A novel investigational coformulation of prandial insulin and pramlintide improves blood glucose control and reduces body weight in people with type 1 diabetes, early research suggests.
The injectable product combines a novel human prandial (pre-meal) insulin (A21G) with the amylin analog pramlintide. The latter reduces post-meal glucose spikes by slowing gastric emptying, reducing postprandial glucagon production, and increasing satiety.
Phase 1 data for the compound, Adocia's ADO09, in a trial of 16 participants were presented June 27 at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The currently marketed version of pramlintide (Symlin, AstraZeneca) is not mixable with currently available premeal insulins and therefore requires a separate injection. It has been approved in the United States for adjunctive use with insulin in type 1 diabetes since 2005, but has not been widely used.
"The coformulation ADO09 combines the established characteristics of insulin and pramlintide into one injection," said Grégory Meiffren, PhD, clinical development director at Adocia, who presented the results.
Asked to comment, ADA session moderator Rajesh Garg, MD, professor of medicine and director of clinical diabetes at the University of Miami, Florida, told Medscape Medical News that the weight loss seen with the combination is a potential major benefit.
"I think it's brilliant...One of the biggest problems we're having in type 1 diabetes is weight gain. Pramlintide, even though it's been around for almost 15 years now, has not been much used. If they can come up with a combination mealtime insulin, that will be great."
Combination Injection Reduces Post-Meal Glucose, Weight
The randomized, double-blind, two-period crossover trial involved 16 patients with type 1 diabetes who were taking a total prandial insulin dose of 40-75 units/day. Both ADO09 and insulin aspart were titrated by participants with the support of physicians.
After a 28-day run-in with optimization of degludec basal insulin, participants were randomized to either ADO09 or insulin aspart injected immediately before each meal. Following a 3-day inpatient mixed-meal test period, participants spent the next 4-23 days taking the test drug before meals in their daily lives at home, then returned for another meal tolerance test. After a 5-7 day washout period, they were switched to the other drug for the same time periods.
All but one of the participants were male, with a mean age of 46.5 years, diabetes duration of 19.7 years, A1c of 7.4%, mean body weight of 101.2 kg (223 lb), and mean BMI of 30.5 kg/m2. All participants were White. Of the 16 patients randomized, 15 completed the trial.
ADO09 significantly improved postprandial glycemic control and time-in-range.
On day 24, mean postprandial plasma glucose concentrations were reduced by more than 100% at both 1 and 2 hours (both P < .0001), and by 69% at 4 hours (P = .0266) with ADO09. Compared to aspart, plasma glucose with ADO09 was 82 mg/dL lower at 1 hour (P < .0001).
Continuous glucose monitoring (CGM) profiles showed increases of 58 minutes for time in blood glucose range of 70-180 mg/dL (P = .0432) and 63 minutes spent between 80-140 mg/dL (P = .0107). Time above 180 mg/dL was reduced by 80 minutes (P = .0049).
However, time below 70 mg/dL and below 54 mg/dL were increased slightly, by 13 minutes (P = .1486) and 4 minutes (P = .0766), respectively. Overall mean blood glucose was reduced by 7 mg/dL (P = .0127) with ADO09.
The overall prandial insulin dose was reduced by 12 units/day (P = .0004) with ADO09, while the basal doses didn't change significantly.
Participants lost an average of 1.6 kg (3.5 lb) with ADO09, compared with a gain of 0.4 kg with aspart (P = .0065).
The combination also significantly reduced both gastric emptying and glucagonemia in the first 1-2 hours after the meal.
More Gastrointestinal Side Effects, No Serious Adverse Events
Overall adverse events were more common with ADO09, with 22 events in 11 participants versus 10 events in 6 participants with aspart. Most were gastrointestinal, including nausea and decreased appetite.
"Both are known effects of pramlintide and tend to disappear as duration of use of pramlintide increases," Meiffren said.
Asked about this, Garg said, "I don't think it would be a major problem, because that's how they work, basically...I think most patients with type 1 diabetes would be willing to take that side effect because weight gain is a major issue. Patients cry for something to help them. I end up giving them [glucagon-like peptide 1 agonists]."
"If there's something like this that they have to take anyway that helps with glycemic control...I think it would be beneficial for many patients."
Hypoglycemic events during the outpatient period were also about 20% more common with ADO09 than aspart, at 96 events in 12 participants versus 79 events in 13 participants, respectively, but none occurred during the night and none were severe, Meiffren noted.
"ADO09 was safe and well-tolerated in subjects with type 1 diabetes using large doses of prandial insulin, and hence, exposed to large pramlintide doses," Meiffren said.
Based on the results of this study, ADO09 clinical development continues in a phase 2 trial launched earlier in 2021.
Another Combo to Be Investigated for Use in Insulin Pumps
In a statement released on June 29 after the ADA meeting , Adocia announced it had also initiated a phase 1 study of another insulin-pramlintide combination product to be tested in insulin pumps. This one would use the company's investigational rapid-acting analog insulin BioChaperone Lispro and the study will test it against lispro alone.
Regarding that product, Garg said: "I think the utility will depend on weight loss. Closed-loop systems are quite good at controlling [blood] sugars. Therefore, I doubt that adding pramlintide will lower A1c in a clinically meaningful manner."
Meiffren is an employee and shareholder of Adocia. Garg has reported no relevant financial relationships.
ADA 2021 Scientific Sessions. Presented June 27, 2021. Abstract 197-OR.
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Cite this: Insulin-Pramlintide Combo Improves Type 1 Diabetes Control - Medscape - Jul 06, 2021.