In an interview with PharmaShots, Emmanuel Dulac, Pharm.D., Ph.D., President and CEO of Zealand Pharma shares insight on the US FDA's approval of Zegalogue and its availability in both an auto-injector and a prefilled syringe in June 2021. He also highlighted the importance of approval for the company and patients with hypoglycemia.  

Shots:

• The approval is based on results from three pivotal trials in adults and children with diabetes, showing median time to blood glucose recovery from severe hypoglycemia of 10mins. following injection of 0.6 mg/0.6 mL Zegalogue
• Zegalogue will be available in both an auto-injector and a prefilled syringe for the treatment of severe hypoglycemia in patients with diabetes age 6 or older
• Dasiglucagon is a glucagon receptor agonist, which increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver

Tuba:  Discuss the epidemiology of Hypoglycemia?

Emmanuel: Severe hypoglycemia is an acute, life-threatening condition resulting from a critical drop in blood glucose levels associated primarily with insulin therapy and is one of the most feared complications of diabetes treatment[1]. Children with diabetes on insulin are particularly affected, with 7 out 100 children up to the age of 18 reporting severe hypoglycemia in the previous 6 months[2]. While patients have the ability to monitor and adjust their blood glucose levels to remain in proper glycemic control, it's not always possible to prevent a severe hypoglycemic event. We believe there is a significant unmet need in the treatment of severe hypoglycemia, despite currently available options, as well as an underappreciation of the risk of severe hypoglycemia in adults.

Tuba:  Discuss the clinical data that were the basis of the US FDA's approval of Zegalogue (dasiglucagon) injection.

Emmanuel: The FDA approval was based on efficacy results from three randomized, double-blind, placebo-controlled multicenter Phase 3 studies of Zegalogue in children aged 6 to 17 and in adults with type 1 diabetes. The primary efficacy endpoint for all three studies was time to plasma glucose recovery (treatment success), defined as an increase in blood glucose of =20 mg/dL from time of administration.

The primary endpoint was successfully achieved across the adult and pediatric studies with a significantly faster median time to blood glucose recovery of only 10 minutes following Zegalogue administration compared to 30-45 minutes for placebo. In the main Phase 3 adult trial 99% of patients recovered within 15 minutes.  

Tuba:  What does this approval mean for the company as well as the patients with hypoglycemia?

Emmanuel: It is not always possible to prevent a severe hypoglycemic event but given the magnitude and consistency of effect seen in the pivotal Phase 3 studies, we believe Zegalogue represents a new and attractive choice for people with diabetes to manage the potential consequences of their disease.

This approval, our company's first, marks our evolution from a research and development organization to a fully integrated biopharmaceutical company. We are committed to bringing innovative treatment options to patients and aim to have five marketed products by 2025.

Tuba:  What makes Zegalogue an ideal treatment for Hypoglycemia? Also, discuss the MOA of the therapy.

Emmanuel: We believe Zegalogue is an important treatment option for severe hypoglycemia because, in addition to the positive efficacy results I have already mentioned, we were also pleased with its safety profile. Dasiglucagon is a glucagon receptor agonist, which increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for dasiglucagon to produce an anti hypoglycemic effect.

Tuba:  When can we expect its availability in the US?

Emmanuel: We plan to execute a full product launch in late June.

Tuba:  What would be other geographies (apart from the US) for seeking approval of Zegalogue?

Emmanuel: Right now, we are focused on the launch of Zegalogue in the U.S., but we aim to serve as many patients in need as possible and have global rights to most of our assets in the pipeline, and are evaluating our regulatory and commercial strategies outside U.S. for all programs on an ongoing basis.

Tuba:  What are Zealand's other efforts to target gastrointestinal, metabolic and other specialty diseases?

Source: Zealand Pharma

Emmanuel: We are also studying dasiglucagon for congenital hyperinsulinism (CHI), an ultra-rare disease caused by a defect in pancreatic beta cells. In late 2020, we completed a Phase 3 trial in children with CHI and are awaiting the outcome of a second Phase 3 trial in neonates up to 12 months old with CHI. We are also developing dasiglucagon for use in dual-hormone artificial pancreas pumps for automated management of Type 1 diabetes and are collaborating with Beta Bionics on the iLet® bionic pancreas device, which utilizes dasiglucagon, with the plan to initiate the Phase 3 program in the second half of 2021.

In addition to dasiglucagon, we have been broadening our pipeline of therapies to target obesity and non-alcoholic steatohepatitis (NASH), which we consider key value drivers for the future. Alongside our partner Boehringer Ingelheim, we progressed the clinical development of our GLP-1/glucagon dual agonist in 2020 with the initiation of a Phase 2 trial in type 2 diabetes and recently initiated two additional Phase 2 studies in obesity and NASH.

We have two late preclinical assets in development for obesity, both of which have shown additive weight loss effects when co-injected with a GLP1 analog. We anticipate starting Phase 1 trials with our amylin analog ZP8396 later in the year and we expect to bring our GIP analog ZP6590 into Phase 1 trial in 2022.

In addition to the advancement of our metabolic programs, we have made significant progress in the clinical development of our gastrointestinal candidates and recently announced some new pre-clinical candidates. Glepaglutide is a long-acting GLP2 analog with an effective plasma half-life of approximately 50 hours and is being developed in an easy-to-use disposable autoinjector to simplify its administration for the treatment of short bowel syndrome (SBS). We are progressing with patient enrollment for the pivotal Phase 3 trial which evaluated one- and twice-weekly dosing of glepaglutide versus placebo over 26 weeks and expect the results of the trial in 2022.

Last year we completed a Phase 1a trial for dapiglutide, also in development for the treatment of SBS. While GLP2 mainly stimulates intestinal absorption capacity, GLP1 slows down intestinal motility thereby likely contributing positively to enhanced absorption.  We, therefore, believe that dapiglutide has the potential to take treatment of SBS to the next level and get patients one step closer to regaining full enteral autonomy. The Phase 1b multiple-ascending dose trial, evaluating once-weekly doses of dapiglutide, is ongoing with results of this trial expected later this year. 

Tuba: Why do you think peptide-based product candidates can help people with gastrointestinal & metabolic diseases?

Emmanuel: Peptides have proven to be effective drugs in a number of different diseases, with a significant untapped potential across many therapeutic areas. Peptides generally have a number of advantages as drug candidates, such as high selectivity with effects only on the intended target, lower risk of toxicity, high potency with strong effects even at low concentration, and favorable safety profiles with minimal drug-to-drug interactions. Since peptides are smaller than proteins on a molecular level, they can offer potential benefits in terms of therapeutic administration. Zealand has a track record of successfully inventing and developing novel high potency, high stability, extended half-life, high specificity peptides. This success is based on our deep understanding of peptide chemistry and extensive experience in improving the therapeutic characteristics of naturally occurring peptides by modifying and optimizing their structures.

Peptide-based therapies can be particularly helpful to people with gastrointestinal and metabolic disease because peptide hormones such as insulin, glucagon, and glucagon-like-peptide 1 (GLP-1) are involved in blood glucose regulation, and others, such as ghrelin, regulate appetite.

Tuba:  Can you discuss about the company's patient support or engagement programs?

Emmanuel: We are committed to providing a patient support program to ensure education and access for patients and caregivers and will reveal more information about that program as we approach the Zegalogue launch.  

Tuba:  What can we expect from Zealand Pharma in 2021?

Emmanuel: As we prepare for the commercial launch of Zegalogue in June, we are also excited for the multiple milestones expected this year in programs across our clinical and early-stage pipeline, including an additional Phase 3 data readout for dasiglucagon in CHI; initiation of a pivotal Phase 3 trial for the iLet bionic pancreas device; initiation of a Phase 1 trial for our amylin analog ZP8396 in patients with obesity; and dose escalation in our Phase 1b trial of dapiglutide in patients with SBS. Progress across these clinical programs will position us well to deliver on our vision of offering five commercialized products by 2025.

Reference:

[1] Strandberg RB, et al. Diabetes Res Clin Pract. 2017:11-19.

[2] Saydah S et al. Endocrinol Diab Metab. 2019;2:e00057

Image Source: The Indian Express

About Author:

Emmanuel Dulac is the President and CEO of Zealand Pharma, since 2019. Emmanuel holds a Doctorate in Pharmacology from the University of Paris XI and an MBA at the ESSEC School in Paris.

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