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

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 US . 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

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 US 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

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

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 Nexavar to be used in patients 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

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

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

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

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

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

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

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

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

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):1317-26J 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

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 US and ranks as one of the major causes of nervous-system disability in young adults 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 disturbances in 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

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]