Just a day after the FDA cleared a fourth drug to treat obesity, the agency's Metabolic Drugs Advisory Committee (adcom) on Thursday voted 14-1 to recommend that the agency approve Saxenda, a 3-mg dose of the Novo Nordisk A/S drug liraglutide for adult obesity ahead of its Oct. 20 PDUFA date.

Despite desiring deeper long-term safety data on some points, adcom members set aside worries about selective glucagon-like peptide-1 (GLP-1) receptor agonists – the class to which liraglutide belongs – and obesity drugs in general as they sought to put in doctors' hands a new tool for helping patients fight obesity and, by extension, stave off diabetes in some cases.

"After decades of rising obesity rates among adults, the rate of increase is beginning to slow," noted the Robert Wood Johnson Foundation in a recent repornt on the state of obesity in the U.S., "but rates remain far too high and disparities persist."

Liraglutide is already sold at a lower dose as Victoza for type 2 diabetes. If the FDA moves to approve Saxenda's higher dosage for obesity, it would build on Wednesday's approval of Contrave (naltrexone and bupropion, Orexigen Therapeutics Inc. and Takeda Pharmaceuticals U.S.A.) and other therapies, including Belviq (lorcaserin, Arena Pharmaceuticals Inc./Eisai Inc.) and Qsymia (phentermine/topiramate, Vivus Inc.). (See BioWorld Today, Sept. 10 and Sept 11, 2014.)

"We are pleased with the clear recommendation from the advisory committee," said Mads Krogsgaard Thomsen, Bagsvaerd, Denmark-based Novo's executive vice president and chief science officer. "Obesity is a serious public health issue in the U.S. and we are committed to making Saxenda a new treatment option for adults with obesity."

The recommendation was based on data from clinical trials of Saxenda, including the phase III SCALE clinical trial program, which involved more than 5,000 people with a body mass index (BMI) of greater than or equal to 30 kg/m2, or who were overweight, with BMI greater than or equal to 27 kg/m2 with comorbidities.

As a baseline, FDA guidance endorses any weight loss of 5 percent or more as clinically meaningful. Patients taking Saxenda combined with a low-calorie diet and increased exercise in a phase IIIa diabetes trial, called SCALE, achieved mean weight loss of 5.9 percent compared with 2 percent placebo weight loss at 56 weeks, while an earlier trial showed even greater weight loss. (See BioWorld Today, May 19, 2014.)

Despite the benefits illustrated in the Novo's pivotal trials of the drug, some adcom members worried about the magnitude of response to drug, potential cardiovascular risks and an imbalance in neoplasias that appeared in late-stage trial data.

One patient representative, Lynn McAfee, director of the Medical Advocacy Council on Size & Weight Discrimination put her concerns bluntly, saying that "I think that on the whole the sponsor has met the efficacy standards, but barely."

But FDA staff addressing the adcom said their review of Novo's Saxenda application showed the drug effective for weight loss, adding that, in their analysis, data provided by Novo neither confirmed nor excluded the possibility of a causal role for the drug in thyroid and breast cancer.

With regard to comorbidities, adcom members agreed that there were relatively few concerns about cancer, but that perhaps further study of incidents of breast cancer should be studied. Though, it was suggested that slightly elevated rates of the cancer in the study could have been attributable not to the drug but rather from higher rates of mammography and other screening for obese women.

Adcom members also agreed that though there was not a strong signal in any of the data linking it to medullary thyroid cancer (MTC), the few cases that did occur in the trial population may bear discussion in the Saxenda's package insert along with other side effects including elevated risks of pancreatitis, nausea and vomiting should the drug be approved.

BUMPING UP THE BEAT

Given the checkered history of cardiovascular risk in obesity drugs, the panel took particular interest in data showing that Saxenda raised the heartbeats of patients taking the drug by two to three beats per minute. Nonetheless, members agreed that because there's little research on the long-term effects of slightly elevated heart rates, that impact was not of tremendous concern.

There was general consensus on the committee that there was no worrying signal on cardiovascular disease attached to Novo's data on liraglutide injected at 1.8 mg per day, and no preliminary data that a 3 mg dose illustrated any increased risk of detrimental cardiac effects. That suggested it would be unlikely, at least if the adcom's recommendation is fully followed, that Novo would be required to run a large and expensive trial to assess CV events for the Saxenda alone.

Nonetheless said Novo's global chief medical officer Alan Moses, the company is examining CV events, including arrhythmias, heart failure, thrombosis and the elevated heart rate in LEADER, an international study investigating Victoza.

In the end, just David Kelsen, an attending physician in the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center voted against recommending the FDA approve Saxenda. He said he didn't believe the committee had enough information to mitigate the risks of malignancy and would like to see populations at high risk for malignancies addressed by FDA in the drug's label.