In a 7 to 4 vote, an advisory panel to the US Food and Drug Administration (FDA) determined that the potential benefits of the investigational once-weekly basal insulin analog icodec (Novo Nordisk) don’t outweigh the increased risk for hypoglycemia in people with type 1 diabetes.
The May 24 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee was convened specifically to advise the FDA of the benefits versus risks of icodec in people with type 1 diabetes based on the results of ONWARDS-6, one of Novo Nordisk’s randomized clinical trials of icodec.
Five other ONWARDS trials were conducted in people with type 2 diabetes. The FDA hasn’t publicly raised concerns about efficacy and safety seen in any of those trials.
In the phase 3a ONWARDS-6, in which 290 patients were randomized to icodec and 292 patients to once-daily degludec (Tresiba), icodec was noninferior in improving A1c at 26 weeks. However, there was a significant increase in serious or severe hypoglycemia with icodec compared with degludec (4.66 vs 1.0 events per 100 patient-years; 14 events in nine patients versus three in three patients), with the greatest incidence in the icodec group on days 2-4 after injection. None of the events resulted in treatment discontinuation or study withdrawal.
Novo Nordisk representatives presented several possible risk mitigation strategies for icodec, including limiting use to patients wearing a continuous glucose monitor (CGM), restricting use to people with low glycemic variability, avoiding use in those with a history of hypoglycemic unawareness, and/or using alternative dosing strategies such as reducing mealtime bolus insulin doses on days 2-4 after injection.
Panel members discussed at length whether the potential advantages of once-weekly versus daily basal dosing, such as possible improved adherence and convenience, outweighed the increased risk of hypoglycemia and whether the mitigation strategies would be workable in the real world. Regardless of their vote, most panelists agreed that the company should conduct further trials to gather evidence for the proposed mitigation strategies and determine which patients with type 1 diabetes could benefit most from the drug.
Need for Contingencies “Makes Me Nervous”
Committee chair Cecilia C. Low Wang, MD, professor of medicine at the University of Colorado Anschutz Medical Campus, voted no to the benefits of icodec outweighing the risks, explaining: “I struggled with the vote because I think adding more treatment options…is super important for my patients with diabetes, especially my patients with type 1 diabetes, because that’s kind of an under-investigated area right now…I’m concerned that approving icodec for use at this point with inadequate data might be a disincentive for further trials, which I think are needed to use it safely in type 1 diabetes.”
Panel member Matthew T. Drake, MD, PhD, of the Division of Endocrinology at Mayo Clinic College of Medicine, Rochester, Minnesota, also voted no, noting that “when compared to the current gold-standard degludec, which has a good safety profile in my experience, and based on review of the data today, this was an incremental increase [in hypoglycemia].”
Moreover, “I am also concerned about the potential that this would need to be sort of approved with contingencies, specifically the need for CGM. So that makes me nervous. The patients who may be most likely to benefit from this in my clinical practice are unfortunately the ones who tend to be the least likely to actually monitor their blood sugars with some regularity.”
A New Paradigm for Insulin Administration
Rita R. Kalyani, MD, professor of medicine in the Division of Endocrinology, Diabetes, & Metabolism at Johns Hopkins University School of Medicine in Baltimore, Maryland, also cited the need for further studies of patient-reported outcomes, subgroups who would benefit the most, and optimal titration schedules.
Nonetheless, she voted yes. “As a once-weekly insulin, icodec offers a new paradigm for insulin administration, which may reduce treatment burden and facilitate medication-taking behavior for some individuals with type 1 diabetes. On the other hand, bolus dose adjustment required to prevent hypoglycemia during days 2 to 4, and potentially to prevent hyperglycemia on days 5 to 7, may add to the treatment complexity.”
However, Kalyani said, “Overall given that the primary outcome for A1c efficacy has been demonstrated as noninferior to insulin degludec, risk mitigation strategies to prevent and identify hypoglycemia in a timely manner are available ideally through CGM or alternatively self-monitoring blood glucose, and that effective treatments for hypoglycemia are readily available, guided by the compelling need to offer people with diabetes another treatment option to choose from as part of patient-centered care, my vote is yes.”
Patient representative Paul Tibbits, Jr, a health policy and communications professional in Washington, DC, also voted yes but said the decision was “a significant struggle” and icodec “is only approvable with significant caveats.”
Tibbits added, “I certainly want to help people with diabetes, but I also don’t want to hurt them. And I think this product has the potential to do both. So, I would put the onus on the FDA to work with the applicant to make sure that if this is approved there are as many guardrails as possible to make sure we don’t harm people with type 1 diabetes.”
Technology, When Possible, Is “First Choice”
Asked to comment, endocrinologist Anne L. Peters, MD, director of the University of Southern California Westside Center for Diabetes, Los Angeles, told Medscape Medical News that automated insulin delivery (AID) systems, which only use short-acting insulin, are her first choice of treatment for patients with type 1 diabetes — and even some with type 2 diabetes — who are able to access and use them “because we’re talking about a system that is infinitely adjustable versus a system that is infinitely not adjustable…It’s night-and-day different.”
However, she also said select patients with type 1 diabetes might benefit from a once-weekly basal insulin, particularly those not using an AID system who don’t reliably take their daily doses. “This would give them a baseline of insulin that could be helpful…There are so many times when I’m in type 1 clinic in [an under-resourced part of Los Angeles] that I wish I had a once-weekly insulin because it would keep people out of the hospital…It certainly isn’t for everybody, but then nothing is.”
Insulin icodec was approved earlier this year in Canada, Switzerland, and the European Union for people with type 1 or type 2 diabetes.
Advisory panel members are vetted for disclosures and waivers granted for participation if needed, but none were required for this meeting. Peters has reported serving on advisory boards for Abbott Diabetes Care, Becton Dickinson, Boehringer Ingelheim, Eli Lilly, Lexicon Pharmaceuticals, Livongo, Medscape, Merck, Novo Nordisk, Omada Health, Optum Health, sanofi, and Zafgen. She has reported receiving research support from Dexcom, MannKind, and AstraZeneca, and serving as a member of a speakers bureau for Novo Nordisk.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.
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