Cannabinoids, opioids and pain...new approaches to neurodegeneration

DailyUpdates 31st May: Today's edition of DailyUpdates focuses on a controversial area of neurotransmission: opioids, cannabinoids and their overlap. Our featured press release is from Allon Therapeutics and announces further progress on their novel approach to neurodegenerative disorders. Read on for an overview or visit today's edition of DailyUpdates here

Cannabinoids and opioids - their intereaction in the modulation of pain: Cannabinoid therapeutics have the potential to be used in multiple indications and therefore have blockbuster possibilites (see Cannabinoids - A potential blockbuster market), The activity of the endogenous cannabinoid, arachidonylethanolamide (anandamide) is mediated through its binding to the cannabinoid receptors, CB1 and CB2. The signal subsequent to receptor activation is switched off through its transport into various cells by a specific transporter and then the degradation by the fatty acid amide hydrolase (FAAH). Multiple strategies are currently being investigated in an attempt to modulate cannabinoid activity including receptor ligands; agents that bind to the transporter protein; and inhibitors of FAAH. The latter represent an attractive approach to the treatment of chronic pain condition through the prolongation of the analgesic activity of cannabinoid receptor activation by endogenous cannabinoids. The neuropathic pain market has traditionally been a poorly defined area, with widely varying drug classes prescribed. Gabapentin remains the gold standard treatment to beat in the 5 EU and US neuropathic pain markets, which are estimated at a combined total of $2,543m in 2005, reaching $4,118m in 2007. More recently Lyrica (pregabalin) and Cymbalta (duloxetine) have entered the market as alternatives to gabapentin in the treatment of pain (see Pipeline Insight: Neuropathic Pain - Pipeline Drugs Fail to Nail Neuropathic Pain). Today’s featured report, published by researchers at Johnson & Johnson represents an in depth study of the pharmacology of the FAAH inhibitor, OL135 in pain models and suggests that a major component of its analgesic effect results from the activation of CB2 receptors and opioid pathways.

Allon's broad potential neuroprotective agent passes through phase 1b studies Market analysis shows that products currently used that have a neuroprotective effect had a market value of 5.1 billion in 2005. 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 and further to $24 billion (see our two features World Neurodegeneratives Disease Markets, 2005-2009 and Neuroprotection - Drugs, Markets and Companies). Allon is one company actively involved in the develop,ment of neuroprotectives. The company's platform originated from studies on vasoactive intestinal peptide (VIP) which has been shown to be a broadly acting neuroprotectant. VIP was shown to exert its neuroprotective effects by causing neuroprotective proteins to be secreted from glial cells. Activity-dependent neuroprotective protein (ADNP) and activity-dependent neurotrophic factor (ADNF) were identified as the proteins secreted by glial cells that provide neuroprotection in response to VIP. For ADNP, in addition to its neuroprotective efficacy, it was shown to be critical for brain development. Further research showed that an eight amino acid peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAP), and a nine amino acid peptide, Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (also termed ADNF-9), from ADNP and ADNF respectively, are necessary and sufficient to reconstitute neuroprotective activities. AL-208 is an intravenous formulated eight amino acid neuroprotective peptide based on NAP. AL-208 protects neurons against numerous toxins and cellular stresses including Alzheimer’s disease neurotoxin (B-amyloid peptide), excitotoxicity (N-methyl-D-aspartate), the toxic envelope protein of HIV (gp120), electrical blockade (tetrodotoxin), oxidative stress (hydrogen peroxide), dopamine toxicity, decreased glutathione, and tumor necrosis factor (TNFα)-associated toxicity. AL-208 has neuroprotective activity in a variety of animal models including the learning deficient apolipoprotein E knock-out mice (a model related to AD), mouse paradigms of traumatic head injury (a risk factor for AD), fetal alcohol syndrome (severe oxidative stress), as well as rat models of cholinotoxicity(with cholinergic loss being a whole mark of AD) and stroke (associated with vascular dementia). It is active at unprecedented low concentrations (femtomolar). AL-208 is thought to prevent neuronal cell death by binding to neuron-specific tubulin, subsequently repairing the microtubular network as well as potentially restoring both axonal transport within nerve cells and chemical transmission between them. Allon’s compounds also promote neurite growth, which is dependent on microtubule formation. Today's featured press release from Allon announces data from a phase 1b study of AL-208 demonstrating safety and tolerability.

The problem of catheter infections plus advances in the treatment of colorectal cancer

DailyUpdates 30th May: As the drug discovery sector returns after various public holidays around the world, we too return with another edition of DailyUpdates. Amongst the 60 or so features today, we highlight work at Kane Biotech conducted in an attempt to reduce the major problem of catheter infection, plus news on the development of a liposomal candidate designed to deliver the active metabolite of Camptosar to colorectal cancer tumors. Summaries of this work are provided below - today's edition in its entirety can be accessed here

Attacking biofilms to reduce the problem of catheter infections: Urinary tract infections are the second-most common type of bacterial infection, after those of the respiratory tract, with more than 35 million medically treated infections across the seven major markets each year (2003 figures according to Urinary Tract Infections - Ciprofloxacin Leads the Way). This translated into sales in excess of $1.1billion across key markets. The formation of bacterial biofilms on urinary tract catheters represents one segment of the urinary tract infections market. Biofilms, which contribute to 80% of all human bacterial infections, are matrix-enclosed microbial populations adherent to each other and/or surfaces or interfaces. Biofilms are highly resistant to various anti-infective strategies and biofilm colonies on urinary catheters can be more than 1,000 times more resistant to antibiotics than their planktonic counterparts. Foley catheter infections lead to approximately 900,000 noscomial urinary track infections annually in the US at a cost of $0.65-3.5 billion. In addition to the financial burden, biofilm formation frequently leads to the infection of surrounding tissue and often requires removal of the catheter subjecting the patient to discomfort. Today’s featured study reports on work conducted at Kane Biotech which has led to the development of an antibiofilm composition comprising an N-acetyl-d-glucosamine-1-phosphate acetyltransferase (GlmU) inhibitor and protamine sulfate, a cationic polypeptide. This composition demonstrated antimicrobial efficacy against a range of microbes and represents a licensing opportunity. Since biofilm formation represents a problem which extends past the urinary tract such technology is likely to have wide-ranging relevance in infectious diseases including for example vascular cannula infections, a serious problem in the ICU setting.

Improved treatments of colorectal cancer on the horizon: Drug delivery remains a challenge in management of cancer. One area that is being extensively researched in an attempt to overcome this problem is the development of liposome technology. Liposomes are artificial lipid micelles used to transport active agents to their site of action. Such agents can range from steroids for the treatment of inflammatory disease to cytotoxic agents. One good example of this technology is pegylated liposomal doxorubicin, marketed as Caelyx in the UK and as Doxil in the USA . Liposome delivery affords tumor targeting and reduced toxicity. The administration of poorly soluble chemotherapeutics can also be improved by liposome technology (see Drug Delivery in Cancer - technologies, markets and companies). Today’s featured press release comes from NeoPharm who announce that patient enrollment has commenced in a multi-center Phase II clinical trial of LE-SN38 in the treatment of patients with metastatic colorectal cancer. LE-SN38 is NeoPharm's NeoLipid liposomal formulation of SN-38, the active metabolite of irinotecan (Camptosar). Camptosar is converted into SN-38 in colorectal cancer cells at different rates in different patients, and this variability in conversion rates may result in suboptimal treatment with Camptosar. Although SN-38 is highly active, its poor solubility restricts its direct delivery. Liposomal SN-38 should reduce this limitation and be of considerable benefit in the treatment of colorectal cancer.

DailyUpdates 26th May, 2006: As our daily trip around the drug discovery world continues we hit Friday with some revealing information on sepsis and new phase 3 data on Wyeth's antidepressant desvenlafaxine. Read on for more about these highlight on visit today's edition of DailyUpdates for more on these advances or any of the other 50+ items featured today

Defining the problem 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, relying on a range of interventions. Sepsis is widely regarded as the most challenging problem in intensive care (see Sepsis our new feature for an in depth look at this field). Today’s featured research article focuses on SOAP, a multiple-center, observational study of 198 intensive care units in 24 European countries designed to better define the incidence of sepsis and the characteristics of critically ill patients in European intensive care units. The study identifies the lung as the most common site of infection in patients with sepsis, while Staphylococcus aureus, Pseudomonas species, and Escherichia coli were most commonly the causative pathogen. Patients with sepsis had more severe organ dysfunction, longer intensive care unit and hospital lengths of stay, and higher mortality rate than patients without sepsis.

Phase 3 data on Wyeth's SNRI, desvenlafaxine: Major Depressive Disorder is estimated to affect over 34 million individuals yearly across the seven major markets. Only a fraction of this patient population is treated adequately, resulting in lost productivity, unnecessary patient suffering and unfulfilled revenue potential for manufacturers (see our recent feature Major Depressive Disorder). Most of the leading antidepressants are selective serotonin reuptake inhibitors. In addition the class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now occupies a significant portion the antidepressant market. Lilly’s Cymbalta (duloxetine), launched in the Q3 2004 for the treatment of major depressive disorder and diabetic peripheral neuropathic pain, generated $233.3 million in sales in Q1 2006. This compared to $945 million in sales for Wyeth’s Effexor (venlafaxine) over the same time period. While long-term, head-to-head studies comparing SNRIs with SSRIs are rare, evidence suggests that Effexor is comparable to the SSRIs in terms of remission rates, and venlafaxine may bring patients to remission earlier than SSRIs. Today’s lead news item highlights phase 3 data presented for the first time on desvenlafaxine succinate (DVS-233), a metabolite of Effexor. Overall, the phase 3 data results showed desvenlafaxine succinate significantly improved depressive symptoms in adult patients compared to placebo. An NDA was submitted to the FDA in December 2005.

Advances in autoimmune disease therapeutics

DailyUpdates 25th May, 2006: Today both featured items from DailyUpdates focus on autoimmune disease and remarkably neither are biologics. The first, a press release from Synta announces the advancement of an IL-12/IL-23 inhibitor in development for rheumatoid arthritis and IBD; the second is a review of potassium channels as targets for the treatment of multiple sclerosis. Information on this content as well as all other reports and press releases can be accessed here.

Improving nerve conductance as an approach to multiple sclerosis - targeting the potassium channel: Today’s headline research article also focuses on autoimmunity, this time multiple sclerosis. This inflammatory disease of the central nervous system is characterized by demyelination, with a relative sparing of axons. Patients suffer many neurologic signs and symptoms which have been attributed to the underlying conduction deficits. Today’s headline paper published by Susan Judge and Christopher Bever at the University of Maryland reviews the intriguing concept that restoring the conductance of damaged neurons could improve neurologic function. Two broad-spectrum potassium channel blockers have yielded promising activity in the clinical despite the prevalence of use-limited toxicity. The review will hopefully direct drug development groups towards the more selective targeting of potassium channel subtypes and hence the development of more clinically useful therapeutics.

Targeting the IL-12 family - Synta advances apilimod, STA-5326: Rheumatoid arthritis is a chronic, progressive autoimmune disease that is characterized primarily by inflammatory joint damage producing chronic pain, loss of function and disability. The condition affects approximately 1% of the worldwide population. Given the inflammatory nature of this disease, numerous candidate molecular targets exist. These include T- and B-cell surface molecules - see our recent reports:

Autoimmune Disorders & Transplant Rejection - T-cells Targeted Therapeutics

BAFF & APRIL: Emerging Targets for autoimmune disease

In addition a vast array of inflammatory mediators has also been investigated for candidate targets. In a third report Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates, one area of focus is the IL-12 family. IL-12 is a novel cytokine cloned from B-cell lines and has a broad array of potent biologic activities, acting as the master regulator of the TH1 pathway, which drives major chronic inflammatory diseases, including rheumatoid arthritis. IL-12 deficient mice develop experimental disease with reduced frequency and severity. Cambridge Antibody Technology have developed a human anti-IL-12 monoclonal, ABT-874 which was licensed out to Abbott and is currently is in Phase II studies for autoimmune diseases, including psoriasis and multiple sclerosis. Today’s headline news item highlights data from Synta Pharmaceuticals who are also targeting IL-12. In this case however the candidate, apilimod mesylate (STA-5326) is an orally active molecule that inhibits the transcription of IL-12 as well as IL-23, two cytokine which are related through the sharing of a common p40 subunit and binding to IL12 receptor beta-1. The release announces that two separate Phase 2a clinical studies have been initiated, one in patients with rheumatoid arthritis and another in those with a second autoimmune disease, common variable immunodeficiency (CVID). Apilimod mesylate is currently in a large multinational Phase 2b trial for Crohn’s disease.

Improved detection of the influenza virus...New candidate for the treatment of Chronic Lymphocytic Leukemia enters the clinic:

DailyUpdates 24th May, 2006: With the threat of influenza hanging over our heads on a seemingly continuous basis, improving the ability to rapidly and accurately identify patients infected with influenza and furthermore the strain of virus remains paramount. Today we feature research from CombiMatrix concerning their activities in this area. We also headline news coming out of Denmark's Genmab announcing the advance of HuMax-CD20, the company's CD20 monoclonal, into the clinic for the treatment of Chronic Lymphocytic Leukemia. Access to these two articles plus a full listing of all of today's featured items can be made here

Improved detection of the influenza virus: The influenza virus continues to pose a significant public health problem. Vaccines represent the primary foil against this infectious disease with annual sales predicted to rise to $3.7 billion by 2010 (for a detailed analysis of this market see our featured report: Influenza Vaccines). Despite the use of vaccines, influenza still infects 10-20% of the global population every year causing up to 500,000 deaths. Improved therapeutics for the treatment of at risk infected individuals is thus required, however for optimal treatment, more rapid and accurate subtype identification is required. Ideally new point of care diagnostic tools are required to facilitate rapid treatment either in a primary care setting or at remote locations (for an analysis of POC tools see Point Of Care Diagnostic Testing World Markets). Today’s featured report presents data on CombiMatrix’s semiconductor-based DNA chip technology. The technology is based on a semiconductor adapted for biological applications and is comprised of multiple chambers, each of which is able to synthesis in situ and under the control of a PC, a specific reagent. In the case of the influenza diagnostics the reagents are oligonucleotides synthesized to react with the viral genome. This allows rapid detection and accurate typing of flu strains; the system is able to recognize hemagglutinin subtypes 1 through 15 and neuraminidase subtypes 1 through 9. This system is currently available as an R&D tool or as a service from CombiMatrix. Further development is expected to lead to the availability of a field deployable biodetector. Also described in today’s feature is the adaptation of the technology to facilitate enzymatic assay that can be used for sequencing, thereby facilitating the detection of novel strains of influenza.

New candidate for the treatment of Chronic Lymphocytic Leukemia enters the clinic: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults in the US and most of Western Europe . The incidence is 8,100 to 12,500 new cases in the US per year and 85-95% of the cases are of B-cell origin. CLL is a subgroup of non-Hodgkin’s lymphoma (NHL) and together with small lymphocytic lymphoma (SLL) corresponds to around 20% of all NHL cases. Prolonging disease-free survival in chronic leukemia relies on the eradication of minimal residual disease and the treatment of refractory disease driving the development of novel pharmacotherapy (see Chronic Leukemias - Curative Intent Raises the Bar). First line treatment of CLL generally involves the use of nucleoside analogs and especially fludarabine which produce overall responses in as many as 80% of patients and complete remission in 37%. Therapy with monoclonal antibodies has been evaluated in patients with CLL and the most useful agent in clinical trials so far appears to be CAMPATH-1H (alemtuzumab), an antibody directed at CD52. The goal for developers of novel CLL pharmacotherapy is to innovate drug treatments that can salvage patients refractory to CAMPATH-1H. Today’s headline press release concerns the development of one such agent, Genmab’s HuMax-CD20 (ofatumumab). The company announce the start of a Phase III pivotal study of approximately 100 CLL patients who have failed treatment with fludarabine and CAMPATH-1H or who have failed fludarabine and are intolerant to or ineligible for alemtuzumab.

Benazepril offers hope to patients with advance renal disease

DailyUpdates 19th May, 2006: Today's edition of DailyUpdates (see it in full here) carries a couple of important articles on renal disease. One loks at the outcome of patients with renal dysfunction across various acute coronary syndromes. The featured article however demonstrates the efficacy of Novartis' Benazepril in treating advanced renal disease

Benazepril offers hope to patients with advance renal disease - Angiotensin-converting-enzyme (ACE) inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency. More advanced disease continues to present a major problem however. Increased prevalence of diabetes, obesity, and cardiovascular disease, all causal factors of renal disease, drives growth of the end-stage renal disease (ESRD) sector. On average, an ESRD patient uses >$7,000 of drugs/year, representing a significant opportunity for pharmaceutical companies in treating the symptoms, comorbid conditions and treatment side effects of ESRD (see Drug Treatment in End-Stage Renal Disease). Today's featured study from Novartis is important since it establishes the ACE inhibitor, benazepril as an effective treatment of more advanced renal insufficiency. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Only 41% of benazepril-treated patients with the most advanced renal insufficiency reached this end-point as compared to 60% of patients receiving placebo. This benefit did not appear to be attributable to blood-pressure control.

Battle of the Antidepressants

DailyUpdates 18th May, 2006: As the antidepressant sector continues to go through a period of turbulance we report on new data for one blockbuster from this class - Lexapro. Selected for special mention from over 50 journal articles today's feature demonstrates great timing appearing at the same time as our feature - Major Depressive Disorder. Today's edition of DailyUpdates can be seen here

Comparative efficacy of Escitalopram (Lexapro) in an increasingly dynamic and turbulent market - Major Depressive Disorder is estimated to affect over 34 million individuals yearly across the seven major markets. Only a fraction of this patient population is treated adequately, resulting in lost productivity, unnecessary patient suffering and unfulfilled revenue potential for manufacturers. Despite this in 2004 total world revenues for branded antidepressant drugs was worth over $13bn, but with only ten drugs on the market. Escitalopram (Lexapro) is the most selective of the selective serotonin reuptake inhibitor (SSRI) antidepressants (for an analysis of current treatments and prescribing trends, see our 2006 feature Major Depressive Disorder). Previous studies have suggested that escitalopram is superior to citalopram (Celexa) in efficacy. Forest Laboratories markets both of these agents in the US generating $1.9 billion and $0.2 billion respectively. Today's featured journal article presents a meta-analysis of studies in which escitalopram was compared with other antidepressants to assess the relative efficacy of these agents. In this meta-analysis, escitalopram showed significant superiority in efficacy compared with the active controls. During the period 2006-2010 nine out of these ten drugs faces a loss of patent; Lexapro's patent expires in 2009 with a possible extension to 2012. As the appearance of generics gradually increases clinicians will have to see Lexapro as being more effective in order for this therapeutic to resist competion from cheaper alternatives and today's feature meta analysis is important in this context. For an in depth look at the future of the antidepressant arena see The World Market for Antidepressants 2006

Ether a go-go potassium channels and cancer

DailyUpdates 17th May, 2006: As more and more molecular targets emerge that may present opportunities for future oncology therapeutics we highlight one one promising target, the ether-a-go-go potassium channel. Today's edition of DailyUpdates can be seen in its entirety here

Ether a go-go potassium channels and cancer: A number of classes of voltage activated potassium currents (Kv) have been distinguished including transient outward K⁺ currents (I_to) and delayed, outwardly rectifying K⁺ currents (I_K). The latter include rapidly inactivating I_Kr currents carried by hERG and non-inactivating currents carried by Eag1. While the former play a major role in in cardiac (patho)physiology, the latter is emerging as a major player in cancer. Importantly eag is recognized in over 80% of human tumors and this channel is now accepted as a key contributor to cancer progression. In particular eag is though to contribute to the control of cell proliferation, especially in leukaemias; the regulation of tumor cell invasiveness, possible through a physical and functional interaction with adhesion receptors of the integrin family; and the control of tumor cell neoangiogensis, through the modulation of angiogenic factor secretion. Today’s featured article offers an up to date review of this exciting target for cancer therapeutics

Cancer Research: For the rest of this week, instead of featuring press releases on industry's efforts to fight disease we would like to highlight one individual's role in helping to support research into cancer. Releases will still be listed in the news area of DailyUpdates. On Sunday May 21st our colleague Eileen Lewis will be running the Race for Life. This fundraising event organized by Cancer Research UK is dedicated to conquering cancer through world-class research. It is the UK's leading cancer charity, with a dedicated team of 3,000 scientists and an annual scientific spend of around £213 million. Its funds are raised almost entirely through voluntary donations. Sunday's event will attract 4,000 runners each raising sponsorship to support the fight against cancer. Please help us to support Eileen's efforts sponsoring her and leaving your messages of encouragement here at the Race for Life's website. Together we can help discover new therapies but for the rest of this week let's try and help support the research behind these advances.

VEGF: Same molecular target....new approaches to cancer

DailyUpdates 15th May, 2006: Amongst the 50 or so papers and press releases featured today two focusing on VEGF jump out as being of especial interest. The first, a paper published by Stanford University, reports on the anti-cancer activity of an oncolytic virus in combination with gene therapy. The virus was engineered to selectively replicate in and kill cancer cells . The gene therapy encoded a soluble version of Flk1, one of the VEGF receptors. The two approaches together produce effective anticancer activity and prompt the development of a single treatrment comprised of the virus further engineeered to produce soluble Flk1. The second publication is a press release from PTC Therapeutics who are similarly targeting VEGF, but instead have developed a small molecule orally active candidate able to prevent the prost-transcriptional activation of VEGF. Further details on these two publication plus the rest of today's information can be accessed here.

Oncolytic viruses and soluble VEGF receptor gene therapy combines to produce a highly novel and potentially effective approach to cancer: VEGF exists in multiple isoforms. The original VEGF, now denoted VEGF-A, is regulated under the hypoxic conditions found within tumors, and binds to VEGFR-1 as well as -2. VEGFR-2 (also know as Flk1) is expressed on endothelial cells and its activation plays a pivotal role in endothelial cell differentiation and the formation of new vessels in adulthood. Despite the therapeutic success of Avastin as a strategy for limiting tumor neovascularization and growth (see Innovative Cancer Therapies: Targeted therapy, a clinical and commercial revolution), as a class, the clinical efficacy of angiogenesis inhibitors has been rather limited. One of the potential problems of this approach is that VEGF is known to play a role in wound healing and also has a number of effects on cardiovascular homeostasis. The inhibition of such effects is likely to contribute to the gastrointestinal perforation and wound dehiscence (wound rupture) and hemoptysis (blood in the sputum) observed in some patients treated with Avastin and represent a class-related risk. Thus targeting Flk1 blockers to the tumor environment represents a promising approach. Today's featured journal article reports on data from Stanford demonstrating a novel approach to this challenge using oncolytic viruses (see Developments in oncolytic viruses - An emerging approach to cancer therapeutics). The Stanford group has found that an oncolytic virus engineered to selectively replicate in cancer cells lacking the G(1)-S cell cycle checkpoint enhanced the expression of an adenovirus encoding soluble Flk1 in tumors. These most exciting data, which underlies a licensing opportunity (contact Dr Steve Thorne for details), suggest a possible dual approach to the treatment of cancer whereby tumors may be destroyed both directly by the virus and indirectly through the interruption of their blood supply by interrupting VEGF signaling. Of even greater potential would be the development of a variant of the oncolytic virus engineered to encode soluble Flk1. The ability of such a virus to selectively replicate in, express soluble VEGF receptor and kill tumors would represent a truly targeted and hopefully efficacious approach.

PTC Therapeutics advance PTC299, a small molecule inhibitor of VEGF post-transcriptional modification: While oncology therapies currently in development lean heavily on biologic approaches, the ability to avoid the drug delivery challenges associated with antibodies, antisense, gene therapy, or RNAi offers significant advantages. PTC Therapeutics are one company addressing this issue - the company's pipeline is focused on small orally active molecules that are able to selectively block the expression of target proteins. Continuing today's theme PTC have recently announced that it has commenced a Phase 1a clinical trial of PTC299. This candidate is an orally administered small-molecule compound designed to inhibit the production of VEGF in tumors; specifically the post-transcriptional control processes that regulate VEGF formation.

Movement in cancer vaccine development plus breaking antidepressant research

DailyUpdates 12th May, 2006 (click here for entire bulletin): Today appears to be cancer vaccine day with two important announements being made. First off, Genitope Corporation announce the initiation of an ealry phase clinical trial of their MyVax idiotype immunotherapy; this was followed by an announcement by Biovest reporting that fast track status had been awarded to their phase 3 candidate, BiovaxID. This follows in the footsteps of the company's announcement that the FDA had approved sale of AutovaxID, enabling technology that should facilitate the use of candidates such as BiovaxID. In addition we highlight a study that will hopefully speed the development of novel antidepressants.

Study opens the way for rapid identification of MAO-A inhibitors as candidate antidepressants: With the global antidepressant market valued at $16.6 billion in 2002, drugs for the treatment of depression have historically provided huge returns on investment. However, several of the leading brands are expecting patent expiries over the next five years (see The World Market for Antidepressants 2006). New strategies are needed to prevent a decline in the antidepressant market. Somerset Pharmaceuticals have adopted a novel strategy having recently (Feb 2006) won the FDA approval of EMSAM, a patch formulation of Selegiline. This monoamine oxidase (MAO) inhibitor was initially approved in capsule form for use in Parkinson's Disease. The once a day patch works by delivering selegiline through the skin. The pharmacokinetic advantage of this mode of administration reduces the risk of hypertensive crisis experienced with currently employed oral irreversible MAO inhibitors due to the inhibition of MAO-A mediated tyramine catabolism. An alternative to improving the pharmacokinetics of irreversible inhibitors is the development of reversible ones. These agents are displaced from the MAO active site by tyramine thereby minimizing the risk of hypertension. Today’s featured study reports on the use of in silico modeling to predict MAO-A inhibitors. The findings were validate using an in vitro assay and it is hoped that this study can now be exploited to rapidly identify candidate antidepressants.

Biovest announce fast track status of cancer vaccine: Given an enhanced understanding of the biological basis for oncogenesis and the benefit of immunotherapy approaches such as Genentech/Roche's Rituxan, it is no surprise that targeted treatments and immunotherapy dominate the pipeline of emerging treatments for hematological malignancy (see Pipeline Insight: Hematological malignancies). Cancer vaccines represent a major class designed to complement current treatment approaches, rather than serve as a replacement. The majority of the cancer vaccine pipeline constitutes off-the-shelf vaccines rather than personalized or cell-based formulations. Although the former are capable of mass manufacture, the latter have shown greater clinical benefit, but encompass a more complex and expensive formulation. It is unclear which class will reach the market first (see Cancer Vaccines and Cell Therapies). Yesterday's announcement by Biovest may help to decide who will win the race. In their press release Biovest reported that they have been granted Fast Track status for BiovaxID, the Company's personalized biologic therapeutic for follicular non-Hodgkin's lymphoma. The targeted anti-cancer immunotherapy, now undergoing pivotal Phase 3 clinical trials at over 20 major medical centers throughout the US, showed extremely positive Phase 2 results (click here for data). This announcement should be read in the context of another release from Biovest highlighted yesterday reporting that the FDA had approved the sale of AutovaxID, the first and only instrument to enable the cost-effective and scalable production of cells or cell-derived products for personalized medicine applications.(click here).

Post-partum depression...emerging HIV treatments and more

DailyUpdates May 11th, 2006: Of the 50 or so breaking articles and drug development press releases featured on today's issue of DailyUpdates (see the entire edition here) we feature data looking at postpartum depression. This condition affects up to 10% of mother. The data suggest that breast feeding reduces the risk of developing depression. If this condition does develop, therapeutic intervention is possible, however it is advised that mothers should switch to formula feeding. This paradoxically situation could conceivably be prevented through the use of antidepressants less likely to appear in breast milk. We suggest that a study be performed comparing this route of elimination for the various agents in use. In addition we feature news on a new candidate HIV treatment.

Postpartum depression - identifying risk factors to optimize prevention, detection and treatment: According to our recent feature The World Market for Antidepressants 2006, in 2004 total world revenues for branded antidepressant drugs was worth over $13bn, but with only ten drugs on the market. However, nine out of these ten drugs faces a loss of patent in the period 2006-2010. The world market is predicted to crash to $7bn by 2010 with a loss of almost 50% of total revenues. The world antidepressants market is therefore in serious trouble. Since the pipeline is lackluster emerging antidepressants stand to benefit from large gains. Equally identifying and treating patients who are not currently benefiting from effective treatment of depression will not only meet underserved clinical needs, it will also help to maintain revenues in this market. One underserved market is postpartum depression. Whilst up to 70% of new mother experience the baby blues, symptoms usually go away within 10 days after delivery. However, some women have more debilitating symptoms or symptoms last longer. This condition, postpartum depression, affects approximately 10% of new mothers and since over 4 million births are recorded per year in the US alone this translates to a large population, potential up to 3% of all individuals suffering from depression. Generally a combination of psychotherapy and medication can reduce these symptoms however predicting at risk women is important in order to optimize early diagnosis and hence treatment. Today's featured journal article identifies risk factors for postpartum depression which include formula feeding in place of breastfeeding, a history of depression, and cigarette smoking. Given these risk factors, prophylactic treatment may represent a challenge and encouraging women to breast feed may represent the simplest strategy. Paradoxically however use of antidepressants may require women to stop breast feeding. This may offer opportunities to the pharmaceutical sector as those antidepressants with the lowest distribution in breast milk may offer significant advantages.

Incyte advance new candidate HIV treatment into the clinic: In the current antiretroviral landscape, resistance in all three of the established classes is proving to be problematic. Accordingly, the emergence of the entry inhibitor class is expected to change the market place. According to our recent feature Pipeline Insight: HIV Therapeutic the CCR5 antagonists are expected to account for at least14% of sales. This figure assumes such agents to be used in salvage therapy and could rise to over 25% if they are to be used first-line. Thus there is expected to be considerable competition between the various CCR5 antagonists. Today's feature press release comes from Incyte who announce the start of a Phase I clinical trial of their antagonist, INCB9471. A Phase IIa trial involving HIV patients is scheduled to initiate later this year.

Acetaminophen - the future of multiple sclerosis & Parkinson's disease therapy?

DailyUpdates May 5th, 2006: The pick of oday's edition of DailyUpdates (see it in full here) provides data to suggest that the long sought after mechanism to explain the analgesic properties of acetaminophen may involve the cannabinoid pathway. But, could these data open up the utility of a therapeutic agent in existence for over 100 years to include the treatment of neurodegenerative disorders such as multiple sclerosis and Parkinson's disease?

Acetaminophen: A new mechanism of action involving the cannabinoid pathway may widen its utility to neurodegenerative disorders? The market for over the counter pain medications is massive (see for example The US Market for OTC Pain Medication). Acetaminophen, commonly referred to by its brand names Tylenol and Paracetamol, is often the first drug used for control of mild to moderate pain especially when aspirin is contraindicated. Although acetaminophen has been used as an analgesic for well over 100 years its mechanism of action is unclear. Today's featured article reports data using the hot plate assay suggesting that the analgesic effect of paracetamol is prevented by cannabinoid CB1 receptor antagonism. This study suggests that acetaminophen somehow activates the cannabinoid pathway and this is consistent with a second recent study (Hoggestat et al, 2005) reporting that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the N-arachidonoylphenolamine (AM404). This molecule in turn is well known as an endocannabinoid reuptake inhibitor; in other words acetaminophen may exert analgesic effects through the amplification of endogenous cannabioid pathways. Considering the blockbuster potential and multiple indications of cannabinoid therapeutics (see Cannabinoids - A potential blockbuster market), based on these two studies the benefit of paracetamol or molecules modelled on its chemical structure may extend past one of analgesia. Of note CB1 receptor activation may be of interest for the treatment of multiple sclerosis or Parkinson's disease. Since acetaminophen appears to be converted to AM404 in the brain an intriguing possibility arises that paracetamol may increase CB1 receptor activation by preventing cannabinoid metabolism in a highly selective fashion in the brain circumventing problems associated with nonselective cannabinoid receptor activation in the periphery. Could acetaminophen or its analogues represent a new approach to neurodegenerative disorders? Feel free to post your comments on our Drug Discovery Forum

Breaking News - Neurobiological Technologies's stroke treatment, Viprinex, moves closer to the market : Stroke is one of the top three causes of death and incidence is expected to increase in the next ten years. Long term disability caused by stroke is a major economic burden on healthcare systems, current treatment options are limited and general awareness of stroke is poor. Therefore the opportunity for new drugs is huge and lucrative for companies willing to invest in increasing awareness (for a full evaluation of this field see our feature Acute Stroke) One company highly involved in this arena is Neurobiological Technologies who have just announced the initiation of its second Phase III study of Viprinex (Ancrod) in patients with acute ischemic stroke. Clinical data suggest that Viprinex is a powerful defibrinogenating agent causing enhanced blood flow, a fibrinolytic agent, as well as an anticoagulant helping to limit stroke extension.

From pancreatic cancer to the prevention of heart attack

DailyUpdates from May 4th, 2006: Today we headline with breaking research describing a candidate therapeutic that is able to reduce the drug resistance of pancreatic cancer. In addition we feature news from Icelandic company deCODE Genetics who are moving ahead with the development of a FLAP inhibitor that reduced LTB4 production with the intention of reducing the risk of heart attack. The FDA has now given the green light to commence phase III testing of this promising compound. As usual readers are invited to access today's edition of DailyUpdates in its entirity here

Breaking the resistance of pancreatic cancer to chemotherapy: Failure of cancer chemotherapy is largely caused by multidrug resistance in tumor cells, mediated by ABC transporters that pump many cytostatics out from the cells. This family includes the mammalian P-glycoprotein (MDR1) family and the multidrug resistance-associated protein (MRP). Pancreatic adenocarcinoma is the fifth leading cancer-related cause of death despite its relatively low prevalence, a factor related to its aggressive nature and resistance (see Pancreatic Cancer - Gold Standard Gemcitabine Waiting to be Challenged). Inhibition of the activity of P-glycoprotein efflux pumps offers considerable hope for the treatment of cancer and particularly those that are most highly susceptible to drug resistance. Today's featured journal article presents data on the disiloxanes, synthetic resistance modifiers that suppress not only the multidrug resistance gene but also MRP in various cancer cell lines. The featured study demonstrates that among these compounds, the organosilicon molecule SILA-409 delays tumor growth in a pancreatic cancer xenograft model. This was associated with a reduction in P-glycoprotein expression and an increase in apoptosis. It should be noted that this activity was in the absence of exogenous chemotherapeutics and further studies looking at the combination of such agents with SILA-409 are eagerly awaited.

deCODE advance FLAP inhibitor DG031 towards phase III as an antiinflammatory aimed at reducing myocardial infarction: Cardiovascular disease has been the leading therapeutic category for over two decades and is set to continue its pace of expansion and dominance over the global drugs market. The cardiovascular market has expanded from a value of $60 billion in 1997 to $351.8 billion in 2003. With new drugs in the pipeline, competition in the cardiovascular market has never been greater (see The Cardiovascular Report). deCODE genetics is one company in this arena and yesterday they announced that it has reached an agreement with the FDA on the design of its Phase III clinical trial for DG031, deCODE’s lead developmental compound for the prevention of heart attack. deCODE have previously shown that variants of two genes regulating LTB4 production contribute to risk of heart attack through an increase in plaque inflammation and instability. deCODE thus in-licensed DG031 from Bayer, an inhibitor of the 5-lipoxygenase activating protein, or FLAP. This protein is important for LTB4 synthesis.

Improving hypertension control...An emerging approach to metastasis

Today' s edition of DailyUpdates features over 40 breaking journal articles and drug development news items across multiple therapeutic area. We have selected two, one describing advances that should lead to better control of hypertension, and another announcing the advance of a promising oncology candidate that appears to block metastasis. To view today's edition of DailyUpdates please click here, or alternatively read on for more on our selected items

Featured Journal Article (from DailyUpdates - Cardiovascular Disease) - Predictors of adverse outcome among patients with hypertension and coronary artery disease: LeadDiscovery's recent feature Hypertension markets and therapeutics estimates that there are currently 192m people with hypertension in the seven major markets, and this number is set to rise to 212m by 2015. Yet, a significant fraction of this sizeable patient pool remains undiagnosed or aborts treatment. Optimizing the use of antihypertensives thus remains a clinical objective. This is likely to involve the treatment of a higher proportion of patients with hypertension and also the optimization of treatment choice in individuals. The latter will hopefully improve the befit:risk/adverse effect relationship and in turn improve adherence and safety. Today's featured journal article (J Am Coll Cardiol. 2006 Feb 7;47(3):547-51) reports on predictors for adverse outcomes in hypertensive patients with coronary artery disease. This study is of considerable importance, not least due to the large numbers of patients with both conditions.

Breaking News (from DailyUpdates-Oncology): Candidate treatment of metastasis advances through the clinic: Metastasis is a major cause of morbidity and mortality in human malignancies. Sites of metastasis vary according to the primary tumor however vital organs including the brain, liver and lungs as well as bone are commonly affected. Preventing metastasis currently depends on the reduction of the number of cancerous cells to a level that can be regulated by the body's defense system. The development of therapeutics that actively target the metastatic process is therefore crucial. Chemokine Therapeutics are amongst the leaders in this field and today they announce (see release) that it has started patient dosing in a phase Ib/II clinical trial using CTCE-9908. The trial will involve up to 30 patients with late stage cancers to evaluate safety and preliminary efficacy. CTCE-9908 blocks the binding of SDF-1 to CXCR4 and in preclinical studies CTCE-9908 has been shown to reduce cancer metastases by 50-70% and to have demonstrated early evidence of potential anti-angiogenic properties. The development of CTCE-9908 raises a few interesting question such as do metastases metastasize and would candidates targeted against metastasis be expected to demonstrate efficacy in patients who already have metastatic disease?