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R&D Directions October 2008

Top 10 Areas of Research

Numbers fail to tell the whole story by Michael D. Christel

Notable advances in disease targeting are providing hope for a revival of sorts in drug research and development. At the same time, there remains a strong consensus that there is simply not enough focus on true innovation within the life sciences industry, mainly in developing treatments that modify or prevent diseases of particular unmet medical need. "There's always newer, better drugs coming out," says Jon Mirsalis, Ph.D., managing director, Biosciences Division, SRI International (, a nonprofit contract research organization. "In the biotech space, there is some interesting innovation going on, [but] big pharma by and large has not changed their model much in the last 30 to 40 years. It's quantity over quality ­ screen lots and lots and lots of drugs." Meanwhile, despite a consistently growing pool of candidates, drug approval rates are sagging, falling to about a third of what they were just a decade ago. FDA approved just 19 new medicines in 2007 and as of August, have cleared just nine new drugs in 2008. "It's partly that companies are more risk-averse, it's partly that FDA is raising the bar," Dr. Mirsalis says. "And they're not just raising the bar on things like safety, but they're raising the bar on, `Well, why do you think this drug is better than what's out there?' They're more reluctant to approve `me-too' drugs. You have a drug like statins which have their issues, but we know what those issues are and they're well-characterized. So now you have a brand new drug that is absolutely no better and we don't know what the issues are; why would you approve it?" Cancer treatments continue to post the worst approval rate among the top therapeutic areas. The poor odds, however, are not stopping an influx of drug companies from entering the cancer market, which represents the fastest growing therapeutic segment. In an inventory of the R&D Directions database, there are more than 660 cancer drugs in the various stages of active development ­ including awaiting approval, Phase I, Phase II, and Phase III ­ an increase of 14% from this time last year. Spurring cancer research of late have been new achievements in mapping the human genome, more focus on gene network studies, and improved targeting of angiogenesis. "As we learn more and more about genomics and mechanisms, we're trying to target drugs more and more specifically," Dr. Mirsalis says. The central nervous system is the second-most researched area with 252 drugs in development. Cardiovascular therapies rank third at 206. Drugs being designed to treat infectious disease, including bacterial, viral, and fungal infections, rank fourth with 186, but notable 21 less than at this time last year. Diabetes is the fifth largest therapeutic area with 138 product candidates. Rounding out the top 10 are pain and inflammation at 109 drugs in development, respiratory diseases at 92 compounds, blood disorders at 85 drugs, gastrointestinal disorders at 71 drugs, and dermatological disorders at 54 drugs.Cancer remains the fastest growing therapeutic segment, but slumping drug approval rates are prompting pharmaceutical and biotech companies to focus on more

targeted therapies for many diseases. R&D Directions editors profile the top 5 areas of research:


Sputtering approval rates for cancer treatments have not deterred large and midsized companies alike from stepping up efforts in the high-risk/reward oncology market. In fact, experts say the cancer segment may be on the cusp of significant innovation in the coming years with several potential key drug launches that could reduce the complications of today's cancer drugs and increase life expectancy significantly. According to a report boy RNCOS (, a marketing research consulting company, 12 million new cases of cancer were diagnosed in 2007. That annual number is expected to swell to over 17 million by 2020, RNCOS says. Experts report that the global market for cancer drugs is expected to eclipse $78 billion by 2012, growing at a compound annual growth rate of 12.3%. Pharmaceutical and biotech companies are increasingly focusing on developing targeted cancer therapies, where drugs attack target cells and thus limit the severity of side-effects. According to a report by Jain Pharmabiotech (, newer approaches to cancer treatment not only supplement conventional chemotherapy and radiotherapy treatment but are also geared to prevent damage to normal tissues and prevent drug resistance. "Innovative cancer therapies are based on current concepts of molecular biology of cancer," Jain authors say in their report, "Drug Delivery in Cancer." "These include antiangiogenic agents, immunotherapy, bacterial agents, viral oncolysis, targeting of cyclic-dependent kinases and tyrosine kinase receptors, antisense approaches, gene therapy, and combination of various methods. Important methods of immunotherapy in cancer involve use of cytokines, monoclonal antibodies, cancer vaccines, and immunogene therapy." According to RNCOS, cancer vaccines and antiangiogenics will record the fastest growth rate between 2007 and 2012. Experts at BioSeeker Group AB ( report that there are now more than 170 companies developing more than 260 non-antibody based vaccine drugs, including therapeutic and preventive vaccines. According to BioSeeker, vaccines are being developed for over 30 different cancer indications and the number of vaccine targets has increased to over 50 different molecular targets in just a few years. Last month, FDA approved expanded use of Merck & Co.'s ( cervical-cancer vaccine Gardasil for the prevention of vaginal and vulvar cancer caused by Human Papillomavirus, or HVP, types 16 and 18 in girls and women ages 9 to 26. Angiogenesis is the process where blood vessels are formed by the sprouting and extension of existing vessels. In 2004, Roche's Avastin became the first approved angiogenesis inhibitor. More than 300 antiangiogenic drugs have been discovered across disease settings and at least 10,000 patients have been treated with these compounds in clinical trials. "The bottom line is that tumors like all other tissues require continuous supply of oxygen and nutrients provided through the blood vessels," says David Chang, M.D., VP, global development, oncology therapeutics, Amgen ( "When tumors are small, the existing bloods vessels and diffusion of these essential ingredients ­ oxygen and nutrients ­ can occur without the need for new blood vessel

formation. However, as tumors grow in size, the need goes up and at that time tumor angiogenesis really factor in as one of the critical components of continued growth." Amgen antiangiogenesis drug candidates include motesanib, and oral inhibitor of vascular endothelial growth factor, or VEGF, receptor, and AMG 386, a recombinant Fc-peptide fusion protein targeting angiopoietins.


Pharmaceutical companies find that developing safer and more effective medicines for central nervous system disorders is an attractive research investment, despite the complex challenges associated with understanding and targeting diseases of the brain. According to a report by Espicom Business Intelligence (, the global market for CNS disorders has become one of the largest therapeutic sectors with sales estimated at almost $92 billion in 2007. Espicom experts contend that all CNS categories have attracted, and continue to attract, significant investment from the pharmaceutical industry. With a growing number of patients and a comparatively high unmet need in the treatment of many neurological diseases, commercial opportunities abound. According to Espicom, in some areas such as depression and schizophrenia, many of the new agents are considered "me-too" drugs based on similar chemical classes to existing treatments, but may end up being better tolerated and more effective. In contrast, the report says, in conditions such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis there is a wave of innovative drugs emerging that have novel mechanisms of actions. Experts say these compounds may provide benefit as monotherapies and in combination with existing therapies, and in some cases may work to modify the course of the disease. According to Espicom, several CNS drugs are being developed for multiple indications and this is apparent in depression and schizophrenia, where cognitive symptoms are addressed. A report by Datamonitor ( predicts that the psychiatry market, presently dominated by large pharmaceutical companies and a number of multi-blockbuster antidepressant and antipsychotic brands, will begin to decrease from 2010 onwards as key patents begin to expire. Nevertheless, continued investment will eventually see the pipeline yield new improved agents with blockbuster potential.According to Datamonitor, Alzheimer's disease offers the greatest commercial opportunity for pharmaceutical companies in neurology. In 2007, Espicom reports that about $5.5 billion was spent on the symptomatic treatment of Alzheimer's disease, which affects about 19 million people worldwide. The major obstacle in Alzheimer's research is developing treatments to modify and ultimately prevent the disease, which remains extremely difficult to diagnose. Presently, the only conclusive way to measure whether a patient has Alzheimer's disease is to open up the brain after death and check for buildup of amyloid plaque. Espicom experts note that there is considerable research being done in the Alzheimer's disease field although there have been numerous setbacks, including Alzhemed from Bellus Health (, phenserine from Axonyx (, and xaliproden from Sanofi-Aventis' (sanofi-aventis), all of which were discontinued from Phase III trials. Most recently, there was the lack of efficacy demonstrated by Flurizan, which was being developed by Myriad Genetics ( and H. Lundbeck AS ( Espicom says the most anticipated Alzheimer's disease candidate is

bapineuzumab, which is being developed by Wyeth ( and Elan, although this drug is facing challenges as well. In July, data showed that bapineuzumab raised the risk of a potentially serious side effect, especially in people with a genetic risk of Alzheimer's disease. According to Wyeth and Elan (, 12 people with mild-to-moderate Alzheimer's disease who were treated with bapineuzumab developed vasogenic edema, which is build-up of fluid in the brain. Methylthioninium chloride, which is being developed by TauRx Therapeutics (, is showing early promise after Phase II findings were disclosed in July. Researchers from Scotland said methylthioninium chloride, also known as Rember, was successful at halting the symptoms of Alzheimer's disease over a 50-week period. According to published reports, this marked the first time an anti-tau drug had demonstrated benefits in people with Alzheimer's disease. Tau is the protein present in the buildup of abnormal nerve fibers in the brain which are commonly linked to memory loss in Alzheimer's disease. Eli Lilly and Co. ( has two mid-stage Alzheimer's compounds moving into Phase III studies. LY2062430 is a monoclonal antibody intended to decrease the amount of soluble amyloid beta in the brain, making it less prone to aggregate and form amyloid plaques. Lilly's gamma secretase inhibitor, LY450139, is believed to slow the rate of formation of amyloid beta. According to Espicom, the schizophrenia market generated global sales of $19.6 billion in 2007, accounting for 21% of worldwide CNS sales. Experts say innovation within this market has been limited, although a number of products that are in Phase II development are targeting new pathways to treat cognitive impairment associated with schizophrenia through the modulation of neurokinin-3 receptor or 5HT6 receptors. Antidepressants posted sales of $19.4 billion in 2007. Experts predict that the market for depression therapies will show negative growth in the years ahead as the emergence of new products is offset by the impact of generics on leading brands. Espicom says market leaders will launch a number of combination therapies to optimize the life-cycle management of their drugs, including Lilly's Symbyax. Other companies are developing second-generation products such as Pristiq, a metabolite of Wyeth's Effexor.


Despite some decreases in the rate of heart disease and stroke deaths, cardiovascular disease remains the No. 1 killer in the United States. According to the Centers for Disease Control and Prevention, cardiovascular disease claimed nearly 900,000 lives by 2005 estimates, equating to 2,400 cardiovascular disease-related deaths per day, more than the lives claimed by cancer, HIV/AIDS, and accidents combined. The CDC also reports that 80 million Americans ­ nearly 33% of the population ­ have not just one but several types of cardiovascular disease, which includes hypertension, coronary heart disease, stroke, heart failure, and diabetes. The most common red flags for these patients include obesity, tobacco use, poor diet, physical inactivity, and alcohol abuse. One particularly alarming statistic reported last fall by the Journal of the American College of Cardiology states that from 1997-2002, the coronary heart disease rate had been increasing in women ages 35 to 44.

There has also been some promising data reported recently concerning cardiovascular disease, due in large part to increased public awareness on prevention and lifestyle issues. New mortality data from the CDC shows that since 1999, age-adjusted coronary heart disease death rates are down 25.8% and stroke age-adjusted death rates are down by 24.4%. The New England Journal of Medicine reported last year that there was a 40% decline in coronary heart disease deaths from 1980 to 2000 in U.S. adults. According to the report, 61% of the 40% drop in death was due to lifestyle improvements of blood pressure, cholesterol, physical activity, and smoking cessation. Invasive measures such as angioplasty, stents and coronary bypass only accounted for about 17%. Other therapies, which were mainly pharmaceutical, accounted for about 22% of the 40% decline in mortality. "It appears the most cost-effective action is the prevention of coronary artery disease is through lifestyle modification and the least cost-effective are invasive procedures with end-stage disease," Bradley Field Bale, M.D., director of the Advanced Center for the Prevention of Heart Attack, Stroke and Diabetes at Covenant Heart and Vascular Institute (, tells R&D Directions. "We need to be throwing our resources into effective prevention. This should involve assessing a lifetime risk for heart attack and stroke. We need to endorse research that looks for non-invasive inexpensive tests that can detect and monitor early atherosclerosis. Prevention should also involve developing effective techniques for improving lifelong healthy lifestyle adaptations." The cardiovascular market continues to provide the largest single source of revenue for the pharmaceutical industry. The market is expected to top $100 billion in 2008 and is predicted to eclipse $116 billion by 2010. According to a report by Business Insights (, the outlook for the cardiovascular market remains strong, driven by high patient populations and a widespread focus on preventative treatment. Business Insights experts predict that low growth rates in established indications will become the norm due to the growing availability of effective generic medicines and an overall scarcity of innovative new drug launches. According to Business Insights, with product launches in mainstream cardiovascular indications facing continued difficulties, major pharmaceutical companies are now primarily focusing efforts on compliance and protection against the generic threats posed by line extensions and combination treatments. Changes in the competitive positions of leading companies will become inevitable as new revenue sources continue to decline and established portfolios underperform. "We cannot afford to allow American medicine to remain on its historic platform of dealing with end-stage disease," Dr. Bale says. "The most effective means of treating and preventing cardiovascular disease involve lifestyle. This is a major obstacle as this treatment requires excellent patient compliance and an identity change to be long lasting. Once someone has coronary heart failure, they are at the extreme point of end-stage disease. The way to prevent CHF is to prevent heart attacks and diabetes. Hypertension is usually rooted in insulin resistance and sleep apnea may be an occult contributor. We need to develop more cost effective ways to diagnose both of those conditions." Cholesterol treatment has been in the spotlight, stemming from the ongoing controversy surrounding the blockbuster Vytorin marketed by Schering-Plough ( and Merk & Co. ( A European study revealed during the summer that Vyotrin, which is a combination of ezetimibe and simvastatin, was

no better than a placebo at lowering the risk of major cardiovascular events ­ including heart attack, stroke, heart surgery, and death ­ in patients with aortic stenosis. Vytorin's reported possible link to cancer is still under debate, although an independent analysis in England of two ongoing Vytorin studies revealed no credible evidence linking Vytorin to cancer risk. Dr. Bale says testing of the cholesterol-associated enzyme Lp-PLA2 is a valuable tool in detecting a patient's hidden risk for heart attack or stroke. Lp-PLA2 is an enzyme that rides on LDL cholesterol and, according to Dr. Bale, when the LDL gets oxidized in the intima of an artery, the enzyme acts on that LDL to produce two very pro-atherogenic and pro-inflammatory substances. "In a younger individual it could signal an accelerated atherosclerotic process and in an older individual it can signal immanent plaque rupture with a subsequent heart attack or stroke," Dr. Bale says. "The test has been a known marker of increased heart attack and stroke risk for years in both primary and secondary event arenas." The LpPLA2 test, known as PLAC, was approved by FDA for coronary heart disease in 2003 and stroke assessment in 2005 and is the only FDA-approved test for stroke risk assessment. According to Business Insights, heart failure and thrombosis represent the most active areas of current cardiovascular drug development. Increasing competition in these traditionally less competitive therapeutic areas is forecast to become a major trend through 2012. Business Insights says thrombosis will be the major growth driver of the cardiovascular market throughout the short-term, while heart failure has the most favorable dynamics of any indication for rapid market growth.


Although fallen growth rates in recent years in the anti-infective market can be blamed on a number of factors, antibiotic-resistant bacterial disease remains a huge area of unmet medical need. Despite recognized innovation in the segment, researchers continue to be befuddled and frustrated by pathogens that evolve immunity to existing antibiotic therapies. "Infection is quite unique as an area of research in the sense that we're constantly dealing with evolution," David Melnick, M.D., medical science executive director, clinical infection, AstraZeneca, tells R&D Directions. "When oncologists or endocrinologists pick a target for drug action, that target is the same today as it is tomorrow as it is the day after. The challenge in infection is that because our pathogens constantly mutate, our targets are constantly changing. That adds a very interesting dimension to R&D in infectious diseases." According to Michael Barbachyn, Ph.D., director, infection research, AstraZeneca, there are presently only five large pharmaceuticals companies focused significantly in the antibacterial area ­ AstraZeneca (, Novartis (, GlaxoSmithKline (, and Merck & Co. (, which this spring closed down its natural products research facilities. A report by Datamonitor (datamonitor) says 10 players in all account for two thirds of the seven major chemotherapeutic antiinfective sales by value, but just one third by volume. According to the report, as growth rates have fallen in the anti-infective market ­ which includes the antibiotic, antifungal, antiviral, and HIV sectors ­ these companies have collectively been hit the hardest, leading to a need for strategic reevaluations for some of them. At the same time, with fewer companies competing today, commercial opportunities have improved for viable anti-infective products.

Zyvox, marketed by Pfizer (, is one example. The drug treats infections related to methicillinresistant Staphylococcus aureus, or MRSA, including nosocomial pneumonia and complicated skin and skin structure infections. Zyvox is predicted to bring in more than $1 billion in sales this year after posting revenue of $944 million in 2007. Merrem, AstraZeneca's broad-spectrum injectable antibiotic, treats a variety of serious infections, including meningitis and pneumonia. The drug generated sales of $439 million in the first half of 2008. Last year, Merrem brought in revenue of $773 million, up 20% from 2006. "The argument people always make is that the economics of antibiotic development are not that favorable and return of investment is not very good," Dr. Melnick says. "All of that is valid. There is a big philosophical issue, which is [that] the medical profession became complacent. We went through an era where we felt we could invent our way out of any resistance problem. We went through generation after generation of penicillins and cephalosporins and every time a resistant bug came up, somebody had a new drug to treat it. We took our eye off the ball. These organisms are going to mutate and find a way around whatever biochemical roadblocks we put in their place." Dr. Melnick says several recently approved antibiotics and a number of products in late-stage development are promising against some of the important Gram-positive pathogens, in particular Staphylococcus and Streptococcus, but there remains significant unmet need in treating Gram-negative bacteria. Of these pathogens, 90% to 95% are considered to be harmful to the host. Gram-negative bacteria are those strains that do not retain the crystal violet dye in the Gram staining test. Gram-positive bacteria will retain the crystal violet dye when washed in a decolorized solution. Gramnegative pathogens are considered much more resistant than Gram-positive bacteria and experts are warning that the present void in available treatments for these so-called "superbugs" is leaving hospitals inadequately equipped with antibiotics. Health agencies as well as the drug industry are worried that there are not enough reinforcements on the way. Besides Merrem, available Gram-negative commercial solutions are limited. A select few agents in the pipeline may offer help, including iclaprim, being developed by Arpida Ltd. (; and Novexel ( and Forest Laboratories' ( oral streptogramin antibacterial compound NXL 103 and beta lactamase inhibitor, NXL 104. "On the Gram-negatives, there is a huge hole," Dr. Melnick says. "These Gram-negative pathogens are very robust. They have large genomes and therefore are able to develop multiple resistance mechanisms. They are very tricky targets. They're just a difficult target to hit." According to Dr. Melnick, AstraZeneca uses three approaches in tackling bacteria drug resistance ­ exploring novel targets which lack cross-resistance with existing agents, applying pharmacodynamics, and developing better strategies to prevent emergence of resistance in the clinic. Dr. Melnick defines pharmacodynamics as the science or the discipline of understanding how drug concentrations, human pharmacokinetics, and killing kinetics translate to the ability to kill organisms in an animal and therefore cure infection. "We've learned a tremendous amount about how to model the way that antibiotics work and how to model the way that resistance emerges when you try to treat infections," Dr. Melnick says. "We've now got the ability to look at these pharmacodynamics issues in the computer, in the test tube, in animal models, and in human beings."

Being able to use those findings to identify in vitro and in vivo activity and efficacy predictors is a significant benefit Dr. Barbachyn notes, particularly since an antibacterial agent's effectiveness is usually clearly evident by the end of Phase I. "That's a huge advantage that we have in infection over other treatment areas," Dr. Melnick says. "The attrition rates for anti-infectives in late development ­ if we do our job right ­ should be pretty low. By the time we're done with our Phase I studies, we should have a pretty solid idea of whether or not we have a drug, because we have such robust markers." On the discovery side, Dr. Barbachyn says one strategy being used in infectious disease research is screening for whole-cell antibacterial activity using tools such as reverse genomics, macromolecular synthesis, and resistance mapping to rapidly identify the mechanism of action of those whole-cell active compounds and attempt to advance them to preclinical development. With Gram-negative pathogens extremely adept at resisting small-molecule antibiotics, the drug industry is realizing biologic agents may provide the best hope in combating bacterial infections. AstraZeneca, through its acquisition of biotech company MedImmune ( last year, is reexamining proven 19th and 20th century biologic approaches for the treatment of infection, but using updated immunologic technologies to do it. "The idea of using an antibody to go after some of these really nasty pathogens makes a whole lot of sense to me," Dr. Melnick says. "If you look at the history of the clinical specialty of infectious diseases, it's based in immunology. We first learned to treat infections by utilizing the immune system. We did it with vaccines and we did it with immune sera. There is tremendous opportunity, for bringing unique expertise to bear on problems in ways that haven't been done in recent years." Several infectious diseases are shifting to the forefront for pharmaceutical, biotech, and contract research organizations alike. Last month, SRI International (, a nonprofit CRO, initiated a tuberculosis preclinical drug evaluation program in partnership with the National Institute of Allergy and Infectious Diseases, or NIAID, a component of the National Institutes of Health. According to SRI, the company has the capability to test up to 30,000 compounds per year against Mycobacterium tuberculosis strains. Preclinical drug candidates will be provided by tuberculosis researchers via a non-clinical evaluation agreement with NIAID. The findings will be used to guide the development of new medicines against Mycobacterium tuberculosis. Several clinical projects may offer hope in fighting hepatitis C virus. Vertex Pharmaceuticals Inc. ( recently reached agreement with U.S. and EU regulatory authorities to proceed with the Realize trial, a pivotal Phase III study. The protease inhibitor telaprevir is being evaluated in combination therapy for patients with chronic hepatitis C infection who failed to achieve a sustained viral response with prior therapy. Last month, Intercell AG ( disclosed favorable six-month follow up data of IC41, its Phase II vaccine targeting treatment-naive hepatitis C genotype 1 patients. On the HIV front, VIRxSYS Corp., ( has high hopes for its investigational compound VRX496, which according to the company, is different from previous gene therapies because it uses a lentiviral vector derived from HIV-1 itself.

Newly released data from Novartis have demonstrated that the company's Meningitis B vaccine may be the first to also protect infants six months and older against multiple strains of potentially deadly meningococcal B bacteria.


The road to approval for several promising diabetes therapies may be getting a whole lot tougher ­ or at least longer and costlier ­ a not-so rosy scenario as the global prevalence of diabetes continues to grow at an alarming rate. Over the summer, an FDA advisory panel unanimously voted that all new diabetes drugs should undergo longer and more thorough safety testing for cardiovascular risk, a move that is predicted to cost drugmakers tens of millions of dollars in additional clinical trial costs. The testing would take an estimated five to seven years to complete. According to published reports, the panel said pharmaceutical companies could begin safety testing before they file new drug applications to FDA and finish the studies after the drugs are on the market. Nevertheless, these proposed standards would likely lead to longer development timelines for certain diabetes drugs. Stemming from last year's uproar surrounding type 2 diabetes drug Avandia, which studies had linked to increased risk of heart attacks, FDA is under pressure to revaluate how it approves diabetes medicine. Presently, the agency only requires that drugs for type 2 diabetes lower blood sugar. Nearly 24 million Americans are afflicted with type 2 diabetes and the disease affects about 246 million people worldwide, according to a report by Visiongain ( Those numbers are expected to climb further with the International Diabetes Federation predicting 380 million diabetics by 2025. Adding to the concern is the rising population of people estimated to be "prediabetic" or at increased risk for developing diabetes in the future. According to a study by GfK Market Measures' Roper Global Diabetes Group, nearly 77 million Americans fit the pre-diabetes profile, a figure that has contributed to the doubling of diabetes cases in the United States over the past decade. FDA usually follows the recommendations of its advisory panels, but the exact effects tighter drug testing standards would have on the diabetes market remains to be seen. According to Visiongain, the global diabetes drug treatment market was valued at more than $21 billion in 2006 and is still expanding rapidly due to higher prevalence of diabetes and lifestyle changes. The domestic diabetes market grew to more than $6 billion last year, with Takeda Pharmaceuticals' ( Actos, Avandia, sold by GlaxoSmithKline (, and Eli Lilly ( and Amylin Pharmaceuticals' ( Byetta dominating the U.S. market. Last month, Amylin and Lilly disclosed results from a four-week head-to-head study between Byetta and Merck & Co.'s ( type 2 diabetes drug Januvia. According to the companies, results demonstrated that Byetta injection, a GLP-1 receptor agonist, provided significantly lower glucose levels in the post-meal setting when compared with Januvia, a DPP-4 inhibitor. Also, the data demonstrated that patients treated with Byetta reduced post-meal glucagon, showed more efficient use of their body's own insulin, and decreased their food intake when compared to Januvia.

According to IMS Health (, GlaxoSmithKline, AstraZeneca ( and Novartis ( are among the companies vying to grab a share of the domestic diabetes market. Saxagliptin, also known as Onglyza, is awaiting approval in the United States and Europe for type 2 diabetes. The DPP-4 inhibitor, which is being developed by AstraZeneca and Bristol-Myers Squibb (, has been shown in Phase III studies to significantly improve blood sugar control when added to older medicines. According to published reports, there were no reports of skin lesions in the most recent clinical trials, a potential problem with DPP-4 inhibitors, but there were signs saxagliptin increased blood pressure when added to established sulfonylurea treatment. Novartis' Galvus, approved in Europe in February for type 2 diabetes and approved in 18 countries in all, is still seeking clearance to enter the U.S. market. According to Novartis, some small clinical studies have started in the United States amid discussions with FDA on overall steps needed for approval after an "approvable letter" was issued in February 2007. Last month, Novartis said a refiling of Galvus to FDA is not presently planned. The company has revealed new data demonstrating that Galvus is better tolerated and as effective as commonly prescribed anti-diabetic oral medicines called thiazolidinediones when added to metformin. In a study involving more than 2,400 patients treated by primary care physicians, patients who were administered Galvus did not gain weight, a common side effect of other type 2 diabetes drugs. Another company that is expected to hold a competitve place in the diabetes market is Novo Nordisk (, which submitted new drug filings to FDA and the European Union in May for liraglutide. The drug is a once-daily human GLP-1 analog for type 2 diabetes. According to Novo Nordisk, liraglutide works by stimulating the release of insulin only when glucose levels become too high and by inhibiting appetite. Novo Nordisk executives say liraglutide also leads to weight loss instead of weight increase, in contrast to most other antidiabetic treatments. A report by Decision Resources ( predicts liraglutide will become the new Decision Resources' proprietary clinical gold standard for the treatment of type 2 diabetes by 2011. According to Decision Resources, surveyed primary care physicians indicate that liraglutide has competitive advantages in terms of efficacy and safety in comparison to the current gold standard, metformin. Although liraglutide has disadvantages in the area of delivery because of its subcutaneous injectable formulation, its positive efficacy and safety attributes offset that disadvantage, the report says. Glucokinase activators, or GKAs, are an emerging class of small molecule oral treatments for type 2 diabetes. GKAs reduce glucose levels via a dual mechanism of action ­ working in the pancreas and the liver. Glucokinase is the enzyme that senses glucose in the pancreatic beta cells, stimulating insulin release in a glucose-dependent manner. GKAs are being studied by big pharma companies including Roche (, Lilly, and AstraZeneca, as well as the biopharmaceutical company Array BioPharma Inc. ( Array has released positive preclinical data for its GKA candidate, ARRY-403, and plans to begin Phase I studies of the drug in the middle of next year. Much of the new research in diabetes is centering around genes and how they interact with their environment. New research has indicated that a person's genetic profile has a lot to do with their disease. Earlier this year, Merck released two studies providing evidence that genetic susceptibility to obesity involves changes in entire networks of genes and is not limited to mutations in several specific genes. Scientists at Merck Research Laboratories and their collaborators performed genetic and gene expression analysis of tissues from a model of metabolic syndrome ­ a group of conditions that increases

the risk of diabetes and cardiovascular disease ­ and a human population known to be susceptible to obesity. The resulting data were analyzed using powerful computational methods that integrate data from several sources to identify networks of gene interactions altered in individuals susceptible to obesity.


The global pain/inflammation market continues to undergo significant transition, brought on by the decline of the lu-crative cox-2 class of inhibitors just a few years ago. Left with a void in treatment options, the outlook for the global pain market, reportedly valued at over $30 billion, is somewhat murky, although experts are predicting the segment will rebound over the long haul. According to a report by Decision Resources, following recovery from the withdrawals in 2004 and 2005 of two cox-2 inhibitors, Vioxx and Bextra, the chronic pain market will regain momentum over the next decade, with 5% to 6% annual growth in total sales in the United States, France, Germany, Italy, Spain, United Kingdom, and Japan. Decision Resources experts predict that the market penetration of drugs that have been newly labeled to treat neuropathic pain, including Pfizer Inc.'s ( Lyrica and Eli Lilly and Co.'s ( Cymbalta, will be a key driver of growth in the market through 2016. "In contrast to older established drugs like amitriptyline, new agents such as Lyrica and Cymbalta have the safety and efficacy data from large-scale clinical trials that will allow them to compete in this market," says Kate Hohenberg, a director at Decision Resources ( "Both of these drugs will achieve blockbuster status in the chronic pain drug market by 2011 and sales of Lyrica will exceed $2 billion by 2016." In a separate report, Decision Resources predicts that the emergence of novel investigational therapies for pain and inflammatory disorders will help drive long-term growth for the market as well. In the study, "Novel Approaches to Pain," experts find that although strong opioids and non-steroidal anti-inflammatory drugs will continue to dominate the pain market over the next 15 years, novel drug classes will claim over one-fifth of total market share by 2023. According to the report, the overall pain market will reach more than $47 billion in 2023, following two distinct patterns of growth. From 2008 to 2013, experts forecast that reformulations and emerging therapies in existing drug classes will be the primary growth drivers. From 2013 to 2023, growth will result predominantly from the launch of innovative agents representing entirely new drug classes. According to Decision Resources, therapies representing novel drug classes will expand the pain market by adding to the eight major analgesic drug classes, creating as many as 18 drug classes by 2023. Experts say the most successful reformulations and emerging therapies in existing drug classes will be abuse-resistant and dependence-resistant strong opioid formulations, including Remoxy, manufactured by King Pharmaceuticals Inc. ( and Pain Therapeutics Inc. (, as well as safer and more tolerable non-steroidal anti-inflammatory drug formulations such as NicOx's ( naproxcinod and AstraZeneca's ( naproxen/esomeprazole combination; Johnson & Johnson's ( new dual-acting opioid tapentadol; and longer lasting antimigraine formulations such as GlaxoSmithKline's ( Treximet. The need for effective reformulations and innovator pain products is clearly evident in the United States. According to a survey by Harris Interactive released earlier this year, the majority of Americans ­ 72% of

respondents ­ reported experiencing pain in the previous 12 months. The poll also revealed that many, especially acute pain sufferers, are reluctant to seek professional help or take prescription pills. Rheumatoid arthritis and osteoporosis are two diseases of particular unmet need in the pain segment. According to published reports, scientists at Newcastle University are in the process of developing a vaccine that could potentially suppress the effects of rheumatoid arthritis using the patient's own blood cells. Newcastle researchers are close to launching a small-scale safety trial involving the taking of cells from patients before being altered and then injected them back into the affected joint. Developing effective and safe drugs for osteoporosis sufferers continues to be a tough task for the life sciences industry. Often referred to as the "silent epidemic," osteoporosis is considered a global problem that is becoming more prevalent as the population of the world both increases and ages. The World Health Organization recently identified osteoporosis as a priority health issue along with other major noncommunicable diseases. One osteoporosis drug candidate showing particular promise is Amgen's ( denosumab, the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK ligand, the essential regulator of osteoclasts, which are the cells that break down bone. In September, Amgen revealed complete results from its Phase III head-to-head trial of denosumab versus alendronate (also known as Fosamax), where data showed that patients ­ in this case postmenopausal women with low bone mass ­ who were transitioned from alendronate to denosumab achieved significantly greater gains in bone mineral density compared to those continuing on alendronate. In addition, according to Amgen, data from a separate head-to-head trial showed that more than 75% of patients prefer the administration and frequency of twice-yearly subcutaneous injection compared to a weekly oral pill. Amgen's stock rose 5% after the news was released. GlaxoSmithKline and Cellzome (, which develops kinase-targeted drugs, recently launched a partnership that could be worth up to $1.5 billion. The companies' research will target inflammatory diseases such as rheumatoid arthritis or multiple sclerosis. In April, Cato Research Ltd., ( and Advanced Targeting Systems Inc. ( initiated an alliance focused on development and commercialization of SP-SAP, Advanced Targeting's lead drug candidate for chronic pain. SP-SAP is a single-dose, nonopioid, substance P receptor-targeted treatment designed to specifically bind to and eliminate a subset of neurons that send the chronic pain signal to the brain. In late August, BioDelivery Sciences International ( received a complete response letter from FDA regarding the company's new drug application for BEMA Fentanyl, requesting modifications to the submitted risk management program. BioDelivery executives says the company will comply and anticipates approval of BEMA Fentanyl, for breakthrough pain, in the first half of 2009.


The alarming rise in incidence of allergies and allergic diseases across the world is nothing to sneeze at, experts are warning. According to the World Allergy Organization's first comprehensive report on the global extent of allergy and chronic respiratory diseases, the prevalence of allergic diseases has

increased significantly in the last 20 to 30 years, a trend the organization says is showing no signs of slowing. The recently released report estimates that 400 million people worldwide presently experience allergic rhinitis and 300 million people suffer from asthma, with estimated economic costs exceeding those of tuberculosis and HIV/AIDS combined. The report also finds that while the incidence of allergy and associated diseases has risen sharply, the number of healthcare professionals trained in the diagnosis and treatment of allergy has decreased, leaving many patients undiagnosed and untreated. According to the WAO study, due to a changing world climate, higher standards of hygiene, and rapid industrialization of developing nations, allergies are becoming more prevalent, more complex, and more aggressive, with patients frequently suffering multiple allergic disorders that are no longer confined to specific seasons or locations and may be caused by a multitude of natural and synthetic substances not present in our environment 20 years ago. Naturally, these challenges have triggered continued growth in the respiratory pharmaceutical arena. According to a report published earlier this year by Visiongain (, the respiratory market generated revenue of $30.5 billion in 2006, and despite some big-name respiratory drugs losing patent protection, the market is poised to experience strong growth through 2013, driven largely by the rising prevalence of such diseases as asthma. Competition within the respiratory disease drug market is also predicted to grow after the patents expire for blockbuster asthma products Advair from GlaxoSmithKline ( and Symbicort from AstraZeneca ( According to experts at Citeline Inc. (, these expirations, coupled with a growing focus on fixed-dose combinations in asthma management and the increasing use of these combinations in chronic obstructive pulmonary disease, have spurred significant clinical trial activity. In the report published last month in Good Clinical Practice Journal (, Citeline experts, who had examined the fixed-dose-combination trials landscape for asthma and chronic obstructive pulmonary disease, found that GlaxoSmithKline and AstraZeneca are pursuing contrasting strategies in attempts to stave off a new wave of competitors in the respiratory market. "GlaxoSmithKline is protecting near-term market share with next-generation FDCs and exploring novel targets that could result in new revenue streams in the longer term," says Citeline author Sylvia Marecki. "AstraZeneca is not developing any novel clinical-stage FDCs independently or as part of a collaboration but instead is heavily invested in developing novel agents for long-term market growth." In the near term, Ms. Marecki says fixed-dose-combination product-driven growth will likely be dominated by GlaxoSmithKline and new entrants such as Novartis (, Boehringer-Ingelheim (, and Almirall ( Citeline also notes the growing role that alliances are playing in shaping clinical trials involving fixed-dose combinations for asthma and chronic obstructive pulmonary disease. Citeline experts say several combination products are advancing as a result of marketing collaborations initiated by innovator companies who often contribute one or more drug candidates to the program. According to the report, among the top eight collaborations in asthma, chronic obstructive pulmonary disease, and allergic rhinitis ranked by number of ongoing trials, six involve development of a fixed-dose combination.

To soften the near-term blow of Symbicort's patent expiration, set for 2012, AstraZeneca has submitted a supplemental new drug application to FDA seeking approval for a new indication ­ the long-term maintenance treatment of asthma in pediatric patients ages six to 11 years old. Symbicort is already approved in patients 12 years and older. Worldwide sales of the asthma inhaler reached $1.58 billion in 2007, with Europe accounting for $1.34 billion. Also on the asthma front, MedImmune (, which is wholly owned by AstraZeneca, launched a new trial earlier this year for its investigational treatment targeting interleukin-9. The company initiated a Phase IIa trial designed to assess the potential of MEDI-528 in patients with stable asthma and exercise-induced bronchoconstriction. Outside the asthma market, two other respiratory drug candidates of note include PCT124, an experimental cystic fibrosis compound being developed by PTC Therapeutics Inc. ( and Genzyme Corp. ( which showed in a recent study to increase lung function and help relieve symptoms in patients whose disease is tied to certain genetic mutations; and motavizumab, an investigational monoclonal antibody being evaluated by MedImmune for its potential to prevent serious disease caused by respiratory syncytial virus in high-risk pediatric patients.


The blood disorders market continues to face considerable challenges, stemming in large part from growing concerns in recent years over the safety of certain anemia drugs. Those worries have not abated so far in 2008 as evidenced by an FDA advisory panel's recommendation in March to restrict the use of the anemia therapies Aranesp by Amgen Inc. ( and Procrit by Johnson & Johnson (, which research revealed last year could worsen some cancers and also cause heart problems. While agreeing to keep the drugs on the market for cancer patients, the FDA advisory panel voted to significantly limit the two compounds ­ known as erythropoiesis-stimulating agents ­ to only patients with incurable cancer. In late July, FDA ordered changes in prescribing information for Aranesp and Procrit, saying labels must state that the drugs are not intended for patients undergoing chemotherapy. The agency also ruled that patients should not be treated with the drugs unless their hemoglobin levels drop below 10 grams per deciliter of blood. Sales of Aranesp have dropped steadily since the second quarter of 2007. The drug, along with Amgen kidney treatment Epogen, accounted for $6.3 billion in sales for the biotech giant in 2007. Procrit generated $2.9 billion in sales for J&J last year. According to published reports, Amgen recently decided to discontinue offering rebates and discounts designed to boost sales of its anemia drugs, which also include Neulasta and Neupogen, a practice critics said contributed to overuse of Aranesp by doctors during the time questions were raised over its safety. Risk-reward concerns surrounding erythropoiesis-stimulating agents have increased steadily since 2004, when, according to experts at Decisions Resources (, the first of several studies suggesting that these compounds have negative effects on patient survival were published. A new report by Decisions Resources reveals that in 2007, worldwide sales of erythropoiesis-stimulating agents totaled $11.6 billion, a drop of 10% from 2006. Not helping matters for the anemia market was FDA's rejection earlier this year of Daiichi Sankyo's ( iron replacement therapy, injectafer.

The FDA cited safety concerns regarding an apparent increase in adverse events, including death, in patients receiving the treatment. According to a report by Visiongain (, blood diseases cost the United States $114 billion in 2007. In 2004, Visiongain says a reported 232,000 deaths in the United States were attributed to anemia, myeloproliferative and myelodysplastic disorders, bleeding disorders, white blood cell disorders, and thrombosis collectively. The report notes that because blood has vital physiological functions ­ from oxygen delivery to immunological defense to clotting ­ the nature of treatments for hematological disorders are often expensive. Amid the company's struggles with Aranesp, Amgen did receive good news on the hematology front in August when FDA approved Nplate, which Amgen says is the first and only platelet producer for the treatment of adult chronic immune thrombocytopenic purpura, or ITP. This condition, which is recognized as an orphan disease and affects 60,000 adult patients in the United States, is considered a serious autoimmune disorder characterized by low platelet counts in the blood, which can potentially trigger serious bleeding events. According to Amgen, Nplate, the first FDA-approved peptibody protein, works by raising and sustaining platelet counts. A peptibody is an engineered protein, made by recombinant DNA technology, with attributes of both peptides and antibodies, but still distinct from each. Joint developers Bayer AG ( and Johnson & Johnson Pharmaceutical Research and Development ( are presently awaiting approval of their novel anticoagulant rivaroxaban, also known as Xarelto, which they filed with FDA in July. Xarelto was developed for the prevention of deep-vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. The new drug application for Xarelto supported favorable data from the Record clinical program, where more than 12,500 orthopedic patients have tested ­ the largest ever conducted in the prevention of venous thromboembolism in patients undergoing knee or hip-replacement surgery, according to Bayer. Four Phase III trials compared rivaroxaban with enoxaparin, marketed as Lovenox by Sanofi-Aventis ( Bayer says the once-daily rivaroxaban demonstrated superior efficacy over enoxaparin, a twice-daily injectable, in head-to-head comparisons. In all four trials, the two treatments demonstrated similar safety profiles including low rates of major bleeding. If approved in the United States, rivaroxaban will be commercialized by Ortho-McNeil (, a division of Ortho-McNeil-Janssen Pharmaceuticals Inc. The drug would be the first novel oral anticoagulant introduced in the U.S. market for more than 50 years. According to Bayer, filings for rivaroxaban are also under review with regulatory agencies around the world. On July 24, 2008, the drug was recommended for approval in Europe for the prevention of venous thromboembolism following elective hip and knee replacement surgery. A couple notable industry deals in the field of hematology were launched recently. In July, Bayer HealthCare acquired biotech company Maxygen's ( hemophilia program assets, including a next-generation recombinant Factor VIIa protein known as MAXY-VII. The therapeutic candidate was expected to enter Phase I clinical testing in the third quarter of this year. The total transaction is valued at $120 million, including a potential milestone payment of $30 million. This agreement also includes a

license to use Maxygen's MolecularBreeding technology, a novel research platform, for exploiting gene targets. In August, Vion Pharmaceuticals ( entered into an agreement with Hovan, a DutchBelgian cooperative clinical trial group in hematology oncology, to conduct a clinical trial of laromustine with front standard remission-induction therapy in patients aged 18-65 with previously untreated acute myelogenous leukemia and high-risk myelodysplasia.


Significant advances in colonoscopy technology should translate to strong growth for the gastrointestinal market, some experts say. According to a report by Millennium Research Group, the overall GI market was worth more than $1.2 billion in 2007 and is expected to increase to more than $1.6 billion in 2011, driven in part by demand for minimally invasive devices to diagnose colorectal cancer. These devices, Millennium says, include video colonoscopes, video sigmoidoscopes, and Given Imaging's ( technology, PillCam Colon ­ a pill the patient ingests containing a color video camera, light-emitting diodes, batteries, transmitter, and an antenna. Images are then taken of the gastrointestinal tract as the capsule travels through the body. Earlier this year, PillCam Colon was given a "not substantially equivalent" letter from FDA and denied approval for commercial distribution in the United States. The device is available in Europe and experts at Millennium believe should the technology ultimately enter the U.S. market, it will likely help to reduce colorectal cancer deaths as more patients will be willing to undergo the less-invasive diagnostic procedure. "Many individuals find the idea of colonoscopies unpleasant and embarrassing," says Tiffanie Demone, analyst, Millennium Research Group ( "This means not everyone who should be getting colonoscopies actually receives them, which often leads to late detection, and in some cases, death. Currently, colorectal cancer is the second-leading cause of death from cancer in the U.S." Also steering the gastrointestinal market will be strong competition among treatment offerings for Crohn's disease, a disease of the digestive system that occurs when the immune system attacks the gastrointestinal tract. Crohn's disease reportedly affects about 1.4 million Americans. In April, FDA granted approval for Cimizia as the fourth biologic agent for the treatment of Crohn's disease. The drug was developed by UCB Pharma ( Similar to market leader Remicade from Centocor Inc. ( and Humira, manufactured by Abbott (, Cimzia is an antibody that blocks the action of TNF, or tumor necrosis factor. TNF is a pro-inflammatory chemical known to play a central role in causing the pathology of a variety of inflammatory disorders including Crohn's disease and ulcerative colitis. The emerging TNF-inhibitor class has sparked health concerns recently. In September, FDA ordered the manufacturers of Humira, Cimzia, and Remicade to strengthen existing warnings in the prescribing information and medication guides for these drugs due to risks of developing histoplasmosis, an opportunistic fungal infection. Despite these concerns, analysts are predicting continued dominance by

TNF-inhibitors in the Crohn's disease market. According to a report by Decision Resources, Cimzia will earn the advisory company's proprietary clinical gold standard status for the treatment of Crohn's disease by 2011. Other new drug candidates or new indications in gastrointestinal disease include a new indication for Novartis' ( Gleevec; TZP-101, a drug under development by Tranzyme Pharma (; and Z-338, being developed by Japan-based Zeria Pharmaceutical Co. ( and Astellas Pharma Inc. (


Efforts to deliver new treatments for dermatological diseases should be strengthened by several acquisitions and collaborations launched to advance the skin disorder market. According to Visiongain (, revenue for the dermatological market was $16 billion in 2006, 5.1% more than in 2003. Visiongain predicts that the retail market for dermatological treatments will continue to grow significantly in what is an already large market. Corticosteroid agents will still be the main sales drivers in the market and botulinum toxin and other cosmetic treatments will play significant roles in the next several years. The most common skin disorders include acne, dermatitis, psoriasis, rosacea, urticaria, and hair loss. Some notable dermatology deals initiated this year include Antares Pharma Inc.'s ( agreement with Dr. Reddy's Laboratories Inc. ( to develop an innovative, topically applied product, using Antares' ATD Gel platform; PhotoMedex Inc.'s ( $13 million acquisition of Photo Therapeutics Limited (; and Stiefel Laboratories Inc.'s ( purchase of New Jersey-based Barrier Therapeutics Inc., a move that bolsters the pipeline of the world's largest independent dermatology drug supplier. York Pharma (, a specialty dermatology pharmaceutical company, recently acquired the sales and worldwide marketing rights to two dermatological/wound care products, Flammazine and Flammacerium, from Solvay Pharmaceuticals ( for a total consideration of E28.5 million ($22.6 million). In July, Allergan subsidiary Allergan Sales LLC acquired Aczone Gel 5% product, a topical treatment for acne vulgaris, from QLT Inc. ( Allergan paid about $150 million and expects to launch the product in fourth-quarter 2008 in the United States and Canada. According to the American Academy of Dermatology, acne is the most common skin disorder in the United States, affecting 40 to 50 million people. The topical prescription acne market is estimated by Data Monitor ( to exceed $1.2 billion annually. Psoriasis, where there is particular unmet need for effective long-term therapies, is another prominent category in the skin disease market. The market size for the psoriasis segment is deceptive because the treated and severe patient populations are comparatively small. As many as 7.5 million Americans have psoriasis, according to the National Institutes of Health. Ten percent to 30% of people with psoriasis also develop psoriatic arthritis, an inflammatory disease that causes pain, stiffness, and swelling in and around the joints.

According to a survey by BioTrends Research Group Inc. (, most dermatologists reported an increase in their use of biologics for the treatment of psoriasis in the past year, particularly in patients with moderate psoriasis. Certain physician types, particularly those newer to practice, seem to be more aggressive in their use of these agents. Enbrel, manufactured by Amgen ( and Wyeth ( continues to hold its position as market leader among biologics for psoriasis, but Abbott's Humira has increased its share significantly in the past year, and dermatologists expect its growth to continue, primarily at the expense of Enbrel. BioTrend also found that Genentech's ( Raptiva and Astellas' ( Amevive are rarely used, with a collective share of less than 10%. Time will tell whether late-stage interleukin-12 agents, such as Centocor's ( ustekinumab and Abbott's ABT-874, will be able to penetrate the TNF alpha inhibitor dominance in the dermatology setting, although interest in these psoriasis candidates is high. Last month, according to published reports, Allergan claimed two large human studies of its Botox drug, best known for smoothing wrinkles, have shown to benefit adults who suffer from chronic migraines. Allergan, reports say, will ask FDA in a filing next year to expand approval for the drug to cover chronic migraine, a condition the company says affects between 1.2 million and 3.6 million Americans.

Michael D. Christel can be reached via [email protected]


October 2008

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