Introduction

Novo Nordisk’s Awiqli (insulin icodec) is a pioneering once-weekly basal insulin designed to enhance the convenience of and adherence to insulin therapy for people with diabetes. While Awiqli has achieved regulatory approval in Canada and the European Union, it has yet to secure approval in the United States due to concerns over hypoglycemia, particularly in type 1 diabetes (T1D) patients.

Approvals in Canada and the EU

Canada
Awiqli received its first approval from Health Canada in March 2024, making it the first once-weekly basal insulin available in the country. This approval was based on robust clinical data from the ONWARDS phase 3 trials, which demonstrated its efficacy and safety in both type 1 and type 2 diabetes (T2D) patients.

European Union
Awiqli received marketing authorization from the European Medicines Agency (EMA) on May 17, 2024. The approval was based on data showing superior blood sugar reduction and time spent within the recommended blood sugar range compared to daily basal insulin in T2D patients. However, the EMA noted concerns about an increased risk of hypoglycemia in T1D patients compared to daily long-acting insulin.

FDA Concerns and Decision

Despite its success in Canada and the EU, Awiqli has faced significant challenges in gaining approval from the U.S. Food and Drug Administration (FDA). The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against recommending Awiqli for T1D due to the higher risk of hypoglycemia observed in clinical trials.

Hypoglycemia Risks
The primary concern revolves around the increased incidence of severe hypoglycemic events in T1D patients using Awiqli. Clinical data from the ONWARDS 6 trial showed that while Awiqli was non-inferior to (at least as good as) insulin degludec in controlling HbA1c levels, it was associated with a higher rate of level 2 and level 3 hypoglycemia. The FDA’s internal reviewers highlighted that the glucose-lowering effect of Awiqli peaked between days 2 to 4 post-dose, leading to fluctuations that could increase the risk of hypoglycemia.

Proposed Mitigations
Novo Nordisk proposed several risk mitigation strategies to address these concerns, including restricting Awiqli’s use to patients with continuous glucose monitoring (CGM) and without a history of severe hypoglycemia or hypoglycemia unawareness. Despite these proposals, the advisory committee felt that more data was needed to ensure the safe use of Awiqli in T1D patients.

Summary

Awiqli represents a significant advancement in insulin therapy, offering the convenience of once-weekly injections that could greatly benefit people with diabetes, especially those with T2D. While it has been approved in Canada and the EU, approval in the U.S. is hindered by safety concerns, particularly the risk of hypoglycemia in T1D patients. As Novo Nordisk continues to work with the FDA to address these issues, the potential of Awiqli to transform diabetes management remains promising but cautiously anticipated.

Frequently Asked Questions

How does Awiqli work in the body compared to traditional daily insulin?
Awiqli is a long-acting insulin analog designed to be administered once weekly. It binds to a protein called albumin in the bloodstream, which prolongs its action, maintaining steady insulin levels for an entire week. Traditional daily insulins require daily injections because they are shorter-acting and do not stay in the bloodstream as long.

How do healthcare providers determine the correct dosage of Awiqli for each patient?
The dosage of Awiqli is individualized based on the patient's previous insulin regimen and current blood glucose levels. When switching from another long-acting insulin, the first dose of Awiqli may be increased by 50% to achieve faster glycemic control. Ongoing adjustments are made based on regular blood glucose monitoring and patient response.

How does the risk of hypoglycemia with Awiqli compare to other new diabetes treatments?
Awiqli has been associated with a higher risk of severe hypoglycemia in type 1 diabetes patients compared to daily basal insulins. Other new diabetes treatments, like GLP-1 receptor agonists and SGLT2 inhibitors, generally have a lower risk of hypoglycemia. Each treatment has its own risk profile, and the choice of therapy depends on individual patient needs and risk factors.

What are the key differences in regulatory requirements between the FDA, Health Canada, and the EMA?
The FDA, Health Canada, and the EMA have different regulatory frameworks and requirements for approving new medications. The FDA places significant emphasis on the safety profile, particularly concerning risks like hypoglycemia in insulin therapies. The EMA and Health Canada also focus on safety but may have different thresholds for acceptable risk and benefit balances. All agencies require robust clinical trial data to support efficacy and safety claims.

What are the next steps for Novo Nordisk if the FDA continues to withhold approval for Awiqli?
If the FDA continues to withhold approval, Novo Nordisk may need to conduct additional clinical trials to gather more data on safety and efficacy, particularly concerning hypoglycemia risk. They might also explore alternative dosing strategies or additional risk mitigation measures to address the FDA's concerns.