SILVER SPRING, MARYLAND ( UPDATED ) — A US Food and Drug Administration (FDA) advisory panel voted nearly unanimously in favor of approval for Novo Nordisk's once-weekly injectable semaglutide, despite a signal for increased retinopathy.
The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 16 to 0, with one abstention, that the available efficacy and safety data for semaglutide, a long-acting glucagonlike peptide-1 (GLP-1) receptor agonist, support approval for the 0.5-mg and 1.0-mg doses administered once weekly as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
If approved, it would be the seventh GLP-1 receptor agonist on the US market and the fourth once-weekly, although one of those — GlaxoSmithKline's albiglutide (Tanzeum) — is being withdrawn.
Data supporting the indication for semaglutide came from the company's eight phase 3 trials involving over 8000 adults with type 2 diabetes. One of those, SUSTAIN-6, was a 2-year FDA-mandated cardiovascular-outcomes trial involving 3297 patients.
In the five efficacy trials, semaglutide reduced HbA1c by 1.5 to 1.8 percentage points, significantly more than active comparators — including the competing long-acting GLP-1 agonist exenatide extended release (Bydureon, AstraZeneca) in one of the trials. Semaglutide was also associated with a 4.5- to 6.4-kg weight loss.
Two Main Issues
The advisory panel was primarily tasked with discussing two main issues: A significantly increased risk for the prespecified secondary end point of retinopathy seen in SUSTAIN-6 (hazard ratio, 1.76) and the drug's overall cardiovascular safety, as demonstrated by a 0.74 hazard ratio that exceeded FDA's noninferiority requirement.
Regarding retinopathy, the increased absolute risk was seen almost exclusively among study subjects who had retinopathy at baseline — occurring in 8.2% of those taking semaglutide vs 5.2% on placebo, whereas among those without baseline retinopathy the increase was very small: 0.7% with semaglutide vs 0.4% with placebo.
Novo Nordisk argued that transient worsening of retinopathy with dramatic improvements in glycemic control has been well-documented in several large trials in the past and that when researchers accounted for that phenomenon, the increase was no longer significant.
Several panel members expressed discomfort with that analysis, however, with some lamenting the fact that SUSTAIN-6 only lasted 2 years, which they felt was not long enough to prove that the increased retinopathy risk would diminish with time.
Ophthalmologists on the panel also faulted the company's choice of composite outcome for retinopathy — first occurrence of need for retinal photocoagulation, vitreous hemorrhage, treatment with intravitreal agents, or diabetes-related blindness — as being poorly defined.
But the panel unanimously endorsed the cardiovascular safety of semaglutide, and some suggested that there appeared to be benefit, although that did not achieve sufficient statistical power.
Panel member Melissa Li-Ng, MD, an endocrinologist at the Cleveland Clinic, Ohio, said: "I voted yes because of the data that showed sustained HbA1c lowering and safety and also benefits such as sustained weight loss….The risk of worsening diabetic retinopathy seems to be manageable, and I did not think through our discussion that there needs to be a change in the standards of care."
Put Retinopathy Signal in the Labeling
Panelist Frederick L Ferris III, MD, director of epidemiology and clinical applications at the National Eye Institute, Bethesda, Maryland, said he supported semaglutide's approval despite the lack of precise end points for the SUSTAIN-6 retinopathy analysis.
"The primary outcome was clearly met. The adverse events were mostly as expected and not worrisome. I don't know if there is an adverse retinopathy effect or not, but…having something on the label about getting an eye exam is a good idea no matter what," he said.
Several other panel members recommended that the labeling include information about possible retinopathy worsening, as well as a notice to physicians to advise patients to obtain routine eye examinations, per American Diabetes Association recommendations.
Most panel members advised the FDA not to require Novo Nordisk to conduct any further studies postmarketing, although some did say that the company should be compelled to study the retinopathy question longer term.
And a few panelists suggested that if Novo Nordisk decides to do another cardiovascular-outcomes trial with semaglutide powered to show benefit for an additional indication of cardiovascular protection, they could nest within that a retinopathy analysis as well.
Semaglutide is also currently under review by several other regulatory agencies, including the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency.
Medscape Medical News © 2017
Cite this: FDA Advisory Panel Endorses Semaglutide for Type 2 Diabetes - Medscape - Oct 18, 2017.