FDA advisory committee supports insulin degludec/liraglutide for type 2 diabetes

An FDA advisory panel unanimously recommended approval for a fixed combination of insulin degludec and liraglutide for the treatment of type 2 diabetes.

The Endocrinologic and Metabolic Drugs Advisory Committee voted 16-0 Tuesday in favor of a new drug application for insulin degludec and liraglutide (IDegLira), a fixed-ratio combination of a glucagon-like peptide-1 receptor agonist and a basal insulin. Insulin degludec (Tresiba) and liraglutide (Victoza) are both approved agents; the drug combination is developed by Novo Nordisk.

The pre-filled pen injector contains an insulin degludec/liraglutide ratio of 100 U/3.6 mg/mL.

“(The drug) had fewer side effects than the individual components and had the advantage of a once-daily dose that may aid in compliance,” Susan Z. Yanovski, MD, co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, said after the vote. “As far as the patient population, I have mixed feelings about its use in patients on oral antidiabetic medications ... but there could be patients in whom that (use) is appropriate.”

In support of the new drug application, Novo Nordisk submitted data from a series of five phase 3 randomized controlled trials conducted in 28 countries for 26 weeks each (n = 3,488; mean age, 57 years; 52.7% men), evaluating the safety and the glucose-lowering effect of IDegLira. Two of the trials specifically addressed the FDA’s combination drug rule and tested for superiority of IDegLira over insulin degludec (in a trial with a dose cap for the insulin degludec arm) and IDegLira over GLP-1 receptor agonist therapy alone. Three other trials, a factorial study with three arms comparing IDegLira with each of the individual components, a placebo-controlled trial and an active comparative trial against insulin glargine, also were submitted.

Presenting the study data, Stephen Gough, MD, senior principal clinical scientist for Novo Nordisk, said IDegLira met both primary and secondary endpoints in all phase 3 trials and produced a greater HbA1c reduction vs. the drug’s individual components. In trials, 60% to 80% of patients achieved an HbA1c target of less than 7%. In trials in which patients were randomly assigned IDegLira, insulin degludec or insulin glargine, patients assigned IDegLira saw improved postprandial glycemia and lowed their daily insulin requirement vs. basal insulin alone.

Among patients with uncontrolled type 2 diabetes on oral antidiabetic therapies assigned IDegLira as additive therapy, nearly 80% achieved an HbA1c of 7% or less in two clinical trials, according to Gough.

“IDegLira achieved these results using a simple starting dose and titration algorithm,” he said.

Todd Hobbs, MD, chief medical officer for Novo Nordisk, said the clinical trial program demonstrated that the safety profile for IDegLira is consistent with the drug’s individual components while mitigating the side effects typically seen with the individual agents, including gastrointestinal events often seen with GLP-1 receptor agonists and risk for hypoglycemia seen with basal insulin.

Across trials, serious adverse events were low and similar among groups, Hobbs said, and no event occurred in more than 1% of patients.

However, there are challenges in interpreting the HbA1c results, said Tania Condarco, MD, a clinical reviewer for the FDA, in part due to imbalances in the time to dose stabilization for the “uncapped” insulin comparator studies.

“In trial 3952 (the uncapped trial), the participants assigned to the insulin glargine arm were still titrating within 7 weeks of study end,” Condarco said. “This suggests that HbA1c measured at 26 weeks may not be reflective of a period of glycemic stability for the glargine arm, making comparisons (between IDegLira and insulin glargine) challenging.”

In addition, there is a potential loss of dosing flexibility with the product presentation as a fixed-combination drug, as this does not allow the two drugs to be dosed individually, the way the individual agents would be in clinical practice, Condarco said.

David W. Cooke, MD, associate professor of pediatrics at Johns Hopkins University School of Medicine, said additional postmarketing studies should not be required for the drug.

“The data met the primary outcome for efficacy across each of the trials, and with that there weren’t any safety concerns uncovered,” Cooke said after the vote. “With regard to which population it should be approved for, I am in favor of it being approved for all the groups that were studied — both insulin and GLP-1 (receptor agonist) naive, as well as those who have been on insulin or a GLP-1.”

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions. – by Regina Schaffer

For more information:

EMDAC Clinical Briefing Document