SILVER SPRING, MARYLAND — 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 the long-acting glucagon-like 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agonist on the US market and the fourth once-weekly, although one of those — GlaxoSmithKline’s Tanzeum — is being withdrawn.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 hemoglobin A1c by 1.5 to 1.8 percentage points, significantly more than active comparators – including the competing long-acting GLP-1 receptor agonist exenatide extended release (Bydureon, AstraZeneca) in one of the trials. The drug was also associated with a 4.5-6.4kg weight loss.
Two Main Issues
The advisory panel was primarily tasked with discussing two main issues: A significantly increased risk for the prespecified secondary endpoint 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 non-inferiority requirement.
Regarding retinopathy, the increased absolute risk was seen almost exclusively among study subjects who had retinopathy at baseline – 8.2% versus 5.2%, whereas among those without baseline retinopathy the increase was very small – 0.4% placebo vs. 0.7% semaglutide.
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 they accounted for that phenomenon, the increase was no longer significant.
Several panel members expressed discomfort with that analysis, with some lamenting the fact that SUSTAIN 6 only lasted 2 years, 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. Several members recommended that the labelling 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 the company to conduct any further studies post-marketing, although some did say that the company should be compelled to study the retinopathy question longer-term. A few panellists suggested that if Novo Nordisk decides to do another cardiovascular outcomes trial powered to show benefit for a new indication — as their daily GLP-1 drug liraglutide (Victoza) has already received — they could nest within that a retinopathy analysis as well.
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