Dasiglucagon for multiple-dose

Dasiglucagon* (ZP4207) is an analogue of human glucagon, invented by Zealand. Glucagon is a peptide hormone, produced by alpha cells of the pancreas and secreted to prevent blood glucose levels dropping too low, thus playing an essential role for a well-functioning metabolic system. The therapeutic use of native glucagon is made difficult by the peptide’s very poor solubility and low stability in liquid solution.

Dasiglucagon has been shown to have a high solubility and a strong physical and chemical stability profile in liquid solution, while data from preclinical studies suggest that it is comparable to native glucagon in releasing glucose stores into the blood stream. Following insulin-induced hypoglycemia in rats, dasiglucagon demonstrated its ability to rapidly and dose-dependently restore blood glucose to baseline levels or above. Furthermore, this novel glucagon analogue has shown both a pharmacokinetic profile and an effect on blood glucose overall similar to native glucagon in dogs.

*Dasiglucagon is a proposed International Nonproprietary Name (pINN).
*The iLET from Beta Bionics

In Phase 2a development

Zealand has initiated two Phase 2a trials with dasiglucagon in December 2016. The Phase 2a trials are designed to provide the foundation for longer clinical trials with the multiple-dose version of dasiglucagon in the dual-hormone artificial pancreas system.

The aim of the Phase 2a clinical trial with Beta Bionics is to assess, for the first time, the safety, efficacy and tolerability of dasiglucagon as part of the Beta Bionics dual-hormone artificial (bionic) pancreas system in adult patients with type 1 diabetes, compared to a recombinant market glucagon. In collaboration with Beta Bionics and Boston University, the trial is conducted at the Massachusetts General Hospital Diabetes Research Center in Boston, MA, USA, with MD Steven J. Russell as Principal Investigator.

Positive Phase 2a results support use in a dual-hormone artificial pancreas system

The trial was a double-blind, randomized, four-period, sequential complete crossover trial in patients with type 1 diabetes. Four different doses of dasiglucagon were tested under normal blood glucose level (euglycemia) and low blood glucose level (hypoglycemia) conditions and with reference to responses observed with freshly reconstituted glucagon (NCT02916251).

A clear dose-response with increases in blood glucose levels was observed across the broad dose range tested, allowing for titration of dasiglucagon to counteract present or incumbent hypoglycemia. All dasiglucagon doses provided clinically relevant mean increases in blood glucose (mean plasma glucose increases of 20 mg/dl or more) under both euglycemic and hypoglycemic conditions.

Dasiglucagon and Glucagon were observed to be safe and well-tolerated in the trial, with no injection site reactions observed with dasiglucagon. Nausea and vomiting were the most frequent side effects observed, predominantly at the higher dose-levels, with both dasiglucagon and Glucagon.

Collaboration with Beta Bionics

Zealand is collaborating with Beta Bionics on the development of first-in-class dual-hormone bionic pancreas system for treatment of people with type 1 diabetes. The objective of the collaboration is to combine essential proprietary product rights from each party to advance a new dual-hormonal artificial, or bionic, pancreas system to the next step in its clinical development. Such a system has the ultimate potential to offer people with diabetes on insulin therapy more efficacious, safer, and easier blood sugar control for better long-term disease management and outcomes.

The new system under the collaboration is based on an advanced bionic pancreas platform technology, developed at Boston University and Beta Bionics, which has been integrated into a pocket-sized wearable medical device, called the iLet. Boston University has granted an exclusive worldwide license of the iLet technology to Beta Bionics. The bionic pancreas technology in the iLet is designed for automated delivery of both insulin and glucagon analogs and has been tested and refined in nearly 10 years of clinical trials. All of these trials used recombinant human glucagon, which necessitated daily reconstitution at the point of care.

In future trials, Zealand will evaluate a multiple-dose version of dasiglucagon with the iLET.

Phase 1b results and devemopment status

Results from the Phase Ib clinical trial with dasiglucagon, completed in September 2015, demonstrated that dasiglucagon was safe and well-tolerated with the ability to provide a clinically relevant blood glucose response after repeat daily dosing in healthy volunteers. The results support the use of dasiglucagon as a multiple-dose version, including potential as a component in an artificial pancreas device, to correct low blood sugar levels in patients with Type 1 diabetes.

The Phase Ib clinical trial initiated with dasiglucagon, initiated in May 2015, was a randomized, double blind and placebo-controlled study to evaluate primarily the safety and tolerability of the compound after multiple dosing. Secondary endpoints measured the pharmacokinetics and pharmacodynamics (blood sugar levels) of dasiglucagon after multiple dosing. The trial was conducted at a clinical diabetes center in Germany and enrolled 24 healthy volunteers, who each received three different cohorts of daily doses of dasiglucagon over 5 days.

Based on the results from the repeat dosing Phase Ib trial, Zealand will evaluate additional options for further development of a multiple-dose version of dasiglucagon.

For further information, see ClinicalTrials.gov Identifier: NCT02390141

To support preclinical and initial clinical activities related to the multiple-dose version of dasiglucagon, Zealand has been granted USD 1,833,000 from the Helmsley Charitable Trust. The grant will be paid in three instalments with USD 600,000 to be received upfront and the rest in the first half of 2016.

Hypoglycemia and dual-hormone bionic pancreas

Hypoglycemia is a condition in which blood glucose drops to unsafe levels. It is most frequently associated with diabetes and primarily arises in people with type 1 diabetes and those with type 2 diabetes who are on insulin therapy. According to Decision Resources, all people with type 1 diabetes and approximately 20% of people with type 2 diabetes in the United States are treated with insulin. People with 1 diabetes are the most likely to experience episodes of hypoglycemia since they often inject themselves with insulin up to six times per day or use an insulin pump.

Symptoms of a hypoglycemic episode include anxiety, sweating, tremors, palpitations, nausea, and pallor. In severe cases, hypoglycemia can lead to loss of consciousness, seizures, coma, and death. Severe hypoglycemia or “insulin shock” occurs when blood glucose levels become so low that the assistance of another person is required to treat the condition, which typically involves administration of intravenous glucose or glucagon injection. Severe hypoglycemia is classed as a diabetic emergency. According to the American Diabetes Association, hypoglycemia occurs frequently and the fear of another episode often leads to conservative insulin administration and poor glucose control (i.e., allowing blood glucose to remain higher than desired), which, in turn, increases risk of micro- and macrovascular complications (Diabetes Care. 2013, 36:1384–95).

It is also clear that people with type 1 diabetes who experience frequent hypoglycemia become unaware of the symptoms and are then predisposed to most severe expression of the condition because they do not feel the more, subtle impending signs. Many people with type 1 diabetes have hypoglycemia for several hours overnight, which, in itself, is dangerous, but which can also lead to hypoglycemic unawareness in the daytime. (Acta Diabetologica. 1998, 35:183–93) Furthermore, hypoglycemia is considered especially unsafe for children with type 1 diabetes under the age 6, who’s developing brains can be adversely affected by low blood sugars at a level which might not cause harm for the more mature brain. (Journal of Pediatrics. 1999, 134:492–98).