Insulin-Pramlintide Combo Improves Kind 1 Diabetes Management

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A new under-investigation coformulation of prandial insulin and pramlintide improves blood sugar control and reduces body weight in people with type 1 diabetes, early research suggests.

The injectable product combines a novel human prandial insulin (prandial 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 Adocia’s compound ADO09 from a 16-person study were presented on June 27 at the American Diabetes Association’s (ADA) 81st virtual scientific meeting.

The version of Pramlintide currently available on the market (Symlin, AstraZeneca) cannot be mixed with currently available premeal insulins and therefore requires a separate injection. It has been approved for concomitant use with insulin in type 1 diabetes in the United States since 2005, but has not been widely used.

“The ADO09 coformulation combines the established properties of insulin and pramlintide in one injection,” said Grégory Meiffren, PhD, director of clinical development at Adocia, who presented the results.

When asked for 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 was a potential major one Advantage is.

“I think it’s brilliant … One of the biggest problems we have with type 1 diabetes is weight gain. Pramlintide, although it’s been in the market for nearly 15 years, hasn’t been used much. When it does come up with a combination insulin with meals, that will be great. “

Combination injection reduces post-meal glucose and weight

The randomized, double-blind, two-stage crossover study enrolled 16 patients with type 1 diabetes who took a total prandial insulin dose of 40-75 units / day. Both ADO09 and insulin aspart were titrated by the participants with medical assistance.

After a 28-day run-in with optimization of the degludec basal insulin, the participants were randomized and received either ADO09 or insulin aspart, which was injected immediately before each meal. After a 3-day inpatient mixed meal testing period, participants spent the next 4-23 days taking the test drug before meals in their daily home life and then returned for another meal tolerance test. After a washout period of 5-7 days, they were switched to the other drug for the same periods of time.

All but one of the participants were male with a mean age of 46.5 years, a diabetes duration of 19.7 years, an A1c of 7.4%, a mean body weight of 101.2 kg (223 lb), and a mean BMI of 30 , 5 kg / m2. All participants were white. Of the 16 randomized patients, 15 completed the study.

ADO09 significantly improved postprandial glycemic control and time-in-range.

On day 24, mean postprandial plasma glucose concentrations were reduced by more than 100% (both P <0.0001) after both 1 and 2 hours and by 69% after 4 hours (P = 0.0266) with ADO09. Compared to aspart, plasma glucose was 82 mg / dL lower with ADO09 after 1 hour (P <0.0001).

Continuous Glucose Monitoring (CGM) profiles showed an increase of 58 minutes for time spent in the blood glucose range of 70-180 mg / dL (P = .0432) and 63 minutes spent between 80-140 mg / dL (P = .0107) were. The time above 180 mg / dL was reduced by 80 minutes (P = 0.0049).

However, the times below 70 mg / dL and below 54 mg / dL were slightly increased by 13 minutes (P = 0.1486) and 4 minutes (P = 0.0766), respectively. Total mean blood sugar was reduced by 7 mg / dL (P = 0.0127) with ADO09.

The prandial total insulin dose was reduced by 12 units / day (P = 0.0004) with ADO09, while the basal doses did not change significantly.

Participants lost an average of 1.6 kg (3.5 lb) with ADO09, compared with a 0.4 kg gain with aspart (P = 0.0065).

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 side effects

Overall, side effects were more common in ADO09, with 22 events in 11 participants versus 10 events in 6 participants with aspart. Most were gastrointestinal tracts, including nausea and decreased appetite.

“Both are known effects of pramlintide and tend to go away the longer you use pramlintide,” said Meiffren.

When asked about this, Garg said, “I don’t think it would be a big problem because that’s basically how they work… I think most patients with type 1 diabetes would be willing to accept this side effect because it is weight gain a big problem. Patients cry for something that helps them. In the end I give them [glucagon-like peptide 1 agonists]. “

“If you have to take something like this anyway that helps control blood sugar … I think a lot of patients would benefit.”

Outpatient hypoglycemic events were also about 20% more common with ADO09 than with aspart, 96 events in 12 participants versus 79 events in 13 participants, but none occurred during the night and none were severe, Meiffren noted.

“ADO09 was safe and well tolerated in type 1 diabetes patients who used high doses of prandial insulin and were therefore exposed to high doses of pramlintide,” Meiffren said.

Based on the results of this study, the clinical development of ADO09 will continue in a phase 2 study that started in early 2021.

Another combination to be investigated for use in insulin pumps

In a statement released June 29 after the ADA meeting, Adocia announced that it has also initiated a Phase 1 study of another insulin-pramlintide combination product to be tested in insulin pumps. This would use the company’s under-testing fast-acting analog insulin BioChaperone Lispro, and the study will test it against Lispro on its own.

Commenting on the product, Garg said, “I think the benefits will depend on weight loss. Closed-loop systems are pretty good at control [blood] Sugar. So I doubt that adding pramlintide will lower A1c levels clinically meaningfully. “

Meiffren is an employee and shareholder of Adocia. Garg has not reported any relevant financial relationships.

Scientific meetings of the ADA 2021. Presented on June 27, 2021. Abstract 197-OR.

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