An FDA advisory committee mostly agreed on Friday that an investigational once-weekly insulin product carries too much risk for adults with type 1 diabetes to recommend approval in this population.
In a 7-4 vote, the Endocrinologic and Metabolic Drugs Advisory Committee said that Novo Nordisk had not demonstrated that the benefits of its long-acting insulin icodec (proposed brand name Awiqli) outweighed the risks of hypoglycemia for adults with type 1 diabetes. (Though not discussed at the meeting, the product is also under review for adults with type 2 diabetes.)
“The risks are very clear, and the benefits are not,” said Jill Crandall, MD, of Albert Einstein College of Medicine in New York City.
“The fact that we didn’t see any actual benefit demonstrated relative to the comparator in the trial was important to me,” added Erica Brittain, PhD, of the National Institutes of Health in Bethesda, Maryland, who also voted against the product.
Support for a potential indication in adults with type 1 diabetes came from the ONWARDS 6 trial.
In the phase III study, the once-weekly icodec proved non-inferior to once-daily degludec in terms of HbA1c reduction, but from baseline to week 26 the long-acting product was associated with a higher rate of clinically significant or severe hypoglycemia attributed to its peak glucose-lowering effect on days 2 to 4 after injection: 19.9 events per patient-year of exposure as compared with 10.4 events per patient-year with degludec (P<0.0001).
Patient representative Paul Tibbits Jr. said his favorable vote came with “significant struggle.” While he said he thought the once-weekly insulin was approvable for the type 1 population, it would only be after the FDA slapped some “draconian limitations” on it.
If approved, Novo Nordisk’s insulin icodec would be the first basal insulin product for weekly dosing, as all other products on the market are designed for daily dosing.
While the developer made a few suggestions to mitigate the risks of hypoglycemia, many panel members weren’t satisfied and called for even higher safeguards. Some of the proposed mitigation strategies included only using the product with a continuous glucose monitor (CGM), as used in the trial; restricting its use to type 1 diabetes patients whose glycemic variability is less than 36% prior to initiation; only using it in those without a history of hypoglycemia unawareness or recurrence; and only using it in patients after their first year of diabetes onset.
“The patients who may be most likely to benefit from this, in my clinical experience and practice, are unfortunately the ones who tend to be the least likely to actually monitor their blood sugars with some regularity,” said Matthew Drake, MD, PhD, of the Mayo Clinic College of Medicine in Rochester, Minnesota, who also voted against recommending approval.
Representatives of the sponsor on Friday also suggested dosing so the peak glycemic affects take effect over the weekend, when most patients are eating more and have higher blood glucose levels.
But Paul Beringer, PharmD, of the University of South California in Los Angeles, called the proposed risk reduction strategies untested and potentially difficult to implement in practice.
Many panelists agreed that insulin icodec could benefit a subpopulation of patients with type 1 diabetes, but there was no consensus on which population(s) that might be. Some suggested it could be those fearful of needles or those with poor glucose control. Regardless, committee members said it was Novo Nordisk’s responsibility to identify this population, test the weekly agent exclusively on them, and establish safety in another clinical trial.
“It’s not clear that the subpopulation is simply those with low hypoglycemic risk and [those] who use CGM,” argued Robert Greevy, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee. “Notably, those criteria don’t address the key motivation for once-weekly therapy specifically.”
“There should be some work done to identify that subpopulation that we all seem to think is out there,” he added.
Barbara Onumah, MD, of the Diabetes and Endocrine Wellness Center in Largo, Maryland, voted in favor of the weekly product and said she thought there would be a benefit for a subgroup of patients who aren’t able to use once-daily insulin and have suboptimal glycemic control.
While the FDA isn’t required to follow its advisory committees’ recommendations, it typically does.
Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.
