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R&D In Brief

This article was originally published in Pharmaceutical Approvals Monthly

Executive Summary

Zetia/Lipitor combo NDA becomes Merck's latest cardiovascular casualty: FDA refused to file Merck's NDA for a fixed-dose combination pill of ezetimibe (Merck's Zetia) and atorvastatin (Pfizer's Lipitor) known as MK-0653C, the drug maker revealed in a filing with the SEC on Nov. 2. "FDA has identified additional manufacturing and stability data that are needed, and the company is assessing the FDA's response in order to determine a new timetable for filing," Merck said. Ezetimibe, a cholesterol absorption inhibitor, is approved in the fixed-dose combination Vytorin with a different statin, simvastatin (Merck's Zocor and generics), that has faced its share of controversy. The ENHANCE study found that Vytorin was no better than simvastatin alone in preventing the formation of arterial plaque, despite lowering cholesterol (1"The Pink Sheet," April 21, 2008). Other Merck attempts at expanding its cardiovascular franchise have also hit roadblocks, including the heart failure candidate rolofylline, which flunked a Phase III trial in April, and the combination of niacin with the novel anti-flushing agent laropitant, which was deemed "not approvable" in 2008 and is not expected to be refiled until at least 2013 (2"The Pink Sheet" DAILY, June 20, 2008)

Zetia/Lipitor combo NDA becomes Merck's latest cardiovascular casualty: FDA refused to file Merck's NDA for a fixed-dose combination pill of ezetimibe (Merck's Zetia ) and atorvastatin (Pfizer's Lipitor ) known as MK-0653C, the drug maker revealed in a filing with the SEC on Nov. 2. "FDA has identified additional manufacturing and stability data that are needed, and the company is assessing the FDA's response in order to determine a new timetable for filing," Merck said. Ezetimibe, a cholesterol absorption inhibitor, is approved in the fixed-dose combination Vytorin with a different statin, simvastatin (Merck's Zocor and generics), that has faced its share of controversy. The ENHANCE study found that Vytorin was no better than simvastatin alone in preventing the formation of arterial plaque, despite lowering cholesterol (1 (Also see "FDA Changes Its Mind On Vytorin; Ads Must Note “Efficacy Limitation”" - Pink Sheet, 21 Apr, 2008.)). Other Merck attempts at expanding its cardiovascular franchise have also hit roadblocks, including the heart failure candidate rolofylline, which flunked a Phase III trial in April, and the combination of niacin with the novel anti-flushing agent laropitant, which was deemed "not approvable" in 2008 and is not expected to be refiled until at least 2013 (2 (Also see "FDA Seeks Outcomes Data For Merck’s MK-0524A" - Pink Sheet, 20 Jun, 2008.)).

Affymax's ESA Hematide could correct anemia in PRCA patients: Phase II results published in the Nov. 5 issue of the New England Journal of Medicine suggest Affymax/Takeda's erythropoiesis-stimulating agent Hematide could be an alternative anemia therapy in patients with EPO-induced pure red cell aplasia (PRCA). In the trial, Hematide increased hemoglobin and reduced or eliminated the need for blood transfusion in most patients with EPO-induced PRCA, a rare and debilitating autoimmune disorder that can occur when the body produces neutralizing antibodies against the currently marketed EPO products, thus suppressing the production of red blood cells by the bone marrow. The condition can significantly limit treatment options for anemia in patients with chronic kidney disease and requires them to receive regular blood transfusions. Hematide is a synthetic, pegylated peptide-based EPO receptor agonist with no sequence homology with human EPO, and hence is not expected to induce PRCA. The firms' Phase III program is scheduled to wrap up by year end, due to $42 mil. in public and private financing secured in February (3 (Also see "Affymax Swings $42 Million Financing To Push Hematide" - Pink Sheet, 17 Feb, 2009.)).

Phase III begins for Dimebon in AD: Pfizer and Medivation have kicked off another two Phase III trials for their Alzheimer's disease candidate Dimebon (latrepirdine), the firms announced Nov. 3. The new trials, which mean a total of seven studies in the Phase III program, both study Dimebon in combination with other AD therapies. In the CONTACT study, the primary endpoints are the benefits in neuropsychiatric symptoms and activities of daily living when Dimebon is added to ongoing treatment with leading AD treatment donepezil. The second study, CONSTELLATION, will evaluate the cognitive and daily living effects of adding dimebon to memantine. Dimebon, which is also in Phase II development for Huntington's disease, has been shown in preclinical studies to protect brain cells from damage and enhance brain cell survival. The deal between the two sponsors was one of the highest value AD deals ever, with Pfizer paying $200 mil. upfront to Medivation for development rights (4 (Also see "Alzheimer's Partnerships: Sharing Risks, Chasing Potentially Huge Rewards" - Pink Sheet, 10 Aug, 2009.), p. 24).

NovaRx expands enrollment for Lucanix trial: A Phase III trial of NovaRx's non-small cell lung cancer drug Lucanix should progress more speedily now that the firm has expanded patient eligibility to include patients with stable brain metastases, the firm announced Nov. 4. Other amendments to the Special Protocol Assessment agreement between the firm and FDA include expanded stratification criteria and the ability for investigators to treat patients with decreased serum albumin levels. The firm said the eligibility amendment will significantly widen the subject pool since as many as one in three NSCLC patients have stable brain metastases.

New BLOSSOM data could improve outlook for Arena's lorcaserin: Additional analyses from Arena's Phase III BLOSSOM trial of the obesity candidate lorcaserin elucidate additional efficacy parameters that will be important when the weight loss drug faces FDA review. At the Oct. 27 annual meeting of the Obesity Society, the firm touted improvements or favorable trends compared to placebo on the secondary endpoints of body composition, cardiovascular risk factors and quality of life, areas that have previously tripped up obesity drugs. The data build on the basic efficacy data the company played up as supportive of approval, but which disappointed the market because they only met FDA standards on one of two criteria, and only for one of two doses studied (5 (Also see "Obesity Déjà Vu: Arena Airs More Mixed Phase III Data" - Pink Sheet, 18 Sep, 2009.)). Results from BLOOM - the other half of the firm's Phase III program - were greeted with similar investor ambivalence as lorcaserin met the categorical standard, but not the standard that measures results compared to placebo (6 (Also see "Arena Defends Obesity Drug After Phase III BLOOM Wilts" - Pink Sheet, 30 Mar, 2009.)). Arena maintains the efficacy data will support approval, but there has been no test of FDA's policy - and whether the categorical standard alone will suffice - since the draft guidance on obesity drug development was released. If the company is right, the new data could be important. The improvement of patients' cardiovascular risk profiles would separate the drug from the infamous "Fen-phen," pulled from the market in 1997, while the fact that lorcaserin did not increase depression or suicidal ideation would assuage concerns that its central nervous system-acting mechanism of action would be cause for psychiatric adverse events - a pitfall that trapped the CB-1 antagonist class, most notably Sanofi Aventis' rimonabant (7 'The Pink Sheet,' Nov. 10, 2008).

Enrollment begins for Curemark's autism trial: Curemark has enrolled the first patients in Phase III trials for its autism treatment, CM-AT. The firm is hoping to address the underlying physiology of autism rather than just treat symptoms; CM-AT was born from research revealing enzyme deficiencies in autistic children that cause the inability to digest protein - and thus affect the production of amino acids, the building blocks of chemicals essential for brain function. The trials will take place at 12 U.S. sites and enroll a total of 170 children.

Gilead/GSK compare Letairis, tadalafil in outcomes trial: Gilead and GlaxoSmithKline are planning an international morbidity and mortality trial to compare combination therapy and monotherapy for first-line treatment of pulmonary arterial hypertension, hoping to resolve an important outstanding question in PAH. The AMBITION trial will enroll 300 treatment-naïve PAH patients and randomize them to treatment with Gilead/GSK's Letairis (ambrisentan) and tadalafil (Lilly's Cialis/Adcirca ) in combination or each agent as monotherapy. The endothelin receptor antagonist Letairis was approved in June 2007 for treatment of WHO Class I patients with WHO functional Class II or III symptoms to improve exercise capacity and delay clinical worsening. The PDE5 inhibitor tadalafil was approved in May 2009 to improve exercise ability in WHO Class I patients. GSK and Gilead are working with regulatory agencies and the PAH research community on the study design, and hope to start enrollment in 2010.

Peek at Roche/Ipsen liraglutide Phase III data heats up GLP-1 race: Release of the first Phase III data for Roche and Ipsen's human glucagon-like peptide-1 analog taspoglutide may not have given more than a peek at top-line results, but it showcases the changing dynamics of the GLP-1 field - including the dosing and comparative data requirements that will be important to carving out a space in the market. Positive findings of the 1,189-patient open-label Phase III T-EMERGE 2 study, released Oct. 29, showed that once-weekly taspoglutide met the primary endpoint of non-inferiority to Lilly/Amylin's marketed twice-daily GLP-1 analog exenatide ( Byetta ) and showed a superior reduction in HbA1c levels after 24 weeks of treatment. The study is the first of eight Phase III trials on taspoglutide, and the full program is designed to capture comparisons against a gamut of major brands in the type 2 market. Roche and Ipsen hope to capitalize on the continued delay in approval of Novo Nordisk's competitor liraglutide. This once-daily drug, approved in the EU as Victoza in July 2009, was held up at FDA earlier this year following a split advisory committee vote in April over the relevance to humans of a pre-clinical thyroid cancer signal in rodents. Timing of the U.S. approval for liraglutide remains unclear, despite ongoing dialog with FDA (8 (Also see "Novo Disappoints With No Liraglutide News, But Growth Is Strong" - Pink Sheet, 6 Aug, 2009.)).

Dong-A PharmTech's ED drug enters Phase III: Warner Chilcott has initiated two Phase III trials of the investigational long-acting erectile dysfunction drug udenafil, the firm's South Korean partner Dong-A PharmTech announced Nov. 4. The placebo-controlled trials of approximately 1,120 ED patients will be conducted in 80 U.S. sites. The firms are also planning Phase IIb studies evaluating the drug for benign prostatic hyperplasia and pulmonary arterial hypertension. Udenafil would be the fourth phosphodiesterase-5 inhibitor to hit the market. It has been cleared in South Korea since 2005, under the trade name Zydena . Dong-A has conducted a successful Phase II trial in the U.S., and anticipates completing the Phase III program in the next two years.

REMS delays action on GSK's restless leg drug: FDA has extended the action date for GlaxoSmithKline/XenoPort;s restless leg syndrome drug gabapentin/enacarbil by three months to review the Risk Evaluation and Mitigation Strategy it asked GSK to submit. The user fee clock, originally set for Nov. 9, now reads Feb. 9, 2010. If approved, Lazard Capital Markets analyst William Tanner forecasts peak U.S. sales of the drug at $323 mil., and that uptake will be slow due to a fully generic market and established first- and second-line therapies for RLS: dopamine agonists, and gabapentin and Pfizer's Lyrica (pregabalin), respectively. The sponsors argue the drug would be the first non-dopaminergic agent for initial treatment of RLS and would offer potential advantages over GSK's Requip (ropinirole) (9 (Also see "Restless Leg Syndrome Market Prepares To Move As GSK, UCB Advance Drugs" - Pink Sheet, 1 Jan, 2008.)).

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