Glucagon Receptor Antagonist Shows Early Promise in Type 1 Diabetes

Marlene Busko

June 19, 2017

SAN DIEGO — An investigational glucagon receptor antagonist — the human antibody REMD-477 (REMD Biotherapeutics) — has shown promise in a 26-day, phase 1 study of patients with type 1 diabetes.

Specifically, those who received a single subcutaneous injection of REMD-477 used less insulin each day, and their glucose levels were in the target range 15% more often than was seen in patients who received placebo, in the first days after the injection. Adverse effects were mild or moderate, and there were no statistically significant differences in the rate of hypoglycemia.

This proof-of-concept study "support[s] the long-standing theory that blocking glucagon can have a significant clinical impact in patients with type 1 diabetes," Jeremy Pettus, MD, from the University of California, San Diego, told the press prior to his presentation to the President's Oral Session at the American Diabetes Association (ADA) 2017 Scientific Sessions last week.

"I think [this research is] encouraging but preliminary," session cochair Alvin C. Powers, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, told Medscape Medical News. If this antibody or another agent could safely modulate the effects of glucagon without increasing the rate of hypoglycemia, "that would be an advantage," and this could someday perhaps be an add-on therapy for type 1 diabetes, he said.

"It's exciting [research] because we know that type 1 diabetes...is a multiple-hormone disease, and type 2 diabetes [which wasn't part of this study] is clearly a polyhormonal disease...so if we could normalize glucagon regulation this could be a very significant advance," added Jay Shubrook, DO, a family physician and diabetologist at Touro University in Vallejo, California, speaking with Medscape Medical News.

The company plans to start a follow-up study in a few weeks to enroll 75 patients with type 1 diabetes, give them multiple doses of this agent, and follow them for 12 weeks.

Glucagon Secretion Extremely Disrupted in Type 1 Diabetes

Glucagon is the hormone that prevents blood glucose levels from falling too low by causing the liver to convert stored glycogen into glucose and releasing this into the bloodstream.

But in type 1 diabetes, glucagon secretion is "extremely dysregulated," and it is secreted not in response to hypoglycemia but rather to hyperglycemia — which may explain some of the "chaos" in type 1 diabetes, glucose levels that fluctuate wildly, explained Dr Pettus.

Describing some preclinical work in mice models that lacked pancreatic β cells and couldn't produce insulin, REMD-477 — an antibody that blocks glucagon receptor signaling and reduces glucose output from the liver — had "a remarkable effect" of lowering blood glucose without insulin administration, he told meeting attendees.

In the current human trial, he and his colleagues hypothesized that patients with type 1 diabetes who received a single 70-mg subcutaneous dose of this agent would require less daily insulin to maintain glycemic control.  

Proof-of-Concept Study in 21 Patients

The study enrolled 8 men and 13 women at two sites in the United States. The patients were 18 to 60 years old, had type 1 diabetes, used an insulin pump, and had negative fasting plasma C-peptide levels (<0.2 ng/mL).

The patients were monitored for 2 weeks to determine their glucose levels and daily insulin doses. They were then admitted to a research unit for 5 days and subsequently followed for 21 more days at home. 

The patients had "well controlled diabetes" at baseline, as seen by their mean HbA1c level of around 7.3%, Dr Pettus noted. They had a mean age of 42 years and a mean body mass index of 26, and they had had type 1 diabetes for 22 years on average.

During the 5 days in the research unit, the patients received standard meals and insulin infusions to maintain postabsorptive and postprandial plasma glucose levels of 90 to 120 mg/dL and less than 180 mg/dL, respectively.

The target glycemia range was defined as plasma glucose of 70 to 180 mg/dL. Hyperglycemia was defined as a plasma glucose greater than 180 mg/dL and hypoglycemia as less than 70 mg/dL. 

On day 2 in the research unit, the patients had a stepwise reduction in insulin that made them hyperglycemic (plasma glucose, 250 to 300 mg/dL). Ten patients then received a subcutaneous injection of REMD-477 and 11 patients received a placebo injection.

The primary efficacy end point was the difference in the change in daily insulin use from day 1 to day 4 in the two groups.

Clinically Meaningful Reduction in Insulin Use

The daily insulin use increased by 12% among those in the placebo group but decreased by 14% in patients in the antibody-treated group, for a net decrease of 26% (P < .05).

This corresponds to a "clinically meaningful" decrease of 12 units of insulin for patients in the treated group, Dr Pettus said.

"Because the half-life [of this agent] is 7 to 10 days [in humans], once the patients were discharged, this drug would still have activity" for several more days, he explained.

During days 6 to 12, 13 to 19, and 20 to 26, the treated patients' average daily glucose levels decreased by 27 mg/dL, 31 mg/dL, and 20 mg/dL, respectively, compared with their initial levels.

On days 6 to 12, patients who had received the glucagon receptor antagonist injection spent more time in the target glycemic range than did the other patients: 71% vs 56% of the time, for a difference of 15 percentage points (P = .001), or 3.5 hours/day.

Patients who had received the antibody injection also spent less time being hyperglycemic than the other patients: 23% vs 39% of the time (P = .001). But patients in both groups spent a similar amount of time in hypoglycemia (5% and 6% of the time).

The adverse events in both groups were mild or moderate and included headache and oropharyngeal pain.

"In an area with an unmet need," the results of this preliminary study showed that "glucagon receptor blockade with REMD-477 improves glycemic control and reduces insulin requirements in patients with type 1 diabetes," Dr Pettus reiterated.

The study was funded by REMD Biotherapeutics. Dr Pettus is a consultant and author for Sanofi, Novo Nordis, Valeritas, Insulet, MannKind, Senseonics, and Dexcom and is on the speaker's bureau and is an author for Sanofi and Valeritas. Disclosures for the coauthors are listed in the abstract. Dr Powers has used the REMD-477 antibody in research studies but has no financial conflicts of interest related to this research.

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American Diabetes Association 2017 Scientific Sessions. June 13, 2016; San Diego, California.  Abstract 378-OR

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