FDA Highlights Increased Hypoglycemia Risk with Novo's Weekly Insulin

Novo Nordisk's initiative to introduce the first once-weekly insulin to the market has encountered a potential hurdle due to concerns raised by FDA staff scientists. These concerns pertain to an "imbalance" in the risk of hypoglycaemic episodes associated with their experimental treatment, insulin icodec, compared to their current once-daily insulin product, Tresiba (insulin degludec).

Novo Nordisk, the Danish pharmaceutical company, submitted applications for insulin icodec to regulators in the USA, Europe, and China last year. These applications are supported by results from the ONWARDS programme, which included six Phase III studies and enrolled over 4000 adult participants with diabetes. According to briefing documents released ahead of an FDA advisory committee meeting scheduled for May 24, agency reviewers observed that while hypoglycaemia is a known side effect of exogenous insulin use, data from Novo Nordisk’s Phase III ONWARDS 6 trial indicate "excess hypoglycaemia caused by insulin icodec [compared to the active comparator] without any added glycaemic control or other benefits."

The main focus of the advisory committee will be to assess the safety and efficacy of insulin icodec in patients with type 1 diabetes. The briefing documents reveal that, although insulin icodec was non-inferior to daily Tresiba in the ONWARDS 6 trial, it led to 48% to 89% more severe hypoglycaemia incidents by week 26. By week 52, the hypoglycaemia event rates per 100 patient-years were 1700 for insulin icodec, compared to 916 for Tresiba. Additionally, 3.1% of patients treated with insulin icodec experienced 14 serious adverse events (SAEs) related to hypoglycaemia within one year, compared to 1% among those on Tresiba.

Most participants in the trial experienced hypoglycaemia: 91% of those on insulin icodec and 86% on Tresiba had at least one episode during the 52-week treatment period. The FDA staff indicated that this suggested the event-rate analysis was not influenced by outliers. Treatments for hypoglycaemia included dose reductions in five cases, among other measures, though no patients withdrew from the study due to SAEs.

Novo Nordisk has proposed a label for insulin icodec that would restrict its use to type 1 diabetes patients who utilize continuous glucose monitoring devices. They also recommended reducing bolus insulin doses during the peak glucose-lowering period of days 2 to 4 after each weekly injection. However, FDA staff argued that subgroup analyses based on glycaemic variability consistently showed a higher risk of hypoglycaemia with insulin icodec compared to Tresiba. Although alternative dosing strategies were modeled and two out of three approaches lowered hypoglycaemia risk, these strategies also reduced effectiveness. Furthermore, reducing bolus insulin by 30% during days 2 to 4 was predicted to maintain glycaemic control and improve safety, but as these models were not tested in clinical trials, it is uncertain whether patients can adjust their doses accurately.

Novo Nordisk has already received a positive opinion for insulin icodec from European regulators and anticipates final EU approval within the next few months, under the brand name Awiqli. Analysts at Stifel project peak global sales of $3.5 billion by 2030, assuming an 80% chance of FDA approval.

In related developments, Eli Lilly recently reported positive Phase III results for their own once-weekly insulin product, efsitora alfa, in type 2 diabetes patients. This sets the stage for potential competition with Novo Nordisk's insulin icodec.