Updated with correction to accurately describe the 6% mean weight-loss observed in the lorcaserin phase III trials.
The outcome of Thursday's FDA advisory panel is still unknown, of course, but Arena bulls (the "Areniacs") should feel more confident in a positive vote recommending lorcaserin's approval.
Arena shares are up 41 cents, or 15%, to $3.14 in recent trading.Arena's lorcaserin still doesn't help people lose much weight. A 300-pound person is going to lose about 18 pounds after a year of treatment. But the efficacy hurdle for approval of an obesity drug in the U.S. is low, so lorcaserin gets a pass. More important to the outcome of Thursday's FDA advisory panel, the agency appears to be relatively satisfied with lorcaserin's safety. Several of the issues that dogged the drug and caused it to be rejected in 2010 have been addressed, according to my interpretation of FDA's briefing documents released today. FDA seems less concerned about lorcaserin-fueled rat tumors and the potential risk for breast cancers and other tumors in humans. On the subject of mammry adenocarcinomas in rats, FDA reviewers state: "Readjudication by the PWG allowed identification of a 24-fold safety margin for mammary adenocarcinoma relative to the clinical dose of 10mg bid lorcaserin. In general, the Agency interprets a 24-fold safety margin to a non-genotoxic carcinogen in rodents as indicative of negligible risk to human subjects." FDA did conclude that lorcaserin causes significant increases in benign fibroadenomas in rats with no acceptable safety margin relative to human doses, but the agency also downplays the concerns. "Lorcaserin minimally effected plasma and tissue prolactin and differentiation of mammary lobular structures in female rats in mechanistic studies up to three months duration, but the changes that were observed are consistent with hormonal action on mammary tissue. No pattern of change was observed for estrogen, progesterone, or luteinizing hormone, and the Agency is not aware of a threshold of prolactin beyond which mammary tumors emerge. Given the high sensitivity of SD rats to prolactin and the absence of changes in other hormones, it is plausible that minimal increases in prolactin induced by lorcaserin contributed to the emergence of fibroadenoma in female rats." On the question of whether lorcaserin's mechanism is "dirty" and therefore may activate receptors known to cause heart valve damage, FDA says this: "The 2011 receptor potency data provides supportive evidence that off-target activation of the 5HT2A or 2B receptors is unlikely at the proposed clinical dose of lorcaserin (10mg bid). This is consistent with neurological and cardiac assessments in animals which did not identify major toxicities that would be anticipated if 5HT2A and 2B were activated by lorcaserin. However, limitations in neurological assessments and the lack of validated models for drug-induced valvulopathy in animals preclude a definitive prediction that lorcaserin will be devoid of such toxicities should it be approved for marketing." Still, concerns about lorcaserin's negative effect on heart valves -- so-called valvulopathy -- remains. This is probably the most significant risk going into Thursday's FDA panel because heart safety data pooled from the three phase III studies trips a statistical red flag for FDA. "Nevertheless, in the pooled analysis of the Phase 3 echocardiographic data, the relative risk for FDA-defined valvular heart disease (VHD), defined as mitral regurgitation greater than mild or aortic regurgitation greater than trace was 1.16, with a 95% confidence interval (CI) of 0.81 to 1.67. This upper bound exceeds the 1.5 upper bound requested by FDA to rule out an excess risk of VHD. The point estimate and upper bound were similar in a number of sensitivity analyses conducted by the sponsor and FDA statistician. Furthermore, individual valve regurgitation was fairly consistently increased in the lorcaserin treatment group. Whether these findings can be explained by ascertainment or other bias (due to greater weight loss in the lorcaserin group) is unknown." And with all that, the odds of a positive vote at Thursday's panel must go up. I was at 30-40% last week, predicting a negative panel. This morning, I'm at 60% odds favoring a "yes" vote. Lorcaserin appears to be a drug that will help enough people lose a little bit of weight without causing too much harm. We can debate whether such a drug is worthy of widespread use (I say no) but in today's regulatory environment, this seems to be an "approvable profile" for an obesity drug. The experts on FDA's advisory panel get to have their say on Thursday. I will be live-blogging the proceedings all day, so please tune in for the fun. --Written by Adam Feuerstein in Boston.
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