Arena Pharmaceuticals and U.S. partner Eisai reported positive data from a one-year Phase III trial evaluating the NDA-filed weight loss drug locaserin in obese and overweight patients with type 2 diabetes. The placebo-controlled Bloom-DM study met all of its three primary endpoints at week 52. These included: the proportion of patients losing at least 5% of their baseline body weight; change from baseline in body weight; and the proportion of patients losing at least 10% of their baseline body weight. Statistically significant improvements were also seen in multiple secondary endpoints, including levels of HbA1c.
The positive trial data comes just a couple of weeks or so after FDA issued a complete response letter (CRL) to Arena stating that its locaserin NDA, filed in December 2009, was not approvable in its current form. One of the reasons cited was that the weight-loss efficacy of lorcaserin in overweight and obese individuals without type 2 diabetes was marginal. FDA thus recommended that Arena submit the final study report of the Bloom-DM trial in patients with type 2 diabetes.
The Bloom-DM trial included 604 obese and overweight patients with type 2 diabetes. Participants were randomized to receive either locaserin 10 mg twice daily (BID), locaserin 10 mg once daily, or placebo. Primary efficacy endpoints were calculated using a modified intent-to-treat last observation carried forward analysis. At week 52, 37.5% of patients treated with lorcaserin BID achieved at least 5% weight loss, more than double the 16.1% of patients taking placebo. Lorcaserin BID therapy also led to a mean weight loss of 4.5% (4.7 kg), compared with 1.5% (1.6 kg) for placebo. 16.3% of lorcaserin BID patients achieved at least 10% weight loss, compared with 4.4% of patients taking placebo.
With respect to secondary endpoints, data from the first three families for which data is now available showed patients receiving locaserin BID achieved a 0.9% reduction in HbA1c, compared with a 0.4% reduction for placebo patients. Changes in fasting insulin, blood pressure, triglycerides, and total/LDL/HDL cholesterol were not significant.
The locaserin Phase III program involved three studies; Bloom, Blossom, and Bloom-DM. Over 7,800 patients were included. In September this year, in response to the December 2009-filed NDA, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 9 to 5 against approving the drug on the grounds that the available data did not adequately demonstrate that the potential benefits of lorcaserin outweighed the potential risks when used long-term in a population of overweight and obese individuals. FDA’s subsequent CRL to the NDA also stated that there was currently insufficient evidence to alleviate concerns regarding the clinical relevance of the tumor findings in rats. It suggests additional clinical studies may be required to obtain a more robust assessment of lorcaserin's benefit-risk profile.
Arena and Tokyo-based Eisai inked their U.S. locaserin-deal in July. Under terms of the $50 million up- front deal Arena granted Eisai exclusive U.S. rights to commercialize lorcaserin. Arena could receive up to another $90 million in milestone payments on regulatory approval and the delivery of product supply for launch. The firm will manufacture locaserin at its facility in Switzerland and supply the drug to Eisai for distribution in the U.S.
Arena is focused on the discovery and development of oral GPCR-targeting drugs against cardiovascular, CNS, inflammatory, and metabolic diseases. The firm has two additional clinical-stage candidates. APD791 is a selective inverse agonist of the serotonin 2A receptor in development for the treatment of arterial thrombosis and other related conditions. This candidate has completed Phase Ia and Phase Ib clinical trials. APD916 is a histamine H3 inverse agonist intended for the treatment of narcolepsy and cataplexy. A Phase I clinical trial with APD916 was initiated in March 2010. APD811 is a selective agonist of the prostacyclin receptor intended for the treatment of pulmonary arterial hypertension, which is currently in preclinical development.
Arena had in addition been working in collaboration with Ortho-McNeil-Janssen Pharmaceuticals (OMJP) on the development of GPR119-targeting compounds for the treatment of type 2 diabetes and other disorders. Positive Phase I results with the lead compound, APD597 were announced just last week, but OMJP said it had decided not to advance the candidate any further, and was terminating the collaboration. As a result, all compounds and associated IP relating to the partnership are being passed back to Arena.
Data from the Phase I study with APD597 showed the drug was well tolerated, and also provided evidence that APD597 therapy in overweight/obese nondiabetic and type 2 diabetes volunteers led to incretin stimulation (GLP-1, GIP, and PYY) and reductions in post-meal glucose increases. In general, reductions in post-meal glucose increases were greater with APD597 in combination with sitagliptin, a DPP-4 inhibitor, compared to sitagliptin alone.