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

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:

• FDA Advisory Committee Unanimously Recommends Approval of Telaprevir for People with Hepatitis C
• VICTRELIS™ (boceprevir) Unanimously Recommended for Approval by FDA Advisory Committee for Treatment of Chronic HCV Genotype 1 Infection

Further reading:

• R&D Trends: Hepatitis C
• Epidemiology: Hepatitis C - Hepatitis C virus will remain a prevalent bloodborne disease in the seven major markets, primarily transmitted through injection drug use

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

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

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

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

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.

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.