FDA Issues Second CRL for Dasiglucagon (Zegalogue) in Congenital Hyperinsulinism

The US Food and Drug Administration (FDA)) has issued another Complete Response Letter (CRL) for dasiglucagon (Zegalogue) for the prevention and treatment of hypoglycemia in pediatric patients 7 days of age or older with congenital hyperinsulinism.

Announced by Zealand Pharma on October 08, 2024, the company stated the FDA's CRL cited the timing of the third-party manufacturing facility inspection, which was completed in August/September 2024. Of note, issues at the manufacturing facility were cited as the reason for the initial CRL for this indication, which was announced in December 2023.^1,2,3

“We at Zealand Pharma are acutely aware of the significant unmet medical need for newborns and children with congenital hyperinsulinism who have either no or very limited treatment options today,” said David Kendall, MD, chief medical officer of Zealand Pharma. “We are committed to working with the FDA and our third-party manufacturing partner to bring dasiglucagon to patients living with this devastating disease in the months ahead.”

In June 2023, Zealand Pharma announced the FDA acceptance of their New Drug Application for dasiglucagon. In December 2023, Zealand Pharma announced the receipt of a Complete Response Letter from the FDA.^2,3

According to the company, the agency did not cite any deficiencies in the application related to dasiglucagon but were instead related to those identified during an inspection at a third-party manufacturing facility. In May 2024, the company noted the FDA had assigned an October 08, 2024, target action date for their resubmission.^3,4

According to the October 08, 2024 announcement of the CRL, Zealand Pharma pointed out the third-party contract manufacturing facility inspection was completed in August/September 2024 but the manufacturer had not yet received its inspection classification following ther reinspection. The company also pointed out prior deficiencies had been resolved as of this reinspection and the CRL did not state any concerns about the clinical data package or safety of dasiglucagon.¹

The NDA from Zealand Pharma is supported by a pair of phase 3 trials and their long-term extension trial. One phase 3 trial assessed dasiglucagon for reducing the need for intravenous glucose in newborns and infants newly diagnosed with congenital hyperinsulinism who were being treated in a hospital setting and potentially avoid pancreatectomy. The other phase 3 trial assessed dasiglucagon for reducing time in hypoglycemia for children aged between 3 months and 12 years administered in a homecare setting. The final trial used in support of the application was an ongoing long-term extension trial that enrolled 42 of the 44 patients who participated in the 2 aforementioned trials.^1,2,4,5,6

The first trial was a 2-arm, open-label study conducted among 32 children with congenital hyperinsulinism aged 3 months to 12 years and was conducted in a homecare setting. In the study, all participants were treated with dasiglucagon plus standard of care from week 5 until the end of the 8-week study. Results of this study suggested use of dasiglucagon did not significantly reduce the rate of hypoglycemia compared to standard of care alone when assessed by intermittent self-measured plasma glucose.⁵

The other phase 3 trial was a 2-part study. A total of 12 neonates and infants aged 7 days to 12 months were included in the first part, which was a 48-hour crossover study. Results from this part of the study suggested use decreased the need for intravenous glucose infusion by 55% relative to placebo therapy. Part 2 was designed as a 21-day open-label study, which concluded 10 of the 12 neonates and infants were able to discontinue intravenous glucose for at least 12 hours and 7 of the 12 neonates and infants remained weaned off intravenous glucose at the end of the trial without concomitant pancreatic surgery.⁶

References:

1. _{^{Zealand Pharma. Zealand Pharma provides U.S. regulatory update on dasiglucagon in congenital hyperinsulinism. GlobeNewswire News Room. October 8, 2024. Accessed October 8, 2024. https://www.globenewswire.com/en/news-release/2024/10/08/2960183/0/en/Zealand-Pharma-provides-U-S-regulatory-update-on-dasiglucagon-in-congenital-hyperinsulinism.html.}}
2. _{^{Zealand Pharma. Zealand Pharma submits New Drug Application to US FDA for dasiglucagon in congenital hyperinsulinism. GlobeNewswire News Room. June 30, 2023. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2023/06/30/2698007/0/en/Zealand-Pharma-submits-New-Drug-Application-to-US-FDA-for-dasiglucagon-in-congenital-hyperinsulinism.html.}}
3. _{^{Zealand Pharma. U.S. Food and Drug Administration Issues Complete Response Letter for Dasiglucagon in congenital hyperinsulinism for up to three weeks of dosing due to inspection findings at third-party manufacturing facility. GlobeNewswire News Room. December 23, 2023. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2023/12/23/2800891/0/en/U-S-Food-and-Drug-Administration-issues-Complete-Response-Letter-for-dasiglucagon-in-congenital-hyperinsulinism-for-up-to-three-weeks-of-dosing-due-to-inspection-findings-at-third-.html.}}
4. _{^{Zealand Pharma. Zealand Pharma announces financial results for the first quarter of 2024. GlobeNewswire News Room. May 16, 2024. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2024/05/16/2883075/0/en/Zealand-Pharma-Announces-Financial-Results-for-the-First-Quarter-of-2024.html.}}
5. _{^{Zealand Pharma. Zealand Pharma announces data from the first phase 3-trial with dasiglucagon in Congenital Hyperinsulinism (CHI) Z. GlobeNewswire News Room. December 2020. Accessed October 8, 2024. https://ml-eu.globenewswire.com/Resource/Download/157a5a09-f74e-4e14-a760-2f50c3172402.}}
6. _{^{Zealand Pharma. Zealand Pharma announces positive results from phase 3 trial of Dasiglucagon in pediatric patients with congenital hyperinsulinism (CHI) . GlobeNewswire News Room. May 19, 2022. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2022/05/19/2446817/0/en/Zealand-Pharma-Announces-Positive-Results-from-Phase-3-Trial-of-Dasiglucagon-in-Pediatric-Patients-with-Congenital-Hyperinsulinism-CHI.html#xd_co_f=ODdkNGE0YmItYWE1Ni00ZmE2LTg0OGYtNzE4ZGZkMjE1YTkz~.}}
7. _{^{Zealand Pharma. Zealand Pharma Announces Global License and Development Agreement with Novo Nordisk for Zegalogue® (dasiglucagon). GlobeNewswire News Room. September 7, 2022. Accessed October 8, 2024. https://www.globenewswire.com/news-release/2022/09/07/2511078/0/en/Zealand-Pharma-Announces-Global-License-and-Development-Agreement-with-Novo-Nordisk-for-ZEGALOGUE-dasiglucagon.html.}}