- An FDA Advisory Committee voted 11-1 to approve BMS/AZ’s metreleptin for generalized (“complete”) lipodystrophy.
- However, it voted 2-10 against approving the drug for metabolic disorders associated with partial lipodystrophy such as hypertriglyceridemia, diabetes, and/or fatty liver.
An FDA Advisory Committee voted 11-1 today to approve BMS/AZ’s leptin analog, metreleptin, for a generalized (“complete”) lipodystrophy indication and 2-10 against approving it for metabolic disorders associated with partial lipodystrophy such as hypertriglyceridemia and/or diabetes inadequately controlled on existing therapy and/or evidence of hepatic steatosis (fatty liver). The decision to vote “yes” for generalized lipodystrophy was an easy one for the panel – the disease is a devastating one characterized by severe metabolic abnormalities such as extreme insulin resistance, hypertriglyceridemia, liver disease, and severe hunger due to leptin deficiency (please see our meeting preview for background on the disease) – for example, the 72 patients in the pivotal NIH studies for the BLA required a median of ~500 (!) daily units of insulin (some required up to 2,000 units/day) and were still not adequately controlled. In the NIH trials, 93% of lipodystrophy patients had diabetes (those with diabetes had a mean age of only 25 years), 85% had liver disease, 83% had hypertriglyceridemia, and 71% had renal disease. Although the available data are extremely sparse, as would be expected for an orphan disease, it was clear to panelists that metreleptin substantially improved the metabolic abnormalities associated with generalized lipodystrophy (see specific data in our preview of the meeting). Although the data were not perfect (no control group, multiple changes to trial protocol/dosing), and there were serious risks to consider (namely immunogenicity and, to a slightly lesser degree, lymphoma) the severe unmet need of this population warranted approval.
The decision to ultimately vote against approval of the proposed partial lipodystrophy indication was a difficult one for many panelists – most recognized that this group also had a serious unmet need and that there were likely a group of patients who would benefit from access to metreleptin treatment. However, the panelists were not convinced that the data showed a clear benefit that trumped the risks and uncertainties associated with the dataset. The benefits achieved by the partial lipodystrophy group were less pronounced than those achieved by the generalized lipodystrophy group. In addition, some confounding factors, such as the addition or change of concomitant medications soon after enrolling in the study, made it impossible to tell whether the benefits that some patients experienced were due to metreleptin or the confounding factors. Most panelists believed that the partial lipodystrophy indication proposed by BMS was too broad and that if a specific subgroup were identified that clearly benefitted from treatment (e.g., defining a baseline leptin threshold or degree of metabolic dysregulation), then they would feel more comfortable approving the treatment. However, given the limited data available at this point, they had no way to define that population and did not want to unnecessarily expose patients to a risky treatment for uncertain benefit. In our view, the path that would most benefit patients while minimizing risk of unnecessary drug exposure would be for the FDA to approve metreleptin for partial lipodystrophy with a stopping rule that required patients to stop taking the drug if a certain amount of benefit were not achieved. This was an option to which a couple of panelists alluded, and one we wish would have been advocated even more strongly. We hope that BMS/AZ might be able to negotiate a narrower partial lipodystrophy indication than proposed to the Advisory Committee. Such an indication could potentially be expanded if greater clinical experience with the agent demonstrates its safety and efficacy in the broader partial lipodystrophy population.
The patient testimonials delivered at the Open Public Hearing (OPH) were some of the most moving we have heard at any Advisory Committee meeting – most patients (and parents) expressed the sentiment that they (or their children) had absolutely no hope of living a life that even resembled normalcy before initiating metreleptin. The ADA’s renowned Chief Scientific and Medical Officer, Dr. Robert Ratner, also delivered a speech during the OPH (he was the only non-patient/parent to speak) urging committee members to remember “the fact that a therapeutic agent is not appropriate for everyone does not mean that it is not appropriate for anyone.” We are supremely grateful that he spoke.
These were some of the most moving quotes we heard at the OPH:
- “As a child, I wanted to commit suicide every day. Before I started leptin nine years ago, every time I would go into a doctor’s office with an expiration date on my forehead. Doctors never believed in me until leptin… We all have to die someday, but at least with [metre]leptin I can come forward and say I can believe in tomorrow… [taking [metre]leptin away] would be the same thing as taking chemotherapy away from a cancer patient. There are always negatives to a drug, but help us who are in silence be heard, because lipodystrophy was always in silence until leptin.” – 22-year-old patient with congenital generalized lipodystrophy.
- “Partial lipodystrophy may not appear as drastic, but anecdotal evidence for us shows that metreleptin makes extremely significant improvements in quality of life. Extremely significant improvements. We need to have the option, the partial subtype, to expand on our options… We deserve the chance to make the choice with our physicians. We’ll show you it works.” – 41-year-old patient with partial lipodystrophy who was not diagnosed until age 38 but experienced symptoms since puberty; President of Lipodystrophy United.
- “[Before [metre]leptin, my son’s] starvation was unbelievable. At dinner he would eat four quarter pound hamburgers with fixings; from 7:00 – 10:00 PM, three triple decker sandwiches, two to four apples and oranges, and in bed he would hold a package of crackers that he would eat until he fell asleep. When he fell asleep I had to make sure he didn’t have any food in his mouth. He would literally tear doors off hinges to get to food. At school he had a locker for food and one for books. In school he had to eat all day or he could have killed people with the aggression that seized him.” – Father of a 14-year-old with acquired generalized lipodystrophy.
-- by Jessica Dong and Kelly Close