The U.S. Food and Drug Administration (FDA) has issued a second Complete Response Letter (CRL) for Zealand Pharma's dasiglucagon (Zegalogue), intended for the prevention and treatment of hypoglycemia in pediatric patients aged 7 days and older with congenital hyperinsulinism (CHI). The decision, announced by Zealand Pharma on October 8, 2024, is attributed to the timing of the inspection classification of a third-party manufacturing facility.
Manufacturing Inspection Delay
The FDA's CRL is linked to the reinspection of a third-party contract manufacturing facility, completed in August/September 2024, which has yet to receive its inspection classification. According to Zealand Pharma, prior deficiencies at the facility, unrelated to dasiglucagon, had been resolved as of the reinspection. The FDA did not raise concerns regarding the clinical data package or the safety of dasiglucagon.
Clinical Trial Data
The New Drug Application (NDA) for dasiglucagon is supported by data from two Phase 3 trials and an ongoing long-term extension trial. One Phase 3 trial assessed dasiglucagon's efficacy in reducing the need for intravenous glucose in newborns and infants newly diagnosed with CHI in a hospital setting. The second Phase 3 trial evaluated dasiglucagon's ability to reduce time in hypoglycemia for children aged 3 months to 12 years in a homecare setting.
In the first trial, involving neonates and infants, dasiglucagon reduced the need for intravenous glucose infusion by 55% compared to placebo. In the second trial, conducted in a homecare setting, dasiglucagon treatment did not significantly reduce the rate of hypoglycemia compared to standard of care alone when assessed by intermittent self-measured plasma glucose. However, post hoc analysis showed that dasiglucagon reduced time in hypoglycemia (glucose <70 mg/dL) by approximately 50% and reduced continuous glucose monitor-detected hypoglycemia (<3.9 mmol/L) during weeks 2 to 4 by 43% compared to standard of care treatment alone (event rate ratio: 0.57 [0.39; 0.83], P = .0029).
Unmet Medical Need
Congenital hyperinsulinism is a rare genetic disease affecting approximately 1 in 50,000 children, characterized by excessive insulin secretion leading to frequent and severe hypoglycemic episodes. Current treatment options are limited, often requiring continuous intravenous glucose infusions and, in some cases, pancreatectomy. David Kendall, MD, chief medical officer of Zealand Pharma, emphasized the significant unmet medical need for newborns and children with CHI and the company's commitment to working with the FDA and its manufacturing partner to bring dasiglucagon to patients.
Regulatory Pathway
Zealand Pharma submitted the NDA for dasiglucagon in June 2023, receiving a Complete Response Letter in December 2023 due to manufacturing facility inspection findings. The FDA assigned an October 8, 2024, target action date for the resubmission. The company anticipates submitting additional analyses from existing continuous glucose monitoring data by the end of 2024 to support the use of dasiglucagon in CHI for extended periods.
