A US Food and Drug Administration (FDA) advisory panel has voted 14 to 1 in favor of Novo Nordisk's injectable diabetes drug liraglutide for the treatment of obesity.
The specific proposed indication is "for chronic weight management in individuals with a body mass index of 30 kg/m2 or greater, or 27 kg/m2 or greater in the presence of at least 1 weight-related comorbidity."
Available in the United States since 2010 for the treatment of type 2 diabetes as Victoza, the glucagonlike peptide-1 (GLP-1) receptor agonist's proposed brand name for obesity is Saxenda. The dose for obesity will be 3.0 mg, in contrast to 1.2 or 1.8 mg for diabetes.
In support of their vote, panel members cited the drug's efficacy in lowering weight — despite an FDA analysis that showed somewhat lower efficacy than the calculation by Novo Nordisk — and the unmet need for more drugs to treat obesity as informing their decision.
The decision comes the same week that the FDA approved another obesity drug, bupropion/naltrexone (Contrave, Orexigen Therapeutics) — the 3 third available agent on prescription for obesity in the United States. If subsequently approved by the FDA, liraglutide will become the fourth agent for obesity.
Panelists expressed concern about the lack of data beyond 1 year for liraglutide in obesity and a variety of safety issues — including gallbladder disease, pancreatitis, breast and thyroid cancers, and increased heart rate — but most said they were comfortable with those issues being addressed in postmarketing studies.
And a majority of the panel agreed that the ongoing cardiovascular-outcomes trial of the 1.8-mg diabetes dose, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) study, would be sufficient to characterize the cardiovascular risk of the 3.0-mg dose in terms of identifying any signals that would need to be followed. Results from that trial, for which data on neoplasms and other adverse events are also being collected, are due in 2016.
Current labeling for Victoza (up to 1.8 mg) states that the drug is not recommended as first-line therapy for patients with diabetes because of concerns about thyroid C-cell tumors in rodents.
If the drug is approved for obesity, it would presumably be used as first-line pharmacotherapy. Panel members expressed a variety of viewpoints about how to handle that discrepancy. Some felt it was important to be consistent, while others said it wasn't a major problem because the 2 disease conditions are different and there are many more drug alternatives for diabetes than obesity.
Differing Efficacy Estimates
Anne Phillips, MD, senior vice president of clinical, medical, and regulatory affairs at Novo Nordisk, presented efficacy data for 4 phase 3 trials conducted in over 5000 patients, with more than 3000 receiving liraglutide 3.0 mg. Study completion was 70%.
In an analysis of the largest trial (using the last observation carried forward), involving 3731 patients, the liraglutide group lost an average 8% of body weight vs 2.6% with placebo at 56 weeks, thereby meeting the FDA benchmark for weight-loss drugs of a 5% difference between active treatment and placebo.
Significantly more patients taking liraglutide lost 5% or more of their body weight vs placebo (63.5% vs 26.6%), and 32.8% and 10.1% patients, respectively, lost more than 10%. The FDA benchmark for losing 5% or more of body weight is 35% or greater.
However, FDA statistical reviewer Bradley McEvoy, PhD, presented an alternative analysis using "retrieved dropouts" to counter the company's assumption that the weight of patients who dropped out wouldn't change up to the study end at 56 weeks.
That analysis produced treatment differences between drug and placebo of 4.6% and 4.8%, slightly less than the FDA benchmark, but not enough to concern the committee.
Common Adverse Events Mainly Gastrointestinal
In the trials, the most common adverse events with liraglutide 3.0 mg vs placebo were nausea (39% vs 14%), diarrhea (21% vs 10%), vomiting (16% vs 4%), and hypoglycemia when used in combination with sulfonylureas despite a halving of the sulfonylurea dose (15% vs 6%).
Serious adverse events included acute pancreatitis (7 patients with liraglutide vs 1 with placebo) and acute gallstone disease (2.3% vs 0.9%). Dr. Phillips attributed those events to weight loss, but FDA reviewer Julie Golden, MD, said there was not enough information to determine the mechanism.
Another FDA reviewer, Christian Hampp, PhD, presented an analysis of cancer incidence in the clinical trials. Overall, the rate of neoplasms was not significantly greater with liraglutide 3.0 mg, but the incidence of thyroid neoplasm — 4 with liraglutide vs 1 with placebo – was nearly 4 times greater than what would be expected in the general population.
Female breast neoplasms were numerically greater with liraglutide — 12 vs 2 with comparator drugs — but the difference was not significant.
In the ongoing cardiovascular-safety trial, liraglutide 3.0 mg was associated with a significant increase in heart rate of 2 to 3 bpm.
Panel Counting on Postmarketing Data
Panel member Susan Z. Yanovski, MD, codirector of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, voted for approval.
"I think liraglutide appeared to have a favorable risk/benefit ratio [and] may be useful for patients with obesity and dysglycemia....There are still concerns about pancreatitis, but I think that can be addressed postmarketing."
Dr. Yanovski also recommended that the drug's label contain instructions to discontinue use if there is no clinically meaningful weight loss after 12 weeks.
Acting panel chair Kenneth Burman, MD, chief of the endocrine section at Washington Hospital Center, DC, also voted yes, but noted several caveats.
"In general, I certainly agree with the need for additional obesity agents that are useful," he said but added, "the studies here are relatively short term and the chronic use of liraglutide was not analyzed. It's difficult to know if a 5% to 8% weight loss is beneficial with regard to heart outcomes. It’s also difficult to know whether a 2- to 3-bpm increase in heart rate will be detrimental in the long run."
Dr. Burman also said he's "not completely assuaged" about the thyroid-cancer risk, calling for that and other safety concerns to be addressed in postmarketing studies. He also called for guidelines regarding when to stop using the medicine.
And David W. Cooke, MD, associate professor of pediatrics and clinical director of pediatric endocrinology at Johns Hopkins University, Baltimore, Maryland, said, "I thought the data very clearly supported efficacy in terms of weight loss, at least in a very large subset of patients taking it."
However, he added: "I'm less confident in the long-term health benefits, but I think since the safety data didn't raise any marked new concerns beyond what's already been considered for the marketed dosage, at this point I think it's reasonable to have it on the market as a weight-loss drug. [This will] allow the physician and patient to weigh those risks and benefits on an individual basis....Hopefully we'll get more data on the benefits as well as the safety in the postmarketing timeframe."
FDA advisory panel members are vetted for conflicts of interest and waivers granted for participation if necessary. No waivers were granted for this meeting.
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Cite this: FDA Panel Endorses Liraglutide as Obesity Treatment - Medscape - Sep 12, 2014.
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