidates being developed for metabolic disease given the potential role of inflammation in cardiovascular aspects of diabetes [J Biol Chem. 2006 Apr 19; [Epub ahead of print] ]

Featured News Item (from DailyUpdates-Immunology and Inflammatory Diseases): FDA approves the use of Symbicort as a maintenance treatment of asthma Global asthma/COPD sales should grow to $23 billion by 2014, with inhaled corticosteroid/long-acting bronchodilator combinations set to be the leading class by value in 2014, followed by leukotriene antagonists, and anticholinergics (see our feature on Asthma and COPD). One of the most successful combinations is Symbicort, marketed by AstraZeneca, which provides the inhaled corticosteroid budesonide (Pulmicort) and the rapid and long-acting bronchodilator formoterol (Oxis) in a single dose adjustable inhaler (Turbuhaler). Symbicort is indicated for the maintenance treatment of asthma. Although it won initial approval in

Sweden

as long ago as 2000, FDA approval has, as announced in today’s featured press release, only just been granted. Even prior to US market entry, annual sales were in excess of $1 billion, largely due to European success. Approval from the FDA should lift sales of Symbicort considerably although AstraZeneca does not plan to launch Symbicort in the US until mid 2007. AstraZeneca has also filed for European approval of Symbicort for the maintenance and acute symptomologic relief (SMART) of asthma. It is not clear whether AstraZeneca’s delay in launching Symbicort in the US is related to this European filing [source: AstraZeneca]

Johns Hopkins researchers identify candidate treatments of malaria and cervical cancer...A further fast track designation for Nexavar

2006-07-21T18:37:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Infectious Diseases): Johns Hopkins researchers identify candidate treatments of malaria and cervical cancer [Licensing Option] Each year an estimated 300 to 500 million clinical cases of malaria occur, making it one of the most common infectious diseases worldwide. Malaria can cause high morbidity and mortality and indeed it is the cause of 1.5 to 2.0 million deaths/year. The economic burden of malaria is high, costing African healthcare systems as much as $0.5 billion each year. The emergence of drug resistant strains of malaria is significant and is driving the development of novel anti-malarials. Today’s featured research focuses on efforts from Dr Gary Posner’s lab at The Johns Hopkins University. This group has identified artemisinin derivatives with up to 37 fold greater efficacy than sodium artesunate, another derivative of artemisinin which is a component of current anti-malarials. Of interest, other artemisinin derivatives have been identified by Dr Posner’s group as candidate treatments of cervical cancer. This malignancy is diagnosed in about 13,000 American women each year. Although it is hoped that vaccines against HPV, the cause of cervical cancer, will eventually greatly reduce this incidence there will be a need for effective treatments of the disease for the foreseeable future [J Med Chem. 2006 May 4;49(9):2731-4]

Featured News Item (from DailyUpdates-Oncology): A further fast track designation for Nexavar We recently highlighted a press release from Bayer/Onyx announcing that they have received a positive opinion from the CHMP for Nexavarto be used inpatients with advanced renal cell carcinoma. This followed approval by the FDA in December 2005 and in March 2006 in Switzerland . Nexavar has been shown to double progression-free survival in patients with advanced renal cell carcinoma. Nexavar is also being evaluated in Phase III clinical trials for the treatment of hepatocellular carcinoma and was granted Fast Track designation for this disease in June 2006. Nexavar is also being evaluated in a Phase III clinical trial for non-small cell lung cancer. Today’s highlighted release announces that Nexavar has now been granted Fast Track designation by the FDA for the treatment of advanced melanoma. Cancer of the skin (nonmelanoma and melanoma skin cancers combined) is the most common type of cancer, accounting for more than 50% of all cancers. Melanoma accounts for about 4% of skin cancer cases but causes about 79% of skin cancer deaths [source: Onyx]

Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin...CellCept Aproved for the Treatment of Lupus Nephritis

2006-07-20T18:51:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Oncology): Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin In 2002 Novartis announced the FDA approval of ZOMETA (zoledronic acid) for the treatment of bone metastases associated with a broad range of tumor types. These include prostate cancer, lung cancer, and other tumor types. Zoledronic, a bisphosphonate, limits bone metastasis by preventing resorption through a number of proposed mechanisms including the inhibition of osteoclastic activity and the induction of osteoclast apoptosis. In addition to acting on osteoclasts the bisphosphonates have increasingly been shown to act directly on tumor cells interfering with their migratory and invasive ability and their adherence to the bone matrix. These effects are potentiated when used in combination with various chemotherapeutic agents and appear to involve the stimulation of apoptosis, angiostasis, and host immunity. Today’s featured study evaluates the synergistic combinations of clinically available agents with zoledronic acid and data will hopefully help pave the way to broader use of ZOMETA. Already generating global sales in excess of $1.2 billion this should contribute to the ongoing success of this therapeutic [Oncology. 2006;70(2):147-53. Epub 2006 Apr 26]

Featured News Item (from DailyUpdates-Immunology and Inflammatory Diseases): CellCept Aproved for the Treatment of Lupus Nephritis The prevalence of systemic lupus erythematosus (SLE) in the US had been estimated as approximately 500,000 although a recent telephone survey commissioned by the Lupus Foundation of America suggested a prevalence of as many as 2,000,000. SLE is heterogeneous with respect to target organs. Pathologically the majority of patients with SLE may have renal involvement with clinically relevant kidney disease occuring in about 50% of patients. Treatments of systemic lupus erythematosus have remained unchanged for 30 years however in our report Autoimmune Disorders & Transplant Rejection published earlier this year we predicted the market entry of CellCept (mycophenolate mofetil). Today’s featured press release confirmed this prediction announcing the first approval by Malaysian authorities of CellCept for lupus nephritis. CellCept inhibits inosine monophosphate dehydrogenase thereby selectively inhibiting the proliferation of T and B lymphocytes. Initially approved in 1995 to prevent organ rejection, mycophenolate mofetil has been utilized as an off-label treatment of lupus nephritis. CellCept netted over $1 billion in global sales in 2005; more general approval for the use of CellCept in lupus is certain to increase this figure still further. [source: Aspreva]

Improving the treatment of atrial fibrillation...New options for ovarian cancer

2006-07-18T17:04:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Cardiovasculat Diseases): Improving the treatment of atrial fibrillation The commonly quoted figure describing the number of Americans with atrial fibrillation is about 2.2 million. The current prevalence is now considerably larger than this and is set to continue growing. The condition is a risk factor for stroke and patients with atrial fibrillation tend to suffer more severely from strokes than the general population. Pharmacological approaches to atrial fibrillation are currently suboptimal reflecting the poor side effect profiles of rhythm control agents and the limited efficacy of rate control therapeutics. Consequently clinical approaches presently target the prevention of stroke, a common consequence of arrhythmia, or use interventional approaches such as electrical cardioversion (see our recent report Atrial Fibrillation: Emerging drug discovery targets and therapeutic candidates for an evaluation of each of these areas). Electrical cardioversion is very effective (95% success rate) at restoring a normal rhythm, however 75% of patients successfully treated with electrical cardioversion experience a recurrence of AF within 12-24 months. Today’s featured study reports that atorvastatin treatment reduced recurrence from 46% to 13% during the first 3 months. Atorvastatin has been one of the most successful therapeutic approaches to dyslipidemia, itself a risk factor for atrial fibrillation [Am J Cardiol. 2006 May 15;97(10):1490-3. Epub 2006 Mar 29]

Featured News Item (from DailyUpdates-Oncology): New options for ovarian cancer As many as 60,000 cases of ovarian cancer are diagnosed in the seven major markets each year and as a result, of all the gynecological tumors it is associated with the highest level of mortality. Despite this, ovarian cancer has not traditionally attracted the same level of R&D interest as other female cancers; it remains however an important secondary indication for existing and pipeline drugs (see Ovarian Cancer-Growing importance as secondary indication for targeted therapies) as indicated by today’s featured press release from Eli Lilly. Carboplatin plus paclitaxel remains firmly established as the treatment of choice not only in first line but also in second line given the significant proportion of patients retaining platinum sensitivity. Recurrence does however occur in 90% of patients following first line treatment. Yesterday, Lilly reported that following FDA approval, Gemzar will now represent an alternative to paclitaxel as a carboplatin adjunct. Gemzar’s approval was based on a Phase III study comparing Gemzar plus carboplatin against carboplatin alone in locally advanced or metastatic disease in patients previously treated with platinum-based therapy such as carboplatin or cisplatin. Results showed a median progression-free survival increase of 48% in the combination arm compared to the carboplatin monotherapy arm (8.6 months vs. 5.8 months). Gemzar has previously been approved for non-small cell, pancreatic and breast cancer [source: Eli Lilly]

Further development of HDAC inhibitor PDX101...Mechanistic data on the potential therapeutic role of nicotine in Parkinson's disease

2006-07-17T16:35:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Neurodegenerative Diseases): Mechanistic data on the potential therapeutic role of nicotine in Parkinson's disease Market analysis shows that products currently used that have a neuroprotective effect had a market value of $5.1 billion in 2005 out of a CNS market value of $34.6 billion. With the approval of new products and takeover of markets for obsolete symptomatic therapies, the neuroprotection market value will rise $11.5 billion by the year 2010 when it will constitute a major and important component of the CNS market. Two of the major indications within the neurodegerative market are Parkinson’s and Alzheimer’s disease (see World Neurodegeneratives Disease Markets, 2005-2009). There is a growing body of evidence linking alterations in nicotinic receptor number and/or function to both of these diseases as well as other CNS disorders. With respect to Parkinson’s disease, chronic oral nicotine has been shown to partially protect against striatal damage in nonhuman primates, suggesting potential as a treatment. Today’s featured study reports that nicotine treatment has a generalized effect on dopaminergic function preventing the dopamine turnover and the loss of synaptic plasticity in dopaminergic neurons that occurs after nigrostriatal damage [J Neurosci. 2006 Apr 26;26(17):4681-9]

Featured News Item (from DailyUpdates-Oncology): Further development of HDAC inhibitor PDX101 The histone deacetylase inhibitor class of therapeutics represents a highly exciting approach to cancer. Merck's ZOLINZA (SAHA; vorinostat) and Gloucester Pharmaceuticals' Romidepsin (Depsipeptide; FK228) lead this class however PXD101, being developed by CuraGen and TopoTarget is fast in pursuit. In November 2005 updated interim Phase I data on this compound was presented and this was followed in February, 2005 by the initiation of a phase II study in lymphoma (for a full analysis of this field see our feature Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). Although hematological cancers have represented the lead indication for all of the HDAC inhibitors in advanced development clinical studies have broadened to encompass solid tumors and today’s release from CuraGen and TopoTarget announces the initiation of a Phase I/II trial evaluating the safety and potential efficacy of PXD101 for the treatment of hepatocellular cancer. Hepatocellular carcinoma is the fifth commonest cancer worldwide with about one million new cases diagnosed annually. It is estimated that the incidence of HCC in the seven major pharma markets will continue to rise over the next decade. There is no gold standard therapy - the market is characterized by high levels of unmet need, large patient potential and high commercial potential (see Hepatocellular Carcinoma - Growing Market Seeks New Players [source: CuraGen]

Advances in cardiovascular diseases

2006-07-14T16:00:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Cardiovascular Diseases): Impressive data on Biopure's oxygen therapeutic suggesting the potential for improved treatment of myocardial infarction Oxygen therapeutics are biologic and chemical compounds that are intravenously administered into the circulatory system to enhance oxygen delivery to tissues and organs. Such compounds are required under conditions of anemia or ischemia. Ischemia occurs during a variety of serious and common cardiovascular disorders including myocardial infarction, stroke and peripheral arterial disease. Hemopure (HBOC-201) is an oxygen therapeutic developed by Biopure and approved in South Africa for the treatment of acutely anemic surgical patients. The company is also developing Hemopure for use in trauma and as a cardioprotective agent in ischemic conditions. Hemopure consists of chemically stabilized bovine hemoglobin but compared to whole blood it has a lower viscosity and greater oxygen exchange capacity thus conferring oxygenation at low blood pressure and through partially blocked blood vessels thus enabling reoxygenation of ischemic tissue. Furthermore Hemopure is stable for three years at room temperature contrasting with whole blood that is stable for just 42 days and which must be refrigerated. Conferring further advantages, Hemopure is compatible with all blood types obviating blood typing, testing or cross-matching thus allowing more rapid administration. This is important as it is compatible with faster treatment, potentially while in transit to ERs. Moreover, due to its production process Hemopure holds a much reduced risk of contamination. Today’s featured study tests if Hemopure can decrease infarct size during acute, severe myocardial ischemia and reperfusion. Impressively, when administered 15 minutes into reperfussion in a canine model of coronary ischemia/reperfussion, infarction was dramatically reduced as compared to untreated control while cardiac function was essentially unchanged from baseline. It is hoped that thesed data will support the eventual use of Hemopure as a rapid and effective interevention in patients who have suffered myocardial infarction [Am J Physiol Heart Circ Physiol. 2006 Apr 14; [Epub ahead of print]]

Featured News Item (from DailyUpdates-Cardiovascular Diseases): CoGenesys cleared to advance long-acting albumin cojugated form of BNP into the clinic as a candidate treatment of chronic heart failure There is a clear need for new treatments for heart failure, as mortality and morbidity rates, although improving, remain high. Heart failure already represents the leading cause of hospitalization for patients over the age of 65 in Western markets and the aging population in these markets will surely lead to growth in the prevalence of the disease and an increase in healthcare expenditure. The late-stage heart failure pipeline is weak in terms of quantity and quality, 81% of products are in Phase I and II of development (see our feature Chronic and Acute Heart Failure). Today’s featured press release announces the imminent Phase I entry of CoGenesys’ Cardeva, a long-acting form of b-type natriuretic peptide (BNP). BNP stimulates cyclic GMP, which is not only a vasodilator but an inhibitor of the progressive heart muscle structural remodeling that leads to progression of heart failure. A short-acting intravenous BNP formulation, NATRECOR (nesiritide; Scios) has already been approved in 2001 for the treatment of acute congestive heart failure however use in chronic heart failure is precluded by the route of administration. Furthermore, two recent publications have raised questions about the safety of NATRECOR with respect to worsening renal function and death. Preclinical studies have demonstrated that Cardeva, a human serum albumin (HSA)-BNP fusion protein, retains the pharmacological profile of BNP peptide but has a greatly extended half-life and long duration of action. Cardeva is hoped to provide improved long-term options to patients in the community [source: CoGenesys]

New data reported on use of Symbicort for the maintenance and symptomological relief of asthma

2006-07-13T14:26:00.001+01:00

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Immunology and Inflammatory Diseases): New data reported on use of Symbicort for the maintenance and symptomological relief of asthma There is a positive outlook for the respiratory market over the next five years, which will experience a sustained period of growth driven by the expansion of sales in existing classes, the launch of major new products, and the results from several landmark studies. Global asthma/COPD sales should grow to $23 billion by 2014, with inhaled corticosteroid/long-acting bronchodilator combinations set to be the leading class by value in 2014, followed by leukotriene antagonists, and anticholinergics (see our feature on Asthma and COPD). Today’s featured study published by Rabe and colleagues describes an AstraZeneca sponsored study of one of the leading combinations, budesonide/formoterol. This combination, marketed by AstraZeneca as Symbicort, provides the inhaled corticosteroid budesonide (Pulmicort) and the rapid and long-acting bronchodilator formoterol (Oxis) in a single dose adjustable inhaler (Turbuhaler). Symbicort is indicated for the maintenance treatment of asthma in adults and children aged 6 years and above and for the treatment of patients with severe COPD. Today’s featured study compares Symbicort with a higher dose of budesonide plus as-needed terbutaline, a beta-2 adrenoceptor agonist commonly used as a short-term asthma treatment. Patients were randomized to receive either Symbicort for maintenance and, crucially, additional inhalations as needed for symptom relief, or budesonide for maintenance medication plus terbutaline as needed. Use on an as needs basis was built into the study design to evaluate a new approach being developed by AstraZeneca known as SMART. Under these conditions Symbicort showed much greater improvements in morning peak expiratory flow and fewer exacerbations or hospital treatments than patients receiving budesonide; these improvements were achieved with a reduction in total steroid load. Currently Symbicort is approved as a maintenance treatment of asthma in 93 countries following initial approval in Sweden in 2000. Of note FDA approval has yet to be granted although an NDA was filed in 2005. Although US market entry has not yet occurred, annual sales are now in excess of $1 billion, largely due to European success. 2005 saw the publication of two papers supporting the use of Symbicort as a SMART therapy. STAY established improved efficacy using this approach as compared to fixed dosing; COSMOS demonstrated greater efficacy as compared to fixed dose fluticasone/salmeterol (the primary competitor to Symbicort marketed by GSK as Advair). Today’s featured study provides further support ot the SMART approach, regulatory approval for which was filed in 2005. Approval of the SMART approach plus FDA approval should lift sales of Symbicort way past even current figures. [Chest. 2006 Feb;129(2):246-56]

Valentis drug VLTS 934 disappoints in phase 2b trial...New molecular target identified for the treatment of ovarian cancer

2006-07-12T17:22:00.001+01:00

Todays Headlines from across the DailyUpdates network

Breaking News (from DailyUpdates-Cardiovascular Disease): Valentis drug VLTS 934 disappoints in phase 2b trial: In contrast to coronary and cerebral artery disease, peripheral arterial disease (PAD) remains an under-appreciated condition that despite being serious and extremely prevalent is rarely diagnosed and even less frequently treated. The prevalence of PAD has usually been cited as 8-12 million people in the US however total numbers could be as high as 20 million (see our feature Peripheral arterial disease (PAD): prevalence, current treatments & new technologies). Our feature estimates that 25% of patients with PAD require claudication agents; 50% would benefit from anti-hypertensives; 90-100% should receive lipid lowering agents and all patients are suitable for antiplatelet therapy. These figures differ remarkably from the numbers of patients that receive treatment. Not only does PAD represent a major unmet clinical problem but its under-treatment translates to a total of $35 billion in unrealized annual US sales of cardiovascular therapeutics. Needless to say, given the unmet potential of PAD therapeutics the value of companies with a stake in this market stands to increase considerably. Equally however, the risks of being in the PAD arena are considerable as demonstrated today in Valentis’ press release announcing the failure of VLTS 934. This agent appears to have a direct effect of repairing compromised cell membranes, decreasing levels of specific inflammatory mediators and improving cell function, thus making it applicable as a treatment of conditions associated with ischemia. Valentis recently completed a Phase IIa clinical trial of VLTS in patients with PAD in which VLTS 934 demonstrated favorable activity. Unfortunately, Valentis announced yesterday that in a Phase IIb trial VLTS 934 failed to meet any of its end points. The company is currently unable to explain the difference in performance of the drug between the two trials and Valentis now appears to be moving into a period of major change. [Source:Valentis]

Featured Journal Article (from DailyUpdates-Oncology): New molecular target identified for the treatment of ovarian cancer: Despite being the most common cause of death from gynecological tumors, ovarian cancer has not traditionally attracted the same level of R&D interest as other female cancers. Nevertheless, nearly 60,000 cases of ovarian cancer being diagnosed in the seven major markets each year is, by no means, small and therefore, it remains an important secondary indication for existing and pipeline drugs. Carboplatin plus paclitaxel remains firmly established as the treatment of choice not only in first line but also in second line given the significant proportion of patients retaining platinum sensitivity. Opinion leaders interviewed for our recent feature Ovarian Cancer-Growing importance as secondary indication for targeted therapies identified VEGF inhibitors as promising for ovarian cancer. In particular, Genentech/Roche's Avastin is considered to have the most potential, so much so that it is believed to be used significantly off-label despite the halting of a Phase II trial due to safety concerns. There are nine drugs in Phase II development for ovarian cancer including a number of cytotoxic and molecular-targeted therapies. Today’s featured research focuses on much earlier stage candidates, the pygopus proteins. These proteins are critical elements of the canonical Wnt/beta-catenin transcriptional complex and here we highlight research demonstrating that pygopus2 is overexpressed in 82% of epithelial ovarian cancer tumors. Cell line studies demonstrated that antisense neutralization of this protein conferred significant anticancer activity suggesting that pygopus2 may represent a molecular target for future ovarian cancer therapeutics [Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2216-23]

Shinogi announce phase 2 data on anorectic agent S-2367...Clinical data on Sutent (Sunitinib) as a treatment of renal cell carcinoma

2006-07-11T16:39:00.000+01:00

Todays Headlines from across the DailyUpdates network (11th July)

Breaking News (from DailyUpdates-Metabolic Disorders): Shinogi announce phase 2 data on anorectic agent S-2367: The prevalence of obesity has increased by 61% in the US during the period 1991-2001. According to Datamonitor 127m people suffered from the disease in the seven major markets in 2003. Obesity is an active area of research and development and our recent feature from Datamonitor (Obesity - commercial opportunites and therapeutic pipeline analysis) discusses 22 key compounds in Phase I development or above. Neuropeptide Y (NPY) a potent orexigenic agent that acts through five different receptor subtypes represents a therapeutic target for anorectic agents. The predominant NPY orexigenic receptors are NPY-Y1 and NPY-Y5, while activation of the presynaptic Y2 receptor limits the release of NPY thus reducing food intake. One peptide from the NPY family, Peptide YY (PYY) has received considerable attention as it an endogenous Y2 receptor agonist in the arcuate nucleus which acts to reduce appetite. Thus Nastech Pharmaceuticals and Amylin are both developing formulations of PYY 3-36 which are currently in phase 2 and phase 1 development respectively. In addition 7TM Pharma have recently announced positive results from its phase I/II study of TM30338, a dual Y2-Y4 receptor agonist. Today’s featured press release from Shionogi & Co announces top-line efficacy results from a Phase IIa proof-of-concept trial with S-2367 which, uniquely, blocks NPY binding to Y5 receptors [Source:Shionogi]

Featured Journal Article (from DailyUpdates-Oncology): Clinical data on Sutent (Sunitinib) as a treatment of renal cell carcinoma: A meager 20% of metastatic renal cell carcinoma (RCC) tumors respond to standard cytokine therapy, thus rendering 80% of advanced RCC patients without any effective treatment. Further, with up to 50% of stage one to three patients relapsing following nephrectomy and an increasing incidence of this disease, RCC represents a largely unmet disease. Nexavar (Bayer; approved in the US in 2005) and Sutent (Sunitinib; Pfizer; approved in the US in 2006), both indicated for metastatic RCC, look set to compete well to the end of the decade. With Nexavar's first to market advantage and Sutent's purported superior efficacy, revenue margins will lie extremely close. Datamonitor forecasts Nexavar's 2010 revenues will reach $122 million and Sutent's $179 million (Renal Cell Carcinoma - Novel Targeted Treatments). Today’s featured paper report data from an open-label, single-arm, multicenter clinical trial of Sutent monotherapy in patients with RCC [JAMA. 2006 Jun 7;295(21):2516-24]

Oncolytic viruses continue their march forwards...Harnessing CTLA4 as an approach to asthma

2006-07-10T13:58:00.000+01:00

Todays Headlines from across the DailyUpdates network (10th July, 2006)

Breaking News (from DailyUpdates-Technology): Oncolytic viruses continue their march forwards: Today’s featured press release is from Oncolytics Biotech who announce that it has commenced patient enrolment in its Phase Ib UK clinical trial investigating REOLYSIN in combination with radiation therapy as a treatment for patients with advanced cancers. REOLYSIN is human oncolytic reovirus currently in phase I/II development and has been demonstrated to replicate specifically in tumor cells bearing an activated Ras pathway (further information on this virus can be found in our report (Developments in oncolytic viruses - An emerging approach to cancer therapeutics). [Source:Oncolytics Biotech]

Featured Journal Article (from DailyUpdates-Immunology & Inflammatory Diseases): Harnessing CTLA4 as an approach to asthma: CTLA-4 is a negative regulator of T-cell costimulation that acts by preventing the interaction of CD80/86 on APCs with CD28 on T-cells. Interfering with this binding pair has been targeted successfully by Bristol-Myers Squibb’s who have developed abatacept and their second generation belatacept both of which are fusion proteins comprising the extracellular domain of the human CTLA4 molecule and the heavy-chain constant region of human IgG1. Abatacept initially demonstrated clinical efficacy in psoriasis however further development has been focused on rheumatoid arthritis with approval being granted by the FDA at the end of 2005. Belatacept (LEA29Y) appears to be a useful approach to both acute and chronic phases of graft rejection (for a detailed insight into CTLA4 based therapeutics see Autoimmune Disorders & Transplant Rejection - The Potential of T-cells Targeted Therapeutics). Today’s featured article focuses on research being conducted to utilize the cytoplasmic rather than the extracellular domain of CTLA-4 to suppress allergic inflammation. The Korean group, that have published their work in the May edition of Nature Medicine reported that engineering T cells to conditionally express this cytoplasmic domain markedly reduced infiltration of inflammatory cells, secretion of Th2 cytokines, serum IgE levels and airway hyper-responsiveness in a mouse model of allergic airway inflammation. Global asthma sales should continue grow, sharing a market worth $23 billion with COPD therapeutics by 2014. Inhaled corticosteroid/long-acting bronchodilator combinations are set to be the leading class by value in 2014, followed by leukotriene antagonists, and anticholinergics (see our feature on Asthma and COPD). Today’s featured research suggests that biologics focusing on the intracellular component of CTLA-4 may also feature in future pipelines for asthma candidates [Nat Med. 2006 May;12(5):574-9]

Biomarin advance novel antihypertensive...Researchers identify novel molecular target for the treatment of sepsis

2006-07-07T14:53:00.000+01:00

Todays Headlines from across the DailyUpdates network (July 7th, 2006) - In today's edition we highlight Biomarin's development of the novel antihypertensive 6R-BH4 and new research describing a promising molecular target for future sepsis therapeutics. Summaries of this content can be seen below or click here for today's edition of DailyUpdates

Breaking News (from DailyUpdates-Cardiovascular Diseases): Biomarin advance novel antihypertensive: Effective blood pressure control for all hypertensive patients remains an elusive goal. The development trend is currently towards optimizing fixed dose combination therapy rather than the development of single pill alternatives. Rasilez bucks this trend and is set to be the first oral renin inhibitor when it enters the market; it is likely to become a blockbuster by 2010 (see Pipeline Insight: Antihypertensives). The submission for rasilez was accepted for US regulatory review in April 2006; submission for EU approval remains planned for 2006. Today we highlight news from BioMarin who are developing another clinical stage antihypertensive. The company have announced that the first patient has initiated treatment in the Phase 2 clinical study of 6R-BH4 for the treatment of poorly controlled hypertension. The company expects to announce data from this study in early 2007. 6R-BH4 is commonly known as tetrahydrobiopterin, an essential enzyme cofactor that plays a key role in the production of nitric oxide, a molecule that regulates vascular tone. A secondary deficiency of 6R-BH4 disrupts NO production, resulting in loss of vasodilation control and increased blood pressure. Earlier pilot studies have demonstrated that oral administration of 6R-BH4 can reduce blood pressure in individuals who remain hypertensive despite treatment with other medications. 6R-BH4 is the same enzyme cofactor currently being evaluated in BioMarin's Phenoptinfor phenylketonuria. [Source:BioMarin]

Featured Journal Article (from DailyUpdates-Infectious Diseases): Researchers identify novel molecular target for the treatment of sepsis: Sepsis, a complex and rapidly progressing disease with high levels of mortality, presents major challenges with regard to its epidemiology, definition and management. Rising disease incidence has been fuelled by the growing number of surgical interventions and an increase in immunocompromization. Disease management is predominantly non-specific. Recent development has produced only one sepsis-specific drug, Eli Lilly's Xigris. However, according to the analysts Datamonitor, due to the drug's high price point, the narrow label and its contraindications, Xigris has failed to meet expectations, with global 2005 sales totaling $214.6m (see our feature on Sepsis). Takeda's TAK-242, a TLR-4 modulator, is currently in phase 3 development. Today’s featured journal article takes another approach evaluating host modulators of susceptibility to sepsis. The study reports that nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key modifier gene who’s expression plays a major suppressive role on the response to sepsis. Dramatically, within 40 hours following cecal ligation and puncture all mice engineered so that they did not express Nrf2 had died. In stark contrast only 20% of control mice had died. This regulatory process appears to involve the regulation of cellular glutathione and other antioxidants and intriguingly this pathway declines with age. These data suggest that Nrf2 may play a role in the increased risk of death in elderly patients with sepsis as compared to younger patients and suggest that agents able to stimulate Nrf2 expression may be therapeutically useful [[J Clin Invest. 2006 May;116(5):1317-26 J Clin Invest. 2006 Apr;116(4):984-95]

Symphony Medical advance their novel treatment of atrial fibrilation into phase 2 development...Schering-Plough establish IL-23 as a molecular target

2006-07-06T16:24:00.000+01:00

Todays Headlines from across the DailyUpdates network (6th July)- for all of today's content click here

Breaking News (from DailyUpdates-Cardiovascular Diseases): Symphony Medical advance their novel treatment of atrial fibrilation into phase 2 development: The current prevalence of atrial fibrillation in the US is now considerably larger than the 2.2 million commonly quoted and is set to continue growing. The condition is a risk factor for stroke and patients with atrial fibrillation tend to suffer more severely from strokes than the general population (for a detailed look at this condition see our report Atrial Fibrillation: Emerging drug discovery targets and therapeutic candidates). Treatment options are currently sub-optimal largely depending on the use of rate controlling agents and anticoagulants. The global antiarrhythmic market is set to enter a period of revival reaching $3.5 billion by 2015. This resurgence is being led by Cardiome's RSD1235 which is expected to enter the market imminently and predicted to command 27% of the whole market by 2015. Competing with pharmacological treatments are interventional approaches which can be curative. Catheter ablation has been recently replaced by Minimaze surgical procedures as the standard curative approach to atrial fibrillation due to the occurrence of fistulae with the former. In general the invasive nature of interventional approaches have represented a barrier to uptake however this is not the case in a subgroup of patients who are undergoing surgery for related conditions such as mitral valve replacement. Invasive procedures would also be suitable for patients at risk of developing arrhythmias subsequent to thoracic surgery. This is a sizable population since up to 30% of coronary artery bypass patients and up to 60% of patients who undergo a combination valve replacement and bypass procedure develop atrial fibrillation. Cardiologists believe that a prophylactic approach is suitable for such patients and in this respect Symphony Medical have announced that patient enrollment is underway in its Phase II multi-center human clinical trial of a procedure comprising the injection of a biopolymer into the epicardial fat pads that prevents the development of persistent atrial fibrillation. This achieves temporary modulation of the autonomic nervous system of the heart by blocking the vagal inputs to the heart than can serve as an initiating trigger for atrial fibrillation. The biopolymer then dissipates over the next 30 days [Source:Symphony Medical via PR Newswire]

Featured Journal Article (from DailyUpdates-Immunology & Inflammatory Diseases): Schering-Plough establish IL-23 as a molecular target for multiple sclerosis treatment Multiple sclerosis is an autoimmune human disease that affects about 350,000 people in the USand ranks as one of the major causes of nervous-system disability in youngadults between the ages of 15 and 45 years. The primary symptoms of multiple sclerosis are the direct effect of myelin destruction and include tremor, nystagmus, paralysis, and disturbancesin speech and vision. Current therapeutics focus mainly on control as the disease cannot be cured using current options although the recent reintroduction of Biogen-IDEC's Tysabri (Natalizumab; formerly known as Antegren) offers new hope for improved treatment. Although the disease has traditionally been viewed as a CD4⁺ Th1-mediated disease, this view is changing and autoreactive CD8⁺ cells are gaining increasing attention as being involved in the etiology of disease. Regulatory T cells are also involved in multiple sclerosis and in our recent in depth look at T cell molecules as candidate targets for new therapies we suggest that manipulating this subtype of T cell could eventually provide a cure. Today’s featured journal article from Schering-Plough describes IL-23 as another candidate for multiple sclerosis drug discovery efforts. This cytokine is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. The study published in the May edition of JCI demonstrates that therapeutic treatment with anti-IL-23p19 antibody during active disease prevented subsequent disease relapse [J Clin Invest. 2006 May;116(5):1317-26]

Phase 2 testing commences on Abiogen's anxiolytic ABIO 0801...Novel drug delivery technology facilitating the use of therapeutic macromolecules

2006-07-05T17:03:00.000+01:00

Todays Headlines from across the DailyUpdates network (from DailyUpdates 5th July)- Although press releases are quite thin on the ground today because of the July 4th holiday in the US, Abiogen have released important information regarding the start of phase 2 testing of the company's anxiolytic, ABIO 08/01. In addition we feature a review describing a potentially groundbreaking drug delivery technology. This technology harnesses protein transduction domains (PTDs), endogenous peptide sequences that can be conjugated to the desired macromolecule facilitating their cellular entry. This technology can be extended to multiple diseases however the review focuses on cancer. In addition we feature the most recent entries onto Jobs.LeadDiscovery.co.uk, our recruitment area for pharmaceutical and R&D personnel

Breaking News (from DailyUpdates-Psychiatric Disorders): Phase 2 testing commences on Abiogen's anxiolytic ABIO 0801: The global anxiety disorders market is set to decline from $4.5 billion in 2006 to $2.6 billion by 2015. This will be primarily due to generic incursion (see Anxiety Disorders - A decade of declining revenues). Despite loss of revenue for currently marketed agents there is significant demand for new clinical options, especially those with improved efficacy and this has driven the development of several novel anxiety drugs will be launched over the next few years. Expected newcomers include Predix's PRX-00023 in Phase III for generalized anxiety disorder. This condition is a common subclass of the anxiety disorders which affects an estimated 5% of people. Today’s featured release announces the start of Abiogen Pharma’s Phase II clinical trial of a second candidate for this anxiety disorder, ABIO 08/01 (BTG1640). This candidate is also being developed to treat other anxiety states such as panic disorder.[Source:Abiogen via Businesswire]

Featured Journal Article (from DailyUpdates-Technology): Novel drug delivery technology facilitating the use of therapeutic macromolecules Drug delivery remains a challenge in the management of cancer. Until quite recently, approaches focused on technologies such as liposomes to overcome the poor solubility of cytotoxics; and monoclonal antibodies to target cytotoxic agents to cancer cells. More recently intracellular macromolecules such as siRNAs have risen to prominence as oncology candidates bringing a new set of challenges centered around intracellular access. Overall the market value of drug delivery technologies has been estimated at $7.5 billion rising to $18.4 billion by the year 2010 and $38.5 billion by the year 2015. Technologies and markets in the cancer drug delivery area are evaluated in our feature Drug Delivery in Cancer - technologies, markets and companies. Today’s featured paper reviews an exciting approach to cancer drug delivery which is ideal for optimizing therapeutic macromolecules with an intracellular mode of action including siRNAs, genes and proteins. This approach harnesses protein transduction domains (PTDs), endogenous peptide sequences that can be conjugated to the desired macromolecule facilitating their cellular entry. This technology can be extended to multiple diseases however the review focuses on cancer [Breast Cancer. 2006;13(1):16-26]

Cannabinoids continue their march toward possible blockbuster status...Data support switch from typical to atypical antipsychotics

2006-06-30T18:22:00.000+01:00

Todays Headlines from across the DailyUpdates network (June 30th)- to see today's bulletin click here

Breaking News (from DailyUpdates-Pain Therapeutics): Cannabinoids continue their march toward possible blockbuster status: The cannabinoids represent a potential blockbuster class of therapeutic agents with multiple indications (see Cannabinoids - A potential blockbuster market). Analysts say that the market grew by 6.3% between 2004 and 2005 and that growth of the market will continue through to 2010. The approval last week (June 21^st, 12006) of anti-obesity therapeutic Acomplia in Europe and launch next month in the UK is expected to contribute strongly to this growth. Acomplia will join Marinol from Unimed Pharmaceuticals and Nabilone marketed by Cambridge Laboratories and more recently GW Pharmaceuticals’ Sativex. Savitex was launched in 2005 in Canada as an analgesic for use in multiple sclerosis patients. This indication represents a segment of the worldwide analgesic market which in total was worth $50 billion during the year 2005 and is expected to increase to $75 billion by the year 2010 and $105 billion by 2015. Other larger segments include acute pain and neuropathic pain (see Pain Therapeutics - Drugs, Markets and Companies). Today’s featured press release announces the advance of a further cannabinoid in development for the treatment of pain, Pharmos’ cannabinor (PRS-211,375). Pharmos announce that European regulators have approved a Phase 2a clinical study of this CB2-selective synthetic cannabinoid ligand in healthy subjects experiencing pain following third molar dental extraction. In Q3 2006, the Pharmos expects to initiate a second phase 2a intravenous trial that will test the analgesic activity and safety of cannabinor in experimentally induced neuropathic pain. [Source:Pharmos Release]

Featured Journal Article (from DailyUpdates-Psychiatric Disorders): Data support switch from typical to atypical antipsychotics The atypical antipsychotics have found favor among clinicians and are now considered to be first line treatments for schizophrenia and are gradually replacing the typical antipsychotics. The first atypical antipsychotic medication, clozapine, has been replaced by agents with a more favorable side effect profile such as olanzapine, risperidone, and quetiapine, and more recently ziprasidone and aripiprazole. These second generation antipsychotics continue to drive the antipsychotic market with a growth rate of 27% between 2002-2003, yielding revenues of over $9.5 billion in 2003 responsible for a 93.3% share of the market (see Antipsychotics - From Blockbuster Brands to Billion Dollar Generics). Our featured journal article today examined whether patients with schizophrenia who were judged to be stable on long-term treatment with conventional antipsychotic medications would further benefit from a switch to an atypical antipsychotic drug (risperidone or olanzapine). The results indicate that both atypical antipsychotic medications provided significant additional improvement in symptom severity in patients with schizophrenia previously on conventional antipsychotic agents. These data should further hasten the shift towards the use of atypical antipsychotics [J Psychiatr Res. 2006 Jun 6; [Epub ahead of print]]

Candidate shows new promise for treatment of COPD...The development of hTERT vaccines for the treatment of cancer

2006-06-28T16:50:00.000+01:00

Todays Headlines from across the DailyUpdates network (28th June, 2006) Today we feature nearly 60 breaking journal articles from 11 therapeutic channels, plus 5 selected drug development press releases and 9 jobs from jobs.leaddiscovery.co.uk - featured research is from Norway where scientists are developing an hTERT vaccine for the treatment of cancer; our headline press release announces phase IIb data for a COPD candidate

Breaking News (from DailyUpdates-Immunology & Inflammatory Disorders): Candidate shows new promise for treatment of COPD: Global asthma/COPD sales should grow to $23 billion by 2014, with inhaled corticosteroid/long-acting bronchodilator combinations set to be the leading class by value in 2014. Today’s headlined press release from Vectura Group and Sosei announces phase IIb data for one their products, NVA237. This candidate was outlicensed to Novartis in 2005 and is in development for the treatment of COPD both as a monotherapy and in combination with Novartis’ once daily bronchodilator indacaterol. NVA237 is a long-acting anti-muscarinic (LAMA) bronchodilator relatively devoid of anti-muscarinic side effects. If it approved NVA237 is expected to be the second once-a-day anti-muscarinic treatment to be approved for marketing for COPD. Spiriva, the first LAMA product, received marketing approval in Europe and the US in April 2002 and February 2004 respectively and is expected to achieve peak annual sales of more than US$3 billion (see our feature on Asthma and COPD) [Source: Vectura Release]

Featured Journal Article (from DailyUpdates-Cancer Immunotherapy): The development of hTERT vaccines for the treatment of cancer Inhibition of telomerase activity in cancer cells results in telomere shortening, and leads to cell cycle arrest or apoptosis. Human telomerase activity is conferred by a complex comprising hTERT and an RNA component known as TERC. The pathological consequences of telomerase activation has been exploited by Geron who are developing GRN163L an hTERT inhibitor and also a vaccine that targets the host immune system to cells expressing hTERT. This vaccine has been evaluated in a 20 patient phase 1/2 trial in prostate cancer patients. The vaccine produced an immunological response and stabilized PSA levels. Today’s featured article reports on phase 1/2 data from the trial of a second vaccine being developed by GemVax. The vaccine which is a combination of telomerase peptides GV1001 and HR2822 was administered to patients with non-small cell lung cancer. The treatment was well tolerated with minor side effects. A complete tumor response was observed in one of 24 patients and the authors suggest that further studies should be conducted. GV1001 is also in phase 1 development for the treatment of pancreatic cancer and melanoma [Cancer Immunol Immunother. 2006 Feb 21; [Epub ahead of print]]

New clinical data on Vasogen's heart failure candidate...Johnson and Johnson publish on potential asthma candidate

2006-06-27T16:19:00.000+01:00

Todays Headlines from across the DailyUpdates network (June 27th)

Breaking News (from DailyUpdates-Cardiovascular Disease): New phase III data on heart failure candidate, Velacade: There is a clear need for new treatments for heart failure, as associated mortality and morbidity rates are high. Nearly 5 million Americans and 6.5 million Europeans have heart failure and each year, in the US alone, 550,000 new cases of heart failure are diagnosed and nearly 300,000 deaths are registered. The five-year survival rate for patients with heart failure is only 50%. The late-stage heart failure pipeline is weak in terms of quantity and quality, 81% of products are in Phase I and II of development (see our feature (Chronic and Acute Heart Failure). Today’s featured press release highlights one late stage candidate, Vasogen’s anti-inflammatory, Celacade. The release announces initial results from the 2,414-patient phase III ACCLAIM trial. While the ACCLAIM study did not reach the primary endpoint of significantly reducing the risk of death and cardiovascular hospitalization in the total population, this endpoint was met for the subgroup of 692 patients with New York Heart Association Class II chronic heart failure [Source: Vasogen Release]

Featured Journal Article (from DailyUpdates-Immunology & Inflammatory Disorders): Johnson and Johnson researchers publish on new integrin antagonist for the potential treatment of asthma There is a positive outlook for the respiratory market over the next five years, which will experience a sustained period of growth driven by the expansion of sales in existing classes, the launch of major new products, and the results from several landmark studies. Global asthma/COPD sales should grow to $23 billion by 2014, with inhaled corticosteroid/long-acting bronchodilator combinations set to be the leading class by value in 2014, followed by leukotriene antagonists, and anticholinergics (see our feature on Asthma and COPD). Today’s featured journal article focuses on earlier stages of the asthma pipeline. The study published by Johnson and Johnson researchers describes potent antagonists designed to target alpha(4)beta(1) integrin, a cell surface molecule on eosinophils and neutrophils that induces inflammation in the lung by facilitating cellular infiltration and activation. The lead antagonist was found to be active in two animal models of asthma [Bioorg Med Chem. 2006 Jun 15;14(12):4208-16]

Advances in the treatment of peripheral arterial disease...targeting Schizoaffective Disorder

2006-06-27T08:24:00.000+01:00

Todays Headlines from across the DailyUpdates network (June 26th)

Breaking News (from DailyUpdates-Cardiovascular Disease): DeCODE advance in the treatment of peripheral arterial disease (PAD) In contrast to coronary and cerebral artery disease, peripheral arterial disease (PAD) remains an under-appreciated condition that despite being serious and extremely prevalent is rarely diagnosed and even less frequently treated. Consequently mortality in PAD patients exceeds that in patients with myocardial infarction and stroke; indeed only mortality due to colorectal cancer outweighs that of PAD. In addition since the prevalence of PAD is second only to diabetes the problem of long-term disability and health care costs in these patients is immense. Not only does PAD represent a major unmet clinical problem but its under-treatment translates to a total of $35 billion in unrealized annual US sales of cardiovascular therapeutics (PAD has been the subject of three major reports featured by LeadDisocvery over recent months – click here). Today’s highlighted press release announces the initiation of the Phase II clinical development program for DeCODE’s DG041. DG041 is a selective and potent antagonist of the EP3 receptor for PGE2, identified by deCODE as a target for PAD through the company’s population genetics research [Source: DeCODE Release]

Featured Journal Article (from DailyUpdates-Psychiatric Disorders): Cognitive impairment is regarded as a core deficit of schizophrenia. Prevalent in 60% of the schizophrenia population and responsible for significant psychosocial disability, treatments for this aspect of the condition are required (for an in depth analysis of this condition see Cognitive Impairment in Schizoaffective Disorder - Inevitable or Treatable?). Today’s featured paper adds to the proof of concept for the targeting of alpha7-nicotinic acetylcholine receptors by candidate treatments of cognitive impairment in schizophrenia. Defects in the gene encoding alpha7-nicotinic acetylcholine receptors are thought to underlie the genetic components of schizophrenia, while receptor expression is reduced in the brain of autopsied patients. On the other hand nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with the condition, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. This is supported by a recently published trial (Arch Gen Psychiatry. 2006 Jun;63(6):630-8) and a number of companies have recently published small molecule agonists of the receptor including Mitsubishi (J Med Chem. 2005 Apr 7;48(7):2678-86) and Pfizer (J Pharmacol Exp Ther. 2005 Mar;312(3):1213-22). Cognition is a complex mental process which integrates awareness, perception, reasoning, language, judgment, memory and attention. Today’s study establishes the role of alpha7 receptors in attention deficit aspects of cognitive impairment [Eur Neuropsychopharmacol. 2006 Apr 29]

Further development of Remicade...A novel approach to cancer drug delivery

2006-06-22T16:33:00.000+01:00

Todays Headlines from across the DailyUpdates network (June 22nd, 2006) - currently featuring 60+ selected journal articles, 11 drug development press releases and 10 pharmaceutical jobs

Breaking News (from DailyUpdates-Oncology): Further development of Remicade Psoriasis affects about 1 million Americans. This autoimmune disorder has greatly benefited from the advent of biologics such as Amevive/Raptiva. This CD2 blocking immunomodulator has improved the treatment of the once uncontrollable burning sensation and disfiguration of the skin associated with the disease. In addition to dermatological aspects of the disease, psoriasis is associated with arthritis in 10-30% of patients. TNF blockers such as Remicade are able to reduce joint disease severity by 50% in a large number of patients however there is still room for improved control of this aspect of psoriasis (see our feature Autoimmune Disorders & Transplant Rejection). Remicade (infliximab), a neutralizing anti-TNF monoclonal antibody, was approved in the European Union in September 2004, in combination with methotrexate, for the treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to disease-modifying anti-rheumatic drugs. In May 2005, Centocor announced that the FDA had also approved Remicade, for the reduction in the signs and symptoms of active psoriatic arthritis. Remicade had previously gained approval for the treatment of Crohn's disease, rheumatoid arthritis and ankylosing spondylitis. With sales of Remicade already driving global revenue of close to 2.5 billion in 2005, Centocor have now announced that the FDA has accepted its filing of an sBLA for Remicade for inhibiting the progression of structural damage and improving physical function in patients with active psoriatic arthritis [Source: Centocor Release]

Featured Journal Article (from DailyUpdates-Technology): A novel approach to cancer drug delivery: Drug delivery remains a challenge in management of cancer. Approximately 11 million persons are estimated to be diagnosed with cancer worldwide in 2003 and considerable research is in progress for drug discovery for cancer. Cancer drug delivery is no longer simply wrapping up cancer drugs in a new formulations for different routes of delivery. The focus is on targeted cancer therapy (see our feature Drug Delivery in Cancer - technologies, markets and companies). Today's featured article describes a highly novel approach to drug delivery employing T lymphocytes as carriers to deliver chemotherapy coated nanoparticles to tumors [Int J Pharm. 2006 Mar 27;311(1-2):229-36]