Dasiglucagon* (ZP4207) is a novel 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. Currently in phase II development.
Dasiglucagon has been shown to have a high solubility and a strong physical and chemical stability profile in liquid solution, while Phase I data, published in June 2015, shows that dasiglucagon is safe and well tolerated after single-dose administration across all doses evaluated in both healthy volunteers and Type 1 diabetes patients. Dasiglucagon also showed effects in raising blood glucose levels in Type 1 diabetes patients after an insulin-induced hypoglycemic event.
The features of dasiglucagon support its potential use as a ready-to-use rescue pen for the treatment of severe hypoglycemia as well as for the treatment of mild to severe hypoglycemia in the form of a multiple-dosing pen and as an essential component in an insulin-glucagon dual hormone pump, (the ‘artificial pancreas’), which would represent an important advancement in the treatment of patients with Type 1 diabetes. Zealand is currently exploring a multiple dose version of ZP4207 where Phase Ib data showed 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. 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.
Zealand retains all rights to the program which forms an important part of the company’s proprietary pipeline.
*Dasiglucagon is a proposed International Nonproprietary Name (pINN)
Phase II results
In August 2016, Zealand reported results from Phase II trial which was conducted as a single-center. It was a randomized, double-blind clinical study to determine the pharmacokinetic and pharmacodynamic (PK/PD) properties of single doses of dasiglucagon compared to an approved and commercially available hypoglycemia rescue product based on a lyophilized form of native glucagon (GlucaGen from Novo Nordisk). A total of 58 patients with type 1 diabetes were enrolled in the trial and randomized into four groups, each receiving one of four different single doses of dasiglucagon administered subcutaneously after an insulin-induced hypoglycemia event. In the lowest dose group, a parallel design was applied, and in the three highest dose groups, patients were dosed with both dasiglucagon and approved glucagon in a cross-over design. Zealand initiated dosing in the trial in February 2016. For further details, see ClinicalTrials.gov – Identifier: NCT02660008.
Results from the trial showed that all subjects treated with one of the three highest doses of dasiglucagon or with the approved glucagon product achieved a blood glucose concentration of >70 mg/dL within 30 minutes of dosing. In the same dose groups, time to clinically relevant plasma glucose increases of >20 mg/dL was shown to be similar for dasiglucagon and approved glucagon with a median time of 9-10 minutes. In the trial, dasiglucagon was observed to be well tolerated and have a similar safety profile compared to approved glucagon.
Zealand plans to discuss the results of the Phase II trial with the U.S. Food and Drug Administration (FDA) later in 2016 with the objective of defining the next development steps for dasiglucagon as a single-dose rescue treatment.
Phase I trial
Zealand initiated the dasiglucagon single-dose Phase I trial in November 2014 as a two-part study to evaluate safety and tolerability in both healthy volunteers and Type 1 diabetes patients. The enrollment and treatment of 64 healthy volunteers and 20 patients with Type 1 diabetes was completed ahead of schedule.
In the first part of the Phase I clinical trial, conducted at a selected diabetes centre in Germany, Zealand enrolled up to 64 healthy volunteers who were treated with single-ascending doses of dasiglucagon. The trial objectives were primarily to evaluate safety and tolerability and secondarily to evaluate various pharmacokinetic and pharmacodynamic measurements, as compared to native glucagon. In the second part of the trial, the same endpoints were evaluated in 20 patients with Type 1 diabetes, who were made hypoglycemic before treatment to get an indication of the efficacy of dasiglucagon to release glucose stores and increase blood sugar levels in a cross-over design with native glucagon as active comparator.
Data from preclinical studies with Zealand’s novel glucagon analogue suggest that it is comparable to native glucagon in releasing glucose stores into the blood stream, while being suitable for long term storage in a liquid dosage form. During insulin-induced hypoglycemia in rats, Zealand’s glucagon analogue has demonstrated its ability to restore blood glucose to baseline levels or above in a dose-dependent manner. Further, the glucose analogue has shown pharmacokinetic and blood glucose profiles overall similar to native glucagon in dogs.
Acute, severe hypoglycemia
Hypoglycemia is a condition where blood glucose (sugar) levels in the blood become too low. Patients undergoing a hypoglycemic episode experience anxiety, sweating, tremors, palpitations, nausea and pallor. Depending on severity, the hypoglycemia can lead to mild confusion, loss of consciousness, seizures and a coma and in some cases death.
Severe hypoglycemia occurs when blood glucose levels become so low that the assistance of another person is required to treat the condition by administration of intravenous glucose or glucagon injection.
Severe hypoglycemia is classed as a diabetic emergency (“http://www.diabetes.co.uk/severe-hypoglycemia.html”:) and primarily an issue for diabetes patients treated with insulin and, to some extent, patients on sulfonylurea drugs. All patients with T1D and approximately 20% of T2D patients in the US are treated with insulin. T1D patients are the most likely to experience episodes of hypoglycemia since they often inject themselves with insulin up to 6 times per day or use an insulin pump.
There is a great fear, especially amongst the parents of diabetic children, of severe hypoglycemic events. This often leads to over compensatory behavior where including a tendency for the diabetics tend to snack more than necessary, increase their blood glucose monitoring frequency and alter their basal insulin regimen, lowering the insulin dose to avoid hypoglycemic events. Long term, this can lead to poor blood glucose control and increased risk of diabetic complications. In recent T2D clinical studies the event rates for severe hypoglycemia were shown to be in the range of 1.5% to 19.2%, depending on intensity of treatment.