Pharma NewsBytes: Oct 27nd- Nov 17th

LeadDiscovery's intelligence service, DailyUpdates has evolved as a key tool to help all in the drug development sector keep track of breaking journal articles, press releases and pharmaceutical reports. Pharma NewsBytes features selected press releases recently featured on DailyUpdates and offers the reader a leisurely stroll through the past few weeks of activity from within the pharmaceutical industry.

Pharma NewsBytes - Oct 27nd- Nov 17th

• The battle for the anti-hyperlipidemia market [more]
• Recent surges in rheumatoid arthritis development activity [more]
• Depressing news for anti-depressants[more]

The battle for the anti-hyperlipidemia market

In October AstraZeneca announced early figures concerning the sale of Crestor following its US launch in September (see our previous edition of Pharma NewsBytes - click here for access). Although positive, these were put in context nn November 12th when Pfizer released clinical data on Lipitor, Crestor's biggest competitor and indeed the world's top-selling medicine. The Pfizer study, "The Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study" presented at the annual meeting of the American Heart Association followed 502 patients, who were diagnosed with coronary heart disease and required cardiac catheterization, or angiograms. Patients in the 18-month study had at least one arterial vessel with 20 percent or more constriction due to plaque build up. The study compared the effectiveness of Lipitor (80 mg/day) versus Pravachol (40 mg/day) in reducing plaque build-up. Lipitor-treated patients experienced a median 0.4% reduction in total plaque volume. "These results clearly show that aggressively lowering cholesterol levels with atorvastatin calcium stopped the progression of atherosclerosis," said Dr. Steve Nissen, Medical Director of the Cleveland Clinic Cardiovascular Coordinating Center and Principal Investigator of the REVERSAL study. "This study further demonstrates the benefits of aggressively managing cholesterol levels to reduce the risk of atherosclerosis" [more]

Perhaps even more significant was however data released by Esperion Therapeutics a few days earlier on November 5th. According to researchers, patients who took Esperion's injectable experimental drug, ETC-216, for only five weeks reduced their artery plaque by 4.2 percent. This was the first time any drug had been shown to appreciably reverse atherosclerosis. Lipitor and Crestor are statins that inhibit HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. In contrast to the statins which reduce LDL levels, ETC-216 mimics HDL. Pfizer inherited the right to co-market ETC-216 when earlier this year it bought Pharamcia Corp, which had helped Esperion develop the candidate. This, as well as the success enjoyed by Lipitor and Pfizer's late-stage trials of a therapeutic that combines Lipitor with an HDL-raising compound called torcetrapib which works by blocking the so-called cholesteryl ester transfer protein suggests that the companies advantage in the anti-hyperlipidemia market will remain intact. In earlier studies, the Pfizer therapy raised HDL levels by over 50 percent and slashed LDL by up to 60 percent. "Our hope is that an agent like this will be the next blockbuster in cholesterol control," said Charles Shear, a senior Pfizer research executive. "The ultimate goal is to reverse the progression of atherosclerosis". "Pfizer is already in the forefront of cholesterol treatment with Lipitor and now has the opportunity to take the lead in HDL therapies with torcetrapib and their option on Esperion's drug," said Sena Lund, an analyst at Cathay Financial LLC. Lund said Pfizer next year will have the option to co-market ETC-216 in the United States, adding that its sales could be huge if the drug proves potent and safe in late-stage trials. "Anything that can reverse coronary plaque could be a multi-billion dollar drug"[more]

Most recently Esperion released further information on a second drug, called ETC-642, which demonstrated an ability to transport cholesterol off the artery wall at the site of plaque build-ups. No major side effects were observed in the Phase I, 28-patient clinical trial, which tested patients who had fatty plaque build-ups but had not experienced an acute heart problem. Like ETC-216, ETC-642 also demonstrated an ability to raise HDL in the first few hours after the drug was administered. That effect, combined with mobilizing cholesterol off the artery walls, could potentially stop dangerous plaque from building up or even reduce existing plaque[more].

Recent surges in rheumatoid arthritis development activity

October/November proved to be big in rheumatoid arthritis news, coinciding with the Annual American College of Rheumatology meeting. LeadDiscovery's recent state of the art analysis of emerging rheumatoid arthritis therapeutics evaluates many of the new molecular targets for this disease (click here), one of which is the MCP-1/CCR2 chemokine pathway. On October 14th Millennium announced the initiation of a multicenter phase II clinical trial of MLN1202, their novel humanized monoclonal antibody which is specifically designed to block this pathway. Primary objectives of this double-blind, placebo-controlled, multiple dose-escalation study in approximately 30 patients with rheumatoid arthritis are to assess the safety, tolerability, pharmacokinetic, pharmacodynamic properties and biological activity of MLN1202 via synovial biopsy. The study will be conducted in Europe and Australia. A phase I single dose-escalation study was initiated in December 2002 to evaluate the tolerability, pharmacokinetic and pharmacodynamic effects of MLN1202 in healthy volunteers. MLN1202 was well tolerated and no drug-related serious adverse events were reported among the 48 volunteers in that study. In that study, MLN1202 also demonstrated predictable dose-dependent pharmacokinetics and significant blockade of the MCP-1/CCR2 pathway. "Our confidence in the initial data we have reviewed has encouraged us to move MLN1202 rapidly into phase II trials, only nine months after the initiation of the phase I trial," said Arthur Hiller, vice president, global strategic marketing at Millennium. "Rheumatoid arthritis remains a significant area of unmet medical need and we are hopeful that MLN1202's novel mechanism of action may someday provide patients with a new treatment option". The MCP-1/CCR2 pathway plays a central role in the pathogenic inflammatory response cycle of cell signaling, activation and amplification of inflammation. CCR2 receptors are found on the surface of monocytes, macrophages and T-cells and bind monocyte chemoattractant proteins (MCPs). By binding to the CCR2 receptor, MCPs signal monocytes and T-cells to migrate to sites of injury as part of the inflammatory process. MLN1202 is designed to specifically block the MCP-1/CCR2 chemokine pathway and prevent infiltration of immune cells into inflammatory sites, such as arthritic joints [more].

A second press release from Roche, Genentech & IDEC Pharmaceuticals announced positive results from an extended Phase II study of MabThera (Rituxan), a second therapeutic described in LeadDiscovery's "Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates". Rituxan is a monoclonal antibody that targets B cells and is already one of the world's most successful cancer medicines, through its use in the treatment of non-Hodgkin's lymphoma, the most common form of blood cancer. The therapeutic has grown to become Roche's biggest seller, with sales of 2.3 billion Swiss francs ($1.75 billion) in 2002. Earlier this year, Roche predicted peak sales would reach 4.5 billion in cancer treatment alone, before allowing for potential use in arthritis. Previous clinical trials had demonstrated that the benefits of the drug extended to 24 weeks in rheumatoid arthritis patients. In a recent study, investigators followed up with patients who had completed a 24- week clinical trial, in order to assess duration of response with MabThera beyond the initial endpoint of 24 weeks. Participants in the 24 week, four arm, placebo controlled trial were randomized to receive MabThera alone or in combination with cyclophosphamide or methotrexate as compared to patients receiving MTX alone. Data from the trial, which involved 161 patients who had previously failed to respond to other therapies, showed MabThera relieved their symptoms when tested by itself or in combination with other treatments. At 48 weeks, 65 percent of patients receiving a combination of MabThera and methotrexate showed at least a 20 percent improvement in symptoms and 35 percent had at least a 50 percent improvement, Roche said in a statement detailing the results[more].

On a negative note however, Aventis and Vertex Pharmaceuticals announced voluntary discontinuation of phase IIb clinical trials of pralnacasan, an oral interleukin-1 beta converting enzyme (ICE) inhibitor, in rheumatoid arthritis. This decision was based on results from an animal toxicology study that showed liver abnormalities after a nine-month exposure to pralnacasan at high doses. There have been no significant adverse events associated with liver toxicity in subjects and patients who participated in pralnacasan studies to date. The decision was confirmed following a discussion with the Food and Drug Administration (FDA) that Aventis and Vertex had requested. During this discussion, the FDA supported the decision of Aventis and Vertex to discontinue present phase IIb clinical trials in rheumatoid arthritis. Also during this discussion, it was determined that two, shorter-term on- going phase I trials will continue as planned, as the FDA agreed with Aventis and Vertex that the toxicity findings based on longer-term regimens in animals did not imply safety concerns in the significantly shorter phase I trials. "This is an unexpected toxicology finding, and the prudent action is to discontinue the ongoing phase II clinical studies, and fully evaluate the toxicology results before moving ahead," said Frank Douglas, Executive Vice President of Drug Innovation & Approval and Member of the Aventis Management Board. "We are committed to working with Vertex to better understand and hopefully resolve this issue". "Pralnacasan is the subject of an extensive phase II clinical program, reflecting the promise of oral ICE inhibitors as a breakthrough strategy to treat a range of inflammatory diseases. Although we are disappointed with the results of the toxicology study, we support the decision to fully analyze the toxicology data, and we will work diligently with Aventis to evaluate the results to determine the appropriate path forward," said Vicki Sato, President of Vertex. "Both we and Aventis continue to believe that modulation of the ICE enzyme with an oral therapy holds the potential to change the way in which debilitating inflammatory diseases are treated[more].

Such surges in rheumatoid arthritis development activity are required. Up until recently the primary approach was through the use of NSAIDs which do not reverse the course of disease progression, rather, their primary activity is to limit symtoms. The GI side effects are well known and stimulated the development of Coxibs, a therapeutic class that targets the COX-2 enzyme as opposed to the tradditional NSAIDs wich inhibit both COX-2 and COX-1, the latter being responsible for GI ulcer formation. As announced in a recent press release however the Coxibs are related to cardiovascular side-effects. In particular, Brigham & Women's Hospital researchers found that Merck & Co's Vioxx was associated with an increased risk of heart attack, or acute myocardial infarction, compared with patients taking a competing painkiller, Celebrex, from Pfizer. The researchers also found Vioxx, which has annual sales of $2.5 billion a year, was linked to an increased heart-attack risk compared with patients not taking any painkillers. Researchers found that the apparent cardiac risk was greatest in the first 90 days in which a patient is taking Vioxx, which generically is known as rofecoxib. In the first 30 days, the researchers found, Vioxx was linked to a 39% increased heart-attack risk compared with Celebrex. Between 30 and 90 days, that increased relative risk was 37%. After 90 days, there didn't appear to be any increased risk. The absolute risk - that is, what percent of Vioxx users in the study actually had heart attacks - wasn't in the published abstract of this data, and Dr. Solomon the declined to comment[more].

Depressing news for anti-depressants

Following on from the adverse effect reported for Merck & Co's Vioxx (see above), the US drug giants run of dissappointing news continued with an announcement that it is discontinuing its Phase III clinical development program for its NK1 receptor antagonist, MK-0869, for the treatment of depression. The Phase III clinical program was halted because the compound failed to demonstrate efficacy for the treatment of depression. "There are significant challenges in scientific research, and unfortunately, sometimes disappointments," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "While we had reason to believe that the compound could be effective in the treatment of depression, the results of the Phase III trials did not demonstrate efficacy. Although Merck will not be continuing its clinical development program for MK-0869 in depression, we remain committed to our neuroscience research programs at our facilities in the United States and the United Kingdom," he said [more].