Insulin Degludec's Long Duration Sways FDA Panel



SILVER SPRING, MD. – A long duration of action and dosing flexibility were among the attributes of insulin degludec that a Food and Drug Administration advisory panel unanimously agreed would make it a useful addition to currently available diabetes treatments. But concerns over a cardiovascular safety signal resulted in a less than unanimous vote to recommend approval.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 8-4 on Nov. 8 to support approval of insulin degludec (IDeg), a long-acting basal insulin analogue, used alone, and in a combined formulation with the fast-acting insulin analogue aspart (IDegAsp) for the treatment of type 1 and type 2 diabetes, based on clinical trial data from 17 studies.

Panel members voting either way said it was a difficult decision because of a cardiovascular safety signal detected in a meta-analysis of the clinical trials, the major issue discussed at the meeting.

The panel unanimously recommended that Novo Nordisk, the manufacturer of IDeg and IDegAsp, conduct a cardiovascular outcomes trial to further investigate the safety signal, which was an increase in a composite major cardiovascular event (MACE) end point of unstable angina pectoris, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Although panelists agreed that the signal could be caused by chance, they also said that it should be investigated further.

In approving a drug, the FDA has the authority to require that a company conduct a postmarketing safety trial. Novo Nordisk has proposed a postapproval study that would compare cardiovascular outcomes in 7,500 patients with type 2 diabetes, treated with IDeg or another insulin plus standard of care, with up to 5 years’ follow-up. Designed for slower absorption, IDeg forms multihexamers after injection, resulting in a soluble depot from which there is a slow, continuous, and extended release of insulin degludec, with a flat stable profile, according to the company, which markets insulin aspart as Novolog.

In phase-III 26- and 52-week studies of about 6,500 adult patients with type 1 or type 2 diabetes, treatment with IDeg or IDegAsp was noninferior to insulin comparators in reducing hemoglobin A1c from baseline and resulted in lower fasting blood glucose levels, with a reduced risk of hypoglycemia, particularly nocturnal hypoglycemia, according to Novo Nordisk. The company has highlighted the reduced rate of nocturnal hypoglycemia, but FDA reviewers said they were not convinced that it was clinically relevant.

Panelists agreed that IDeg and IDegAsp had features that would be useful in clinical practice, including the combination with a short-acting insulin, which would reduce the number of injections; evidence that it lasts for about 24 hours; and some flexibility if a patient misses a dose – a common problem in clinical practice, several of the endocrinologists on the panel pointed out.
The company’s proposed label recommends that IDeg be taken at about the same time every day, but if a dose is missed the patient can take a catch-up dose at any time as long as 8 hours elapse between doses.

Voting in favor of approval, Dr. David Cooke of the division of pediatric endocrinology at Johns Hopkins in Baltimore, said that, although it was a difficult call, “the pharmacokinetics of this insulin are an advance for our treatment of both type 1 and type 2 diabetes and would provide an additional option that could improve our treatment of these patients.”

Like other panelists, he said that currently available basal insulins do not last for 24 hours and that a basal insulin that provides coverage over 24 hours would be an advantage. The question of whether it increases cardiovascular risk is “far from proven,” but clinicians need to be aware of these issues, he added.

Another endocrinologist on the panel, Dr. Robert Smith, professor of medicine at Brown University in Providence, R.I., agreed that IDeg addressed the need for a long-acting insulin. If the data on efficacy and lower rate of hypoglycemia hold up in clinical practice, he said, “it is likely to be useful and broadly used as a form of insulin in diabetes care.”

Dr. Smith voted against approval, however, noting that there are alternatives and that the benefit of IDeg was “not of such magnitude that it merits taking on significant level of risk.” Despite the uncertainty of the cardiovascular risk signal, a study addressing this issue further should be done before approval, “given the importance of cardiovascular disease in patients with type 1 and type 2 diabetes,” he added.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although one panelist at this meeting was given a waiver. If approved, the company plans to make both IDeg and the combination product available in prefilled insulin pens, which they will market as Tresiba and Ryzodeg.


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