FDA raises safety, efficacy questions for Bristol-Myers' rare-disease drug metreleptin

Bristol-Myers Squibb ($BMY) will go into its Wednesday panel session for the lipodystrophy drug metreleptin with an agency review that offers a grudging concession on signs of efficacy for a subgroup of patients along with some serious questions about potential safety issues and a number of criticisms for the way the clinical trial program was designed and executed.

Patients with lipodystrophy experience a loss of fat tissue under the skin, which in turn causes a shortage of the human hormone leptin, which can cause some severe complications. Metreleptin is an analogue of leptin--meaning it's comparable to the hormone--and only a few thousand patients around the world suffer from the condition. Bristol-Myers snagged the drug in its acquisition of Amylin and then partnered it with AstraZeneca ($AZN) as part of a broad collaboration that advanced the program for the treatment of diabetes and hypertriglyceridema -high levels of triglycerides in the bloodstream.

On the bright side, the FDA notes: "A subgroup of patients appears to have achieved benefits from metreleptin that would be unlikely to have been achieved spontaneously: patients with generalized lipodystrophy (congenital or acquired) with severe insulin resistance resulting in diabetes mellitus and/or severe hypertriglyceridemia not adequately controlled with other therapies." And that response, the agency adds, is consistent with the drug's mechanism of action.

The dark side: Without a control group in the pivotal study, run by the NIH, it's hard to tell whether the drug was assisting patients or whether that was something that was spurred by a change of diet or compliance with other meds. And with lipodystrophy patients already subject to various related medical conditions, the FDA reviewers were left wondering about instances of T-cell lymphoma that occurred in the patient population. Several of the patients developed neutralizing antibodies that raised concerns about the potential breakdown of the immune system, with bacterial infections plaguing one of the subjects.

"With respect to lymphoma, although patients with acquired forms of lipodystrophy may be predisposed to developing lymphoma, it is biologically plausible that metreleptin could act as a cancer promoter," says the review. "It is unknown whether metreleptin had any role in the development of T-cell lymphoma in the three patients with lymphoma in the NIH trial; however, it is also unclear if there is any way to mitigate this risk, given that one of the three patients had no identified risk factors, aside from AGL."

Outside experts for the FDA will now step in for a formal review, offering their thoughts on approval and risk mitigation strategies ahead of a final decision from the agency.

- here's the FDA review (PDF)