Company announcement – No. 31 / 2023

Zealand Pharma announces designation of priority review by the US FDA for dasiglucagon in congenital hyperinsulinism

• US FDA has granted priority review designation to dasiglucagon for the prevention and treatment of hypoglycemia in pediatric patients 7 days of age and older with congenital hyperinsulinism (CHI) for up to 3 weeks of dosing with a Prescription Drug User Fee Act (PDUFA) date on December 30, 2023.
• To ensure the most efficient regulatory process, the review by the US FDA will be conducted in two parts under the same New Drug Application (NDA). Part 1 relates to dosing for up to 3 weeks, whereas Part 2 relates to use beyond 3 weeks.
• The PDUFA date for Part 2 will be set following submission of additional analyses from existing datasets requested by the US FDA, which is expected before the end of the year.

Copenhagen, Denmark, August 30, 2023 – Zealand Pharma A/S (Nasdaq: ZEAL) (CVR-no. 20045078), a biotechnology company focused on the discovery and development of innovative peptide-based medicines, today announced that the US FDA has granted priority review designation for dasiglucagon for the prevention and treatment of hypoglycemia in pediatric patients 7 days of age and older with CHI for up to 3 weeks of dosing.

The regulatory review will be conducted in two parts under the same NDA. Part 1 relates to dosing of up to 3 weeks, whereas Part 2 relates to the use beyond 3 weeks. Supporting the use of dasiglucagon in CHI beyond 3 weeks, the US FDA has requested additional analyses from existing continuous glucose monitoring (CGM) datasets, which are expected to be submitted before the end of the year. CGM was included as a secondary outcome measure in one of the two pivotal Phase 3 clinical trials.

“We are very pleased with the decision of the US FDA to grant priority review for dasiglucagon for the prevention and treatment of hypoglycemia in infants and children with CHI, recognizing the significant and urgent unmet medical need in this patient population”, said David Kendall, MD, Chief Medical Officer of Zealand Pharma.

“We believe that the decision of the FDA to provide such a fast review cycle for the first part of the NDA is a strong testament to the potential value of this product to patients. We remain in close dialogue with the FDA and appreciate the collaborative nature of our work with the agency, recommending a review of the NDA in two parts under the same application to ensure patient access as fast as possible. This approach, and the priority review, underscores the importance of bringing new and better treatment options to the healthcare professionals treating infants and children with CHI. We look forward to continued dialogue with the FDA in generating additional analyses from existing datasets around the use of CGM to be submitted before the end of the year for Part 2 of the NDA review”.

Three Phase 3 clinical trials

The submission of the NDA was based on the results from two pivotal Phase 3 trials and interim results from an ongoing long-term extension trial.

One trial (NCT04172441) evaluated the efficacy and safety of dasiglucagon for subcutaneous infusion in a hospital setting in 12 neonates and infants with CHI aged 7 days to 12 months. In part 1 of this trial, a double-blind placebo-controlled 48 hours crossover study, dasiglucagon reduced the need for intravenous infusion of glucose by 55% compared to placebo. In part 2 of the trial, being 21 days open-label treatment, 10 of the 12 neonates and infants weaned off 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.

A second trial (NCT03777176) evaluated dasiglucagon for subcutaneous infusion in a homecare setting in 32 children with CHI aged 3 months to 12 years. Dasiglucagon treatment did not significantly reduce the number of intermittent self-measured plasma glucose (SPMG)-measured hypoglycemia events per week when compared to standard of care alone. However, when using continuous glucose monitoring (CGM), dasiglucagon treatment, when added to standard of care therapies, reduced the time in hypoglycemia, defined as glucose <70 mg/dL, by approximately 50% and reduced the number of hypoglycemic events by approximately 40% compared to standard of care treatment alone.

In both clinical trials, dasiglucagon for subcutaneous infusion was assessed to be well tolerated. Skin reactions and gastrointestinal disturbances were the most frequently reported adverse events and 42 of the 44 participants in the two trials continued into the long-term trial (NCT03941236), evaluating dasiglucagon for the treatment of infants and children with CHI.

To ensure the most efficient regulatory review process, the US FDA has recommended reviewing the NDA submission in two parts. Part 1 of the review relates to dasiglucagon for the prevention and treatment of hypoglycemia in pediatric patients 7 days of age and older with CHI for up to 3 weeks of dosing, whereas Part 2 of the review relates to the same indication but for use beyond 3 weeks of dosing. The US FDA has requested additional analyses on the use of CGM from existing datasets supporting the use of dasiglucagon in CHI beyond 3 weeks, which Zealand Pharma expects to submit before the end of the year. Part 2 does not represent a supplemental New Drug Application but is under the same NDA.

About congenital hyperinsulinism

Congenital hyperinsulinism is a severe, ultra-rare genetic disease, primarily affecting infants and children, in which the pancreatic beta cells dysfunction and secrete too much insulin, leading to frequent, recurrent, and often severe episodes of hypoglycemia. Persistent episodes of hypoglycemia can result in seizure, brain damage and death.^1,2 It is estimated that CHI develops in one out of 50,000 (or more) children, corresponding to 180-300 newborns being diagnosed with the disease in the US and Europe every year.^3,4

CHI has a significant impact on patient quality of life. Complex care requirements, including continuous intravenous infusion of glucose, can result in lengthy and frequent hospitalizations and make daily social activities difficult for both patients and their families. The only currently approved medical treatment for hyperinsulinism is diazoxide, which can be associated with increased risk of fluid retention, hypertension and acute heart failure. Glucagon and the somatostatin analog octreotide may be used but are not approved therapies. It is estimated that more than 50% of CHI patients do not respond adequately to the medical treatment options currently available, so there remains a significant unmet medical need for more and better treatment options.⁵

About dasiglucagon

Dasiglucagon is being investigated by Zealand Pharma for subcutaneous continuous infusion using a wearable pump system as a potential treatment of CHI. Dasiglucagon is a glucagon receptor agonist that works by causing the liver to release stored sugar to the blood. Zealand Pharma has a collaborative development and supply agreement with DEKA Research & Development Corporation and affiliates for the wearable subcutaneous infusion pump system.

In addition, dasiglucagon injection was approved as Zegalogue® by the US FDA in 2021 for the treatment of severe hypoglycemia in adults and children with diabetes aged 6 years and older. In June 2023, Zealand submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for dasiglucagon injection for the treatment of severe hypoglycemia in adults, adolescents and children aged 6 years and over with diabetes. Zealand Pharma entered a global license and development agreement with Novo Nordisk in September 2022 for the commercialization of dasiglucagon injection for treatment of severe hypoglycemia in people with diabetes. Zegalogue® is a registered trademark of Novo Nordisk A/S.

About Zealand Pharma

Zealand Pharma A/S (Nasdaq: ZEAL) ("Zealand") is a biotechnology company focused on the discovery and development of peptide-based medicines. More than 10 drug candidates invented by Zealand have advanced into clinical development, of which two have reached the market and three candidates are in late-stage development. The company has development partnerships with a number of pharma companies as well as commercial partnerships for its marketed products.

Zealand was founded in 1998 and is headquartered in Copenhagen, Denmark, with a presence in the U.S. that includes Boston. For more information about Zealand’s business and activities, please visit www.zealandpharma.com.

Forward looking statements

This company announcement contains forward-looking statements that provide Zealand Pharma’s expectations or forecasts of future events regarding the research, development and commercialization of pharmaceutical products. These forward-looking statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would” and other words and terms of similar meaning. You should not place undue reliance on these statements, or the scientific data presented. The reader is cautioned not to rely on these forward-looking statements. Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions, which may cause actual results to differ materially from expectations set forth herein and may cause any or all of such forward-looking statements to be incorrect, and which include, but are not limited to, the occurrence of adverse safety events; risks of unexpected costs or delays; unexpected concerns that may arise from additional data, analysis or results obtained during clinical trials; failure to protect and enforce our data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates or expansion of product labelling; failure to obtain regulatory approvals in other jurisdictions; and product liability claims. If any or all of such forward-looking statements prove to be incorrect, our actual results could differ materially and adversely from those anticipated or implied by such statements. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from our expectations in any forward-looking statement. All such forward-looking statements speak only as of the date of this company announcement and are based on information available to Zealand Pharma as of the date of this announcement. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.

Further information/contacts

References

1) Thornton PS et al. (2015) Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children, J Pediatr. 2015;167(2):238-45.
2) Banerjee I et al. (2022) Correction to: Congenital hyperinsulinism in infancy and childhood: challenges, unmet needs and the perspective of patients and families, Orphanet J Rare Dis. 2022;17:61.
3) Arnoux JB et al. (2011) Congenital hyperinsulinism: current trends in diagnosis and therapy, Orphanet J Rare Dis. 2011; 6:63.
4) Yau et al. (2020) Using referral rates for genetic testing to determine the incidence of a rare disease: The minimal incidence of congenital hyperinsulinism in the UK is 1 in 28,389, Plos One. 2020;15(2).
5) Yorifuji et al. (2017) Clinical practice guidelines for congenital hyperinsulinism, Clin Pediatr Endocrinol. 2017;26(3):127-152.