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

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

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

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 The first atypical antipsychotic medication, clozapine, has been replaced by agents with a more favorable side effect profile such as olanzapine, risperidone, and quetiapine, and more recently ziprasidone and aripiprazole.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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

More good news for Avastin...PKC theta as a target for autoimmune disease

Todays Headlines from across the DailyUpdates network (for full bulletin click here)

• Breaking News (from DailyUpdates-Oncology): More good news for Avastin VEGF, a key angiogenic growth factor was discovered by Genentech researchers in 1989 and led to the development of the humanized anti-VEGF antibody, Avastin, beginning in 1997 and in 2004 the FDA first approved Avastin as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. Broader development of Avastin is being aggressively pursued and Phase III clinical trials are now underway for its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers. Earlier this year Genentech also submitted sBLAs for Avastin plus chemotherapy for first-line treatment of advanced non-small cell lung cancer and breast cancer. Today's featured news item announces announced today that the U.S. Food and Drug Administration (FDA)FDA approval of Avastin in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy for second-line metastatic colorectal cancer. The approval is based on Phase III data from patients who had received previous treatment with irinotecan and 5-FU as initial therapy for metastatic disease or as adjuvant therapy. The study showed that patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 percent reduction in the risk of death, the primary endpoint, which is equivalent to a 33 percent improvement in overall survival, compared to patients who received FOLFOX4 alone. The global cancer market is poised for ongoing expansion with sales set to exceed $60bn by 2010. The emergence of novel molecular-targeted treatments will drive a significant proportion of R&D activity and future sales growth in this sector (Optimizing Targeted Treatment in Cancer). Avastin is one of the most successful molecular-targeted treatments with Q1 2006 sales standing at $0.4 billion, double those in Q1 2005; its most recent approval spells good news not only for Genentech, but also for the oncology arena in general [Source: Genentech Release]

Featured Journal Article (from DailyUpdates-Neurodegenerative Diseases): PKC theta as a target for autoimmune disease: As expected on June 5^th (2006) the FDA recommended reintroduction of the multiple sclerosis therapy, Tysabri back onto the market. The recommendation however restricted Tysabri’s use to patients who have not responded well or cannot tolerate other therapies. Furthermore the recommendations prevent combinations of Tysabri with other multiple sclerosis. These conditions are due in part to the occurrence of multifocal leukoencephalopathy (PML) in some patients receiving Tysabri, an adverse effect that forced Tysabri’s earlier market withdrawal. Today’s edition of DailyUpdates features two important studies relating to this area. In the first [N Engl J Med. 2006 Mar 2;354(9):924-33], researchers from the Institute of Neurology in London publish further information on the incidence of PML. In alignment with Elan/Biogen-IDEC’s announcements, of 3417 patients who had recently received Tysabri while participating in clinical trials, only the three previously reported cases of PML were confirmed. Despite these reassurances analysts still believe the market for Tysabri to fall short of initial expectations thus providing further drivers for the development of novel approaches to the disease. The second paper featured today reports data supporting the targeting of protein kinase C theta (PKC theta) serine/threonine kinase as an approach to multiple sclerosis [J Immunol. 2006 Mar 1;176(5):2872-9]. As discussed in depth in our recent target evaluation report, Potential of T-cells Targeted Therapeutics, numerous T-cell targets represent candidate approaches to multiple sclerosis and one such target is PKC theta. This isoform has been implicated in signaling of T cell activation, proliferation, and cytokine production. Today’s featured study from Lilly reports that PKC theta-deficient mice were completely resistant to the development of clinical experimental autoimmune encephalomyelitis compared with wild-type control mice. This was related to a reduction in IL-17 and LFA-1 expression. This study should prompt the development of PKC theta inhibitors and in this respect it is of note that the crystal structure of the enzyme’s catalytic site has recently been solved [J Biol Chem.2004 Nov 26;279(48):50401-9]

ArQule moves forward with their cell cycle modulator...Wyeth develops selective GABA(A) alpha2/alpha3 subtype agonists as candidate anxiolytics

Todays Headlines from across the DailyUpdates network (20th June, 2006): We highlight research from Merck who are developing a novel approach to anxiety and news from ArQule on their oncology candidate - to view today's bulletin in its entirety click here or read on for further information on these two publications

• Breaking News (from DailyUpdates-Oncology): ArQule moves forward with their cell cycle modulator The cell cycle and check-points within the cycle represent a major focus of drug development companies attempting to introduce new cancer therapeutics. One group of molecular targets under investigation is the aurora kinase family (see LeadDiscovery's recent feature Aurora Kinase inhibitors - The dawn of a new approach to cancer). In addition, over the past few weeks we have highlighted work by ArQule who are targeting E2F1 in an attempt to regulate cell cycle checkpoints. At the begining of April (2006) we highlighted a company release reporting Phase 1 monotherapy data demonstrating efficacy in cancer patients with advanced solid tumors who had failed prior treatments with chemotherapy. Today we headline with a further release from the company announcing the enrollment and successful dosing of the first patient in a Phase 2 clinical trial of ARQ 501 in combination with gemcitabine to treat pancreatic cancer. Pancreatic cancer is the fifth leading cancer-related cause of death and is thus a major health issue in the developed world. Its aggressive nature and resistance to conventional therapy results in an exceedingly poor prognosis. For the foreseeable future, gemcitabine will remain the gold-standard treatment for pancreatic cancer and retain its status as market leader. Despite an active late-phase pipeline, no agent is seriously threatening gemcitabine's position (see our feature Pancreatic Cancer - Gold Standard Gemcitabine Waiting to be Challenged). Commercial potential will be increased if benefit is demonstrated in combination with gemcitabine and it is hoped that the trial announced today will move some way towards this goal.[Source: ArQule Release]

Featured Journal Article (from DailyUpdates-Psychiatric Disorders): Wyeth develops selective GABA(A) alpha2/alpha3 subtype agonists as candidate anxiolytics: The global anxiety disorders market is set to decline from $4.5 billion in 2006 to $2.6 billion by 2015 (Anxiety Disorders - A decade of declining revenues). This will be primarily due to the launch of numerous generic anxiety drugs from 2006 onwards, which will offset the revenue growth derived from existing drugs seeking additional anxiety indications, and the launch of several novel anxiety drugs. Novel anxiety drugs expected to be launched after 2006 include Predix's 5-HT1A agonist PRX-00023. In addition to serotonin receptor ligands, benzodiazepine binding-site agonists, exemplified by diazepam, have proven anxiolytic efficacy. This class is however disadvantaged by adverse effects including sedation, physical dependence and a potential for abuse. It is now known that the alpha2- and/or alpha3 subunits of the GABA(A) receptor mediates the anxiolytic activity of benzodiazepines whereas the alpha1 subtype is involved in sedation, prompting the development of selective alpha2- and/or alpha3-receptor agonists. Today’s featured journal article reports on studies conducted by Merck researchers culminating in the development of a series of GABA(A) alpha2/alpha3 subtype selective agonists. These anxiolytic agents with reduced sedative/ataxic potential display good CNS penetration and oral bioavailability thus representing clinical candidates [Source: J Med Chem. 2006 Apr 20;49(8):2600-10]

Micromet develops new lymphoma therapeutic...KD-247, a promising HIV-neutralizing antibody

Todays Headlines from across the DailyUpdates network (19th June - 2006): Today we feature over 60 breaking journal articles including our featured study discussing the development of a new antibody being developed for HIV-1. In addition we highlight news from Micromet on their antibody therapy for the treatment of NHL plus today's featured jobs. To see the entire bulletin click here

• Breaking News (from DailyUpdates-Cancer Immunotherapy): Micromet develops new lymphoma therapeutic Lymphoma is the fifth most common cancer in the US and represents over forty subtypes of cancers arising within the lymphatic system. The two most prevalent types are Hodgkin's and Non-Hodgkin's (NHL) lymphomas. Of the 63,700 estimated new cases of lymphoma in 2005, NHL accounts for about 88% of those cases making it the most common hematological cancer. Disease can be divided into indolent and aggressive forms. Although numerous and quite effective treatments are available to NHL patients, relapses are frequently seen and hence further options are required. In today’s featured press release Micromet announce preliminary data from an ongoing phase 1 trial on MT103 (also known as MEDI-538), a recombinant single-chain bispecific antibody targeting the CD19 antigen. Three out of five patients with relapsed disease showed clinical responses suggesting that this agent may be a valuable addition to the NHL therapeutic arsenal [Source: Micromet Release]

Featured Journal Article (from DailyUpdates-Infectious Diseases): KD-247, a promising HIV-neutralizing antibody: Despite the success of antiretroviral (HAART) therapy in reducing AIDS related mortality in the developed world, it is becoming clear that to achieve the same impact in poorer countries an additional healthcare interventions such as vaccines or the use of antibody therapeutics will be necessary. Japanese researchers have developed the humanized monoclonal antibody, KD-247 which recognizes the V3 tip sequence of HIV-1 clade B primary isolates, the most common form of HIV-1 in the Americas and Europe . Today’s headline study reports that this antibody both neutralizes clade B HIV-1 and protects monkeys from infection and therefore offers considerable promise. [Source: J Virol. 2006 Jun;80(11):5563-70.]

CD40:CD40L as a target for Alzheimers...A new candidate oncology therapeutic to enter the clinic

Todays Headlines from across the DailyUpdates network. In today's edition (see it in full) we report on CD40:CD40L. Traditionally a target for autoimmune/transplant therapeutics, we highlight a study supporting the development of blockers of CD40:CD40L as candidate treatments of Alzheimer's disease. We also highlight a new oncology candidate in development by Lorus

• Breaking News (from DailyUpdates-Oncology): Locus Pharmaceuticals about to enter the clinic with novel cell cycle regulator Cell cycle inhibitors represent a key approach to the treatment of cancer. Therapeutic agents have traditionally targeted early stages of the cell cycle (ie the G1/S phase checkpoint or the S phase) or mitotic spindle formation as exemplified by the alkaloids. Recently drug development activity has started to focus on later stages of the cell cycle from the G2/M check point all the way through to the mitotic checkpoint and late mitosis. We recently evaluated one molecular target which shows great promise as a target for therapeutic agents able to modify later stages of the cells cycle, the aurora kinase family (see Aurora Kinase inhibitors - The dawn of a new approach to cancer). Here we feature news from Locus Pharmaceuticals who have been targeting tubulin as a strategy for blocking the cell cycle. Tubulin has been well recognized as a target for the taxanes. Locus’ candidate, LP-261, which will hopefully soon be moving into the clinic interacts with tubulin at a unique binding site. Unlike the taxanes, LP-261 shows excellent oral bioavailability and it is also effective in cancer cells that are resistant to taxol, vinblastine and Gleevec. LP-261 does not appear to be a substrate for MDR [Source: Locus Press Release]

Featured Journal Article (from DailyUpdates-Neurodegenerative Disorders): CD40:CD40L (CD154) - A target for Alzheimer's disease: Alzheimer's patients remain poorly treated and are growing in number. Currently, cholinesterase inhibitors and the more recent NMDA-receptor antagonists provide only moderate and temporary symptomatic benefit. By the end of the decade, however, novel drugs with the ability to slow the rate of disease progression are expected to be launched (see Pipeline and Commercial Insight: Alzheimer's Disease). One new target for the treatment of Alzheimer's is CD40L (CD154). This T-cell molecule binds to CD40 on antigen presenting cells and plays a key role in T-cell coactivation and hence the drug development sector has been developing blockers of CD40L:CDL as treatments of autoimmune disorders (see Autoimmune Disorders & Transplant Rejection - The Potential of T-cells Targeted Therapeutics). CD40L:CD40 interaction is thought to regulate microglia in the brain of patients with Alzheimer’s disease thus modifying Abeta phagocytosis and the production of inflammatory mediators. Although studies have shown that blocking CD40L reduces Abeta deposition and improves cognition in models of Alzheimer’s, the effect of CD40 blockade has not been directly investigated. This is important with respect to target selection as CD40L can also bind GPII/III on the surface of platelets. Today’s featured study reports that as with CD40L, CD40 deletion also prevents the development of Alzheimer's disease-like pathology. Thus blocking either CD40 or its ligand may be of therapeutic interest and indeed the blockade of the former may be preferable as cardiovascular adverse effects may be reduced [Source: J Neuroinflammation. 2006 Feb 24;3:3.]

Further development of HDAC inhibitors...Novel approaches to the treatment of depression

Todays Headlines from across the DailyUpdates network (access DailyUpdates 15th June, 2006 here)

• Breaking News (from DailyUpdates-Oncology): CuraGen and TopoTarget to test the promising combination of HDAC inhibition and retinoic acid receptor activation in patients with solid tumors The histone deacetylase inhibitor class of therapeutics represents a highly exciting approach to cancer. Merck's ZOLINZA (SAHA; vorinostat) and Gloucester Pharmaceuticals' Depsipeptide (FK228) lead this class however . Both candidates are evaluated in our feature Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies. The lead indication for both of these agents is cutaneous T-cell lymphoma. Despite the efficacy of these agents in lymphoma the full potential of the HDAC inhibitors will not become clear until efficacy has been demonstrated in a wider range of cancers including the most common solid tumors. This issue is starting to be addressed by Merck who are evaluating ZOLINZA in lung cancer and by Gloucester Pharmaceuticals who have ongoing studies in prostate and renal cancer. One of the most exciting aspects of the HDAC inhibitors is their ability to synergize with other therapeutic approaches and clinical trials evaluating different combinatorial strategies are eagerly awaited. Preclinical studies have suggested that ZOLINZA can synergize with Velcade (bortezomib), Gleevec and retinoic acid. With respect to the latter HDAC inhibitors have been reported to increase the expression of the retinoic acid receptors RAR and RXR in cancer cells. In our report Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development we favor strategies able to reintroduce the expression of RAR in cancer cells that otherwise show reduced expression as these may confer such cells sensitive to the antineoplastic effects of retinoid agonists. Today we headline the exciting news that CuraGen and TopoTarget are initiating a phase I study of their HDAC inhibitor, PXD101alongside cis-retinoic acid in patients with various solid cancers [press release].

Featured Journal Article (from DailyUpdates-Psychiatric Disorders): Wyeth publish new data suggesting an improved approach to depression: Major Depressive Disorder (MDD) 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 feature Major Depressive Disorder). Despite this total world revenues for branded antidepressant drugs was worth over $13bn in 2004. The serotonergic class dominates the market, accounting for 58% of market share in 2002. This class includes the serotonin reuptake inhibitors (SSRIs) such as fluoxetine which is the third most commonly prescribed antidepressant in the US . Over 23 million scripts were dispensed for fluoxetine in the US in 2006 but despite this, revenue is quite low due to generic competition. Prior to genericization, Fluoxetine marketed as Prozac by Lilly brought in approximately $2.7 billion in annual sales and was the fourth largest-selling medication in the US . However within weeks of the first generic fluoxetine being released by Barr Laboratories the majority of patients had switched from Prozac. Both serotonin and noradrenaline are involved in depression and early tricyclic antidepressants modified both pathways. In an attempt to improve side effect profiles industry developed SSRIs. Such selectivity may however limit efficacy and thus venlafaxine was developed as a dual serotonin, noradrenaline reuptake inhibitor offering a broader mechanism of action and improved efficacy. While blocking reuptake represents one way of increasing extraneuronal noradrenaline, alpha adrenergic receptor antagonists represents an alternative. This class of agent blocks central presynaptic alpha 2 adrenergic inhibitory autoreceptors resulting in an increase in noradrenaline release. Mirtazapine represents one example of this class. These receptors are present on both adrenergic and serotonergic neurons creating the possibility that their blockade could enhance the efficacy of reuptake inhibitors. Today’s featured journal article, published by Wyeth researchers, suggests that this is indeed the case demonstrating that alpha2A-adrenoceptor antagonism enhanced the extracellullar levels of serotonin and noradrenaline in the rat frontal cortex in the presence of fluoxetine. No such effect was observed when fluoxetine was administered alongside alpha2B- or alpha2C-adrenoceptor antagonists. A number of companies are investigating the development of mixed alpha2 antagonists/SSRIs; the current study suggests that such mixed agents would benefit from selectively targeting the alpha2A-adrenoceptor subtype [Eur J Pharmacol. 2006 Apr 19; [Epub ahead of print]].

Advances in diabetes...combating the menace of HIV/Tuberculosis co-infection

Todays Headlines from across the DailyUpdates network (June 12th, 2006 - access this edition)

• Breaking News (from DailyUpdates-Metabolic Disorders): Metabolex announce phase II/III trial of novel insulin sensitizer Diabetes affects approximately 170 million people worldwide a figure that is increasing with the WHO predicting 300 million diabetics by 2025 (see The World Diabetes Market, 2005-2011). The US alone has 20.8 million people suffering with diabetes. This equates to approximately 6% of the population. It was the 6th most common cause of death as recorded on US death certificates. The global diabetes drugs treatment market was valued at $15 billion in 2005. Oral anti-diabetics were the leading category of drugs. The total sales for insulin were $6.83 billion. The thiazolidinedione insulin sensitizers experienced the greatest growth now accounting for the second largest portion of the market share (see Commercial Insight: Antidiabetic Drugs). Today’s featured press release from Metabolex announces the initiation of a Phase 2/3 trial of another insulin sensitizer, metaglidasen. Unlike Actos and Avandia, both of which are marketed insulin sensitizing thiazolidinediones, metaglidasen is not a thiazolidinedione and moreover it acts as a Selective PPAR Modulator (SPPARM) rather than as a full agonist of the PPAR nuclear receptors. The PPAR receptor controls the expression of genes involved in glucose metabolism, lipid metabolism and inflammation. Again contrasting with currently available thiazolidinediones, metaglidasen modulate the genes needed for insulin sensitization without activating those responsible for weight gain and edema, adverse effects associated with Actos and Avandia. A phase 2 trial in patients with diabetes has already shown metaglidasen to be well tolerated and to lower blood glucose, triglycerides and uric acid levels without causing any increase in weight gain or edema. Preclinical findings have demonstrated that in addition, metaglidasen helps preserve the function of beta cells. The trial initiated today is designed to compare metaglidasen with Actos.

• Featured Journal Article (from DailyUpdates-InfectiousDiseases): Advanced Life Sciences set to advance our treatment of HIV/tuberculosis a highly prevalent co-infection with serious medical consequences: Tuberculosis is one of the leading causes of infectious disease mortality, with 2–3 million deaths annually worldwide. One-third of the world population is estimated to be infected with Mycobacterium tuberculosis however it has been nearly 30 years since the introduction of a novel compound for the treatment of tuberculosis. New treatments are urgently required since existing approaches require a combination of 3-4 drugs, a prolonged treatment time, and cause significant adverse effects. Whilst therapeutic options have remained stagnant the epidemiology of tuberculosis has changed drastically, and of note during this time period HIV infection has emmerged as a global health problem. Notably half of all patients infected with HIV are also infected with tuberculosis. Here we feature potentially breakthrough work by Xu et al from Advanced Life Sciences who describe the optimization of the Calanolides, a therapeutic class which is able to block replication of both HIV and M. tuberculosis class. This is not only important clinically but from a pharmacoeconomic perspective given the importance attached to developing new HIV therapeutics, it should dramatically increase the perceived value of developing novel antituberculosis drugs, a barrier up untill now.

Merck wins the race for HPV vaccine approval in the US...CRP inhibitor shows promise as a cardioprotective agent

Todays Headlines from across the DailyUpdates network (9th June 2006)

• Breaking News (from DailyUpdates-Infectious Diseases): Merck wins the race for HPV vaccine approval in the US HPV is the most commonly diagnosed viral sexually transmitted disease in the US and UK , with conservative annual incidence estimates of 5.5 million in the US alone. Over 100 types of HPV, causing a variety of diseases, have been identified. It is believed that 50-75% of HPV infections involve high-risk HPV types, leading to approximately 500,000 new cases of cervical cancer and 232,000 deaths worldwide each year. Treatment options are limited, with no known cure currently available. However, the causal link between HPV and cervical cancer has prompted development of prophylactic vaccines, aimed at reducing the incidence, and eventually the prevalence, of this widespread disease and, by association, cervical cancer. Merck and GSK have been running neck and neck in the race to win approval for the first vaccine. GSK filed for European regulatory approval of Cervarix March, 2006 with an anticipated US filing late 2006. Yesterday however, Merck announced the FDA approval of their vaccine, Gardasil. This follows Mexican approval last week. The market opportunity for HPV vaccines stand at £2-£4 billion per annum by 2010 (see Human Papillomavirus - Vaccines, Then Antivirals?).

• Featured Journal Article (from DailyUpdates-Psychiatric Disorders): CRP inhibitor shows promise as a cardioprotective agent: 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 nearly $400 billion (see our feature The Cardiovascular Report). The principle aims of cardiovascular therapies are to reduce morbidity and mortality from heart attacks, strokes and other vascular diseases. 17 million deaths occur globally each year due to cardiac related problems. Complement-mediated inflammation contributes to many cardiovascular diseases exacerbating the tissue injury of ischemic necrosis. Human C-reactive protein (CRP), the classical acute-phase protein plays a key role in complement activation. Featured study reports on a small-molecule inhibitor of CRP which abrogates the increase in infarct size and cardiac dysfunction produced by injection of human CRP in an animal model of myocardial infarction. The authors expect this molecule to also provide neuroprotection in stroke as well as therapeutic benefit in a range of other conditions.

More on HDAC inhibitors...Pfizer report development of new 5-HT4 receptor ligands

DailyUpdates 7^th June: ASCO is finished for this year now but not before Gloucester Pharmaceuticals managed to counter yesterday’s news from Merck with clinical data on their own HDAC inhibitor. Together this means that the two most advanced HDAC inhibitors are progressing nicely towards the market and soon, we hope, cancer patients will be offered another option. Also today we report on Pfizer’s very early stage serotonin 5-HT receptor ligands, a class that is emerging from the arena of IBS to offer possibilities for a range of other indications including Alzheimer’s, atrial fibrillation and urge incontinence. See today’s edition here or read on for more

Featured Journal Article: Continued development of serotonin 5-HT4 receptor ligands: The serotonergic system, and particularly 5-HT4 receptor ligands has risen to prominence with the development of Zelnorm (Tegaserod), a selective serotonin 5-HT4-receptor partial agonist. Zelnorm has been approved for the treatment of constipation predominant IBS and idiopathic constipation in more than 56 countries, including Australia, Switzerland, Canada, the United States, Mexico, China and Brazil. Although European regulators recently recommended against approving the drug, Zelnorm is still one of Novartis' most successful compounds driving 2005 revenues of $418 million. Recent studies have demonstrated that 5-HT4 receptors are also implicated as targets for Alzheimer's disease (agonists), urge incontinence (antagonists) and atrial fibrillation (antagonists). Today's featured paper reports a series of high affinity 5-HT4 receptor ligands being developed by Pfizer.

Breaking News (from DailyUpdates-Oncology): More good news on HDAC inhibitors: Lead candidates from the exciting histone deacetylase inhibitor class are Merck's ZOLINZA (SAHA; vorinostat) and Gloucester Pharmaceuticals' Depsipeptide (FK228). Both candidates are evaluated in our feature Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies, and yesterday Merck announced data on ZOLINZA reporting a 30% objective response in patients with advanced, refractory cutaneous T-cell lymphoma. Today it is the turn of Gloucester who report an overall response rate of 36% in patients with cutaneous T-cell lymphoma. Both trials were pivotal trials and the two companies appear to be taking it to the wire on which will be the first to enter the market with this drug class.

The old and the new: Improving paclitaxel-based therapy...advances in HDAC inhibitors

DailyUpdates 6th June: As ASCO continues in full swing, we again focus on oncology. Today's edition of DailyUpdates includes 10 new papers on oncology research plus a further 20 or so press releases from companies presenting at ASCO. This is of course in addition to the rest of our content from across the drug development sector (see it all here). Today's headline paper unerpins the intriguing idea that the premedication required prior to Taxotere administration may significantly limit its efficacy. Intreresting reading for Sanofi-Aventis as well as APP, makers of Abraxis. The headline news item comes from Merck and focuses on the advance of their HDAC inhibitor

Improving paclitaxel-based therapy: Paclitaxel (Taxotere) is a widely used naturally occurring antineoplastic agent that has shown great promise in the treatment of a variety of human solid tumors, particularly for advanced breast and ovarian cancers. Recent studies have suggested that glucocorticoids may inhibit paclitaxel-induced apoptosis and since glucocorticoids are commonly used prior to chemotherapy this issue is critical. Today's featured study confirms this interaction reporting that paclitaxel-induced apoptosis may be reduced by as much as 25% by premedication. The Taxotere market is entering a dynamic period with its upcoming patent expiry and the recent launch of ABRAXANE (see Commercial Insight: Cytotoxics). ABRAXANE is a novel, albumin-bound formulation of paclitaxel approved by the FDA in January 2005. In a randomized Phase III study in women with metastatic breast cancer who had failed prior combination chemotherapy, ABRAXANE demonstrated a significantly higher response rate than standard paclitaxel (Gradishar et al, 2005). In this study ABRAXANE was administered without pre-medication as hypersensitivity reaction are not a problem with this agent; in contrast paclitaxel-administered patients were pre-medicated. Response rates were 39% and 19% respectively and we ask whether this was more related to the negative effect of the premedication than a benefit of ABRAXANE per se; likewise we ask whether Sanofi-Aventis should increase their emphasis on studying the efficacy of Taxotere in the context of different premedications in order to protect sales of this chemotherapy which was worth 1.6 billion euros in 2005. Comments? Go to our Drug Development Forum

Pivotal data published demonstrating efficacy of HDAC inhibitor: The field of histone deacetylase inhibitors is moving into a new phase of development (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). The exponential growth in the level of research activity surrounding the histone deacetylases witnessed over the past decade has now started to produce success in the clinic, particularly in the field of oncology. The most advanced therapeutic candidates such as SAHA and FK228 are already showing promising activity and today's highlighted press release features the former, also known as ZOLINZA (vorinostat). Merck, who expect to file the NDA for ZOLINZA in Cutaneous T-cell Lymphoma with the FDA this year, yesterday announced pivotal phase IIb data reporting that ZOLINZA produced an objective response in 30% of patients with advanced, refractory cutaneous T-cell lymphoma. This condition is an orphan condition affecting just 20,000 patients in the US; the data are crucial however not only to these patients but also more generally as proof of concept is provided to support a broad body of studies currently underway with other HDAC inhibitors and in other malignancies.

Oncology news from ASCO plus a competitor to antibody therapeutics

DailyUpdates 5th June, 2006: With ASCO (The American Society of Clinical Oncology) now in full swing, cancer is not surprisingly the focus of today's news section and out of the 20 or so press releases featured we highlight and announcement by Cell Genesys describing the development of their GVAX vaccine for the treatment of CML. In their phase 2 trial the company reports that a complete molecular response is seen in 25% of patients whose treatment included GVAX - this compares to historical data of about 10% in patients not receiving GVAX. Many of the studies presented at ASCO involve the development of antibody therapeutics - not surprising given that oncology represents the primary indication of many therapeutic antibodies. Todays featured journal article describes a new competitor to antibodies involving the use of peptides derived from bacteria that are able to penetrate the cell blocking specific protein-protein interactions. For further information on this phylomer technology plus Cell Genesys' announcement, read on; alternatively access today's DailyUpdates for full details of this and all of today's selected press releases and breaking research.

Phylomer technology as a new alternative to antibodies as a approach to proof of concept studies and therapeutics: The monoclonal antibody market is one of the fastest growing and most lucrative sectors of the pharmaceutical industry, with exceptional. It has the potential to triple in value over the next six years and reach $30.3 billion in 2010, driven by technological evolution from chimeric and humanized to fully human antibodies (see our feature Monoclonal Antibody Therapies). Despite success in this arena antibody technology is limited by barriers to delivery and in particular these therapeutics cannot access intracellular proteins. This limitation also applies to the use of antibodies as experimental tools. Today's featured paper describes an alternative approach based on libraries of natural, highly structured bacteria-derived peptides that act as specific inhibitors of protein-protein interactions. This technology, known as phylomer technology is being developed by Australian company Phylogica as an approach to inflammatory diseases. Readers who are interested in Phylomer technology are invited to contact Ms Rolee Kumar (Director of Business Development; Ph +61 8 9423 8830). Further details can also be found at the company's website at www.phylogica.com

Continued development of Cell Genesys' GVAX for the treatment of chronic myelogenous leukemia (CML): As discussed in our feature Chronic Leukemias - Curative Intent Raises the Bar, prolonging disease-free survival in patients with cancers such as chronic myelogenous leukemia (CML) relies on the eradication of minimal residual disease. This is a particular problem given the progressive emergence of Gleevec-resistant CML with continued treatment, coupled with only a 50% response rate in patients with advanced disease. Thus there is the need for novel, efficacious second-line treatment strategies both for patients with Gleevec-resistant chronic phase CML and for virtually all advanced stage patients. Today’s featured press release describes the advancement of one such treatment, GVAX immunotherapy which is being developed by Cell Genesys. The release announces encouraging long-term follow-up data from a Phase 2 trial of GVAX in CML patients with molecular evidence of persistent leukemia following at least one year of Gleevec.

Losartan, a stimulator of insulin release?

DailyUpdates 2^nd June: In today’s edition of DailyUpdates we highlight exciting new data on the potential use of the antihypertensive, losartan as a modulator of insulin release and production and hence a directly acting therapeutic for the treatment of diabetes. This supplements additional beneficial activity resulting from blood pressure control. In addition we report on European approval of Thelin, Encysive’s candidate for the treatment of pulmonary hypertension

The possible use of losartan as a dual metabolic regulator/antihypertensive: As reported in our brand new feature The World Diabetes Market, 2005-2011, diabetes affects approximately 170 million people worldwide and is increasing, with the WHO predicting 300 million diabetics by 2025. The US alone has 20.8 million people suffering with diabetes. This equates to approximately 6% of the population. It was the 6th most common cause of death as recorded on US death certificates. The global diabetes drugs treatment market was valued of $15 billion in 2005. Oral anti-diabetics were the leading category of drugs - $8.19 billion - and showed a growth rate of 6.3% from the total global sales in 2004. The total sales for insulin products increased by 16.5% to total global sales of $6.83 billion in 2004. The search for new therapeutic agents continues and today’s edition of DailyUpdates highlights the intriguing possibility that the angiotensin system may play an important role in the regulation of insulin. The presence of an angiotensin-generating system in pancreatic islets has already been reported; so too has the observation that exogenously administered angiotensin II inhibits insulin release through AT1 receptors. The present study reports that AT1R expression is upregulated in the pancreatic islets of obese and diabetic mice. In addition, the AT1R antagonist losartan improved glucose-induced insulin release and (pro)insulin biosynthesis in the islets of these mice. Over recent years the sartans have been the fastest-growing antihypertensives with sales of losartan hitting $1.4 billion in the first half of 2004. Hypertension is commonly found co-morbidly with obesity and diabetes and together the three make up the metabolic syndrome (see Metabolic Syndrome - Prevalence, Physician Awareness, Therapeutic Options and Developmental Candidates). The current study is intriguing as it suggests that losartan may not only reduce hypertension but that it may also improve glucose handling in these patients.

CHMP approves new treatment for pulmonary hypertension: On March 24, 2006 DailyUpdates highlighted news from Encysive Pharmaceuticals announcing receipt of an approvable letter from the FDA for Thelin (sitaxsentan sodium), which is under review for the treatment of pulmonary arterial hypertension (PAH). Today we headline with an announcement that the CHMP have recommended approval of Thelin for the treatment of these patients