An FDA advisory committee’s endorsement of Novo Nordisk AS’ liraglutide for chronic weight management also could mean a broader label for the glucagon-like peptide-1 receptor agonist’s current use in type 2 diabetes.

Approval of liraglutide (proposed brand name Saxenda) for first-line use in weight management would provide an opportunity for the agency to remove a second-line restriction on liraglutide in diabetes, where it is branded as Victoza.

Novo Nordisk demonstrated efficacy in accordance with FDA’s 2007 guidance on weight management drugs, panelists said.

The Endocrinologic and Metabolic Drugs Advisory Committee on Sept. 11 voted 14-1 that the risk/benefit assessment for liraglutide 3 mg per day supports approval for chronic weight management in individuals with an initial body mass index of 30 kg/m² or greater or 27 kg/m² or greater in the presence of at least one weight-related comorbidity.

In their votes, panelists generally said that Novo Nordisk had demonstrated efficacy in accordance with FDA’s 2007 guidance on weight management drugs. Although some safety concerns remain, such as an imbalance in breast cancer cases in the weight management trials, these could be tracked post-approval, panelists said.

However, panelists recommended that FDA include stopping criteria in labeling to ensure that patients who do not respond within a certain period of time be taken off the drug – similar to labeling for existing obesity drugs. Some committee members also requested that labeling include not just the sponsor’s primary efficacy analysis but also an FDA sensitivity analysis that showed a smaller, though still statistically significant, magnitude of effect in weight reduction.

The vote puts Saxenda on track to become the fourth new entrant in the obesity setting in the last several years, although it would be the only injectable in the pack. The product’s user fee date for the weight management indication is Oct. 20.

The liraglutide meeting was held the day after FDA’s long-awaited approval of Orexigen Therapeutics Inc. and Takeda Pharmaceutical Co. Ltd.’s weight management drug Contrave (naltrexone sustained-release/bupropion sustained-release) ([A#14140911005]).

Contrave joins two other drugs that have had trouble gaining traction in the obesity market – Vivus Inc.’s Qsymia (phentermine/topiramate ER) and Eisai Inc. and Arena Pharmaceuticals Inc.’s Belviq (lorcaserin).

Restricted In Diabetes

FDA’s 2010 approval of Victoza in daily doses up to 1.8 mg for type 2 diabetes came with a boxed warning about thyroid C-cell tumors observed in rodent studies and the caveat that it is unknown whether the drug causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. MTC is rare, accounting for approximately 3%-10% of all thyroid cancer cases.

Victoza labeling includes a recommendation against use as a first-line therapy in diabetics who have inadequate glycemic control on diet and exercise because of the rodent study findings Also see "FDA Clears Victoza, But Warnings And More Studies Pose Hurdles" - Pink Sheet, 26 January, 2010..

However, Novo Nordisk’s proposed indication for the higher liraglutide dose in the weight management setting would not restrict use to second-line treatment.

In its briefing document for the meeting, Novo Nordisk said there have been no cases of MTC reported in patients exposed to liraglutide in completed clinical trials as of Aug. 11. One MTC event has occurred in the ongoing cardiovascular outcomes trial, LEADER, although treatment allocation remains blinded.

“In the post-marketing setting, 12 spontaneous reports of MTC have been observed with Victoza as of 30 June 2014 based on more than 3.3 million [patient years of exposure]. As of January 2014, 13 cases of MTC have been captured by the MTC registry; none of the patients have been exposed to GLP-1 receptor agonists,” the company said.

FDA requested the advisory committee discuss the implications and any concerns about the overlap in populations between the two indications, specifically overweight diabetic patients Also see "FDA Panel To Weigh Relevance Of Liraglutide’s Diabetes Experience In Obesity" - Pink Sheet, 9 September, 2014..

Thyroid Cancer Worries Lessened

While panelists generally were not concerned about the prospect of using liraglutide as a first-line agent for weight management, they debated whether there should be consistency between the two labels across therapeutic settings.

“I think the one small relevant piece here is that we are a little bit further along from the point when liraglutide was approved for type 2 diabetes and at this point we are a little less concerned about the MTC,” said David Cooke, a pediatric endocrinologist from Johns Hopkins. “What little additional data we have has not supported the concern from the rodent data. Now clearly that’s not the final answer, but I think that does relieve me a little of that concern and make it less worrisome to use this more as a first-line agent.”

“My concern is a matter of consistency,” said the Centers for Disease Control and Prevention’s Daniel Budnitz. He was wary about indicating liraglutide for second-line therapy in one indication but first-line use in another when there are other drugs for both indications that could be used as first-line treatment.

“I think there’s two approaches. I think it would have to be consistent – either it’s second-line therapy for both indications or first-line for both indications,” Budnitz said.

However, not all panelists agreed with Budnitz’ desire for consistency between the labels.

“I think we need to look at how things have evolved,” obesity researcher Susan Yanovski, National Institute of Diabetes and Digestive and Kidney Diseases, said. “If the restriction on use as first-line therapy was because of this concern in animal models of medullary cancer and now we have less concern, then I don’t think we necessarily need to roll that over just because it’s in the other label. One can change the other label if it’s no longer a concern, or one can be inconsistent, which I’ve certainly seen in FDA labels before.”

The panel’s acting industry representative, Rob Scott of Amgen, also did not think the two labels needed to be consistent.

“When you’re talking about second-line therapy in diabetes, you have to think about what are the other therapies available, and in obesity again you wouldn’t want to make it second line if the first-line agents were less safe or less well characterized,” Scott said. “I think it depends on how you feel about the other treatment options for obesity so, in that respect, I don’t think they should necessarily be compatible.”

Such a comparative evaluation in the obesity setting is premature, countered University of Colorado cardiologist William Hiatt.

“All the drugs are just recently approved. There’s no comparative effectiveness between drugs, so how would you possibly have enough evidence to make a recommendation as a second line?” Hiatt asked. “It seems to me that you take this drug on its own merits and if you think that the risk/benefit is favorable, it’s a drug that’s an option. If you think it’s not favorable, it’s not an option.”

Christy Boling Turer, an assistant professor of pediatrics and internal medicine at University of Texas, predicted that eliminating the second-line restriction on Victoza would have little practical impact because clinical guidelines recommend oral metformin as first-line therapy for diabetes.

“I don’t see that practitioners would change their practice of that, in part, because it’s an oral medication and I have great trouble getting my patients to take injectable things,” she said.

Novo Nordisk’s Liraglutide Gets Panel Nod For Weight Management

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