FDA committee rejects recommending once-weekly insulin for approval in type 1 diabetes
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Key takeaways:
- An FDA committee voted against recommending insulin icodec to improve glycemic control in type 1 diabetes.
- Concerns over hypoglycemia risk and lack of data on risk mitigation were discussed.
An FDA committee declined to recommend approval for a once-weekly insulin to improve glycemic control for adults with type 1 diabetes.
The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted, 7-4, that the benefits of insulin icodec (Awiqli, Novo Nordisk) did not outweigh the risks for adults with type 1 diabetes. Insulin icodec is a once-weekly ultra-long-acting basal insulin analog being investigated for glycemic control among adults with type 1 and type 2 diabetes.
Some of the committee members who voted no said the data revealed that risk for hypoglycemia outweighed minimal benefits for adults with type 1 diabetes. In the ONWARDS 6 trial, adults receiving insulin icodec had higher rates of level two and level three hypoglycemia than adults receiving once-daily insulin degludec (Tresiba, Novo Nordisk). HbA1c changes from baseline to 26 weeks were similar between the two groups.
Novo Nordisk proposed mitigation strategies and label suggestions to address the hypoglycemia risk, but committee members said more data are needed on those strategies.
“The benefits of the therapy are clearly that once-weekly administration would be easier to do, but that’s likely to be offset by the increased treatment complexity,” Paul Beringer, PharmD, professor of clinical pharmacy at the Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences at the University of Southern California, who voted against the drug application, said during the hearing.
ONWARDS 6 data
Data presented during the hearing were derived from the phase 3 ONWARDS 6 trial. In the trial, 582 adults with type 1 diabetes using multiple daily insulin injections for at least 1 year and with an HbA1c of 10% or less at baseline were randomly assigned, 1:1, to receive once-weekly insulin icodec or once-daily insulin degludec. Both groups received their assigned therapy combined with insulin aspart for 26 weeks. Participants were eligible to continue therapy in a 26-week extension study. The primary outcome in the trial was change in HbA1c from baseline to 26 weeks. Level one hypoglycemia was defined as a glucose concentration of 54 mg/dL to 69 mg/dL, level two hypoglycemia as a glucose concentration of less than 54 mg/dL, and level 3 hypoglycemia was considered severe with cognitive impairment requiring external assistance.
At 26 weeks, insulin icodec met non-inferiority criteria compared with insulin degludec as both groups had a similar decline in HbA1c. The insulin icodec group had a mean 0.47 percentage point decrease in HbA1c from baseline to 26 weeks compared with a 0.51 percentage point decrease for the insulin degludec group. Time in range as measured through continuous glucose monitoring was similar for the two groups. Fasting plasma glucose decreased more from baseline to 26 weeks in the insulin degludec group than the insulin icodec group (mean change, –33.66 mg/dL vs. –15.08 mg/dL). Treatment satisfaction scores were also higher with insulin degludec compared with insulin icodec.
A big focus of the committee meeting was hypoglycemia. In ONWARDS 6, participants in the insulin icodec group were more likely to have a level two or level three hypoglycemia event than the insulin degludec group (RR = 1.89; 95% CI, 1.54-2.33). The increased rates were mostly seen in level two hypoglycemia. Additionally, 70% of the level three hypoglycemia events in the insulin icodec group were experienced by one participant, according to Stephen Gough, MD, FRCP, global chief medical officer and senior vice president of Novo Nordisk.
Proposed mitigation strategies
Novo Nordisk made several labeling proposals to mitigate hypoglycemia risk. The company recommended restricting insulin icodec use to adults with type 1 diabetes who use a CGM and have a coefficient of variation of 36% or less prior to initiation of the agent without a history of severe hypoglycemia or hypoglycemia unawareness. In a post-hoc analysis of ONWARDS 6, adults in the insulin icodec group with a coefficient of variation of 36% or less had 9.99 level two or level three hypoglycemic events per patient-year of exposure compared with 19.92 events per patient-year of exposure for the full insulin icodec group. The company’s second label proposal was to recommend discontinuation of insulin icodec for adults who experience hypoglycemia recurrence while using the once-weekly agent.
The third labeling recommendation from Novo Nordisk was to inform patients and providers that maximal glucose-lowering effects occur from day 2 to day 4 of each dose and that providers should consider reducing bolus insulin doses on those days. Pharmacodynamics data provided by Novo Nordisk showed adults in the insulin icodec group had the highest rates of hypoglycemia on days 2 to 4 of treatment each week. Modeling data from the company proposed that a 30% reduction in bolus insulin on days 2 to 4 could cut the number of hypoglycemic episodes from 21.22 per patient year of exposure in ONWARDS 6 down to 12.76 events per patient year of exposure.
Speaking on behalf of Novo Nordisk, Ildiko Lingvay, MD, MPH, MSCS, professor of medicine in the department of internal medicine/endocrinology at UT Southwestern Medical Center in Dallas, said providers can take steps to individualize treatment for each patient to mitigate hypoglycemia risk.
“The same patient characteristics are associated with a higher risk for hypoglycemia with icodec as with daily basal insulins, and are already known to providers,” Lingvay said. “For example, people with a higher glucose variability on CGM, those with history of recurrent or severe hypoglycemia, hypoglycemia unawareness or multiple comorbidities have a higher risk for hypoglycemia. Providers will have to consider the baseline risk for hypoglycemia when selecting the right candidate for treatment with weekly insulin.”
Committee asks for more data
Risk for hypoglycemia and labeling recommendations were cited multiple times by the seven committee members who voted against the drug application. Matthew T. Drake, MD, PhD, associate professor of medicine and chair of the metabolic bone disease core group at Mayo Clinic College of Medicine in Rochester, Minnesota, referred to the contingencies proposed by Novo Nordisk as a factor for voting no. Martha Nason, PhD, a mathematical statistician in the branch division of clinical research at the National Institute of Allergy and Infectious Diseases and the NIH, also voted against the application and said more data are needed on whether the proposed mitigation strategies can lower hypoglycemia risk with insulin icodec.
“I think it would be really important to put [mitigation strategies] to the test with another clinical trial and be able to show that they are able to increase the safety,” Nason said.
Some committee members said ONWARDS 6 showed insulin icodec would be beneficial for some adults with type 1 diabetes. Barbara Onumah, MD, owner of the Diabetes and Endocrine Wellness Center LLC in Largo, Maryland, voted yes but added that patient education will be needed to ensure hypoglycemia risk is mitigated.
“There will be [benefit] in a subgroup of patients who are not able to use once-daily insulin for whatever reason and therefore have suboptimal glycemic control,” Onumah said. “If they are able to get access to a once-weekly basal insulin, then they will have improved control.”
Thomas J. Weber, MD, professor of medicine in the division of endocrinology, metabolism and nutrition at Duke University Medical Center, voted in favor of insulin icodec and agreed with Onumah about the importance of education to mitigate hypoglycemia risks.
“If it is approved, there should be a dedicated effort for both direct-to-consumer and physician education on insulin dose adjustment and strategy to mitigate that [hypoglycemia] risk,” Weber said.
Other committee members, including Jill P. Crandall, MD, the Jacob and Jeanne Barkey Professor, chief in the division of endocrinology and director of the Fleischer Institute for Diabetes & Metabolism at the Albert Einstein College of Medicine in New York, voted no and said Novo Nordisk did not adequately define which subgroups of adults with type 1 diabetes might benefit most from insulin icodec.
“It’s still not completely clear to me what the target population for the drug would be,” Crandall said. “I’d like to be optimistic about it, I think there could be some theoretical benefits, but I think there needs to be more work done.”
Reference:
Russell-Jones D, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)02179-7.
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May 24, 2024 FDA Endocrinologic and Metabolic Drugs Advisory Committee. Available at www.youtube.com/watch?v=jeJQNP1Ug2I. Published May 24, 2024. Accessed May 24, 2024.
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