New Oral GLP-1 Agonist for Obesity, Type 2 Diabetes

SAN DIEGO, CA – Orforglipron, Eli Lilly’s investigational oral daily nonpeptide glucagon-like peptide-1 (GLP-1) agonist that can be taken with or without food, appears comparable with other injectable and oral agents in the class for treating obesity and type 2 diabetes, suggest two new phase 2 studies.

Currently approved GLP-1 agonists for type 2 diabetes and/or obesity are peptide-based and given by subcutaneous injection or orally. No oral GLP-1 agonists are currently approved for obesity, and only one, oral semaglutide (Rybelsus, Novo Nordisk), is approved for type 2 diabetes.

Oral semaglutide is formulated with an ingredient that helps protect it from degradation and enhances gastric absorption. To maximize absorption and efficacy, patients are advised to take it in the fasting state and not to eat or drink anything for at least 30 minutes after. Nevertheless, the bioavailability of orally ingested semaglutide is only 1% or less.

Orforglipron, in contrast, is a small molecule that isn’t a peptide, so it isn’t degraded in the gastrointestinal tract, Juan Frias, MD, lead author of the phase 2 trial in type 2 diabetes, told Medscape Medical News.

“It’s a chemical, a small molecule that also acts on the GLP-1 receptor, but because it’s not a protein it’s not degraded by enzymes. It’s like any other pill. Earlier pharmacokinetic studies have shown that taking it with or without food doesn’t make a difference,” said Frias, who is principal investigator at Velocity Clinical Research, Westlake, California.  

The results of the phase 2 trial of orforglipron in the treatment of adults with overweight or obesity were presented here June 23 at the American Diabetes Association (ADA) 83rd Scientific Sessions, and the findings were simultaneously published in the New England Journal of Medicine.

The type 2 diabetes data were also presented, as a poster, at the ADA meeting, and simultaneously published in The Lancet.

Asked to comment, moderator of the session during which the obesity study was presented, Elisabetta Patorno, MD, DrPH, told Medscape Medical News: “I think the findings are exciting. It is a formulation that patients might be able to tolerate much more, in terms of not having these very strict restrictions on how to take [oral semaglutide]. It’s very cumbersome. They have to be fasting. They have to wait to eat.”

Of course, orforglipron must go through much further testing, noted Patorno, associate professor of medicine at Harvard Medical School, Boston, Massachusetts. “The results that were shown were promising. We’ll see more as new phases are moving forward in phase 3 and so forth.” 

Beyond Dosing Convenience: Possibility for Improved Access

The advantages of this novel nonpeptide GLP-1 agonist drug class — others are in earlier stages of development — could extend beyond just more convenient dosing, Sean Wharton, MD, PharmD, lead author of the obesity study, told Medscape Medical News.

“You can mass-produce a nonpeptide chemical very easily, much more so than a peptide. I believe this will increase access to care,” said Wharton, medical director of the Wharton Medical Clinic, Burlington, Ontario, Canada. 

He added, “As a clinician who believes in equity, diversity, and inclusion, I believe we need medications that are easily accessible to everybody, including poor people and people who live in different countries. Right now, we don’t have that in the obesity medicine field. I believe this is the game changer in terms of access to care around the world for people with obesity who don’t have the means to afford effective treatments.”  

Wharton presented the phase 2 data on the treatment of adults with overweight or obesity on June 23.

For Obesity, Up to 14.7% Weight Loss at 26 Weeks

The phase 2 double-blind trial included 272 adults with obesity or with overweight plus at least one weight-related complication, with or without diabetes. They were randomized to receive orforglipron in doses of 12 mg, 24 mg, 36 mg, or 45 mg, or placebo once daily for 36 weeks. Mean baseline body mass index (BMI) was 37.9 kg/m² and mean body weight was 108.7 kg (239.6 lb).

The primary endpoint, percentage change in body weight from baseline at week 26, ranged from reductions of 8.6% to 12.6% across the orforglipron doses, compared with just 2.0% with placebo. At week 36, there were mean weight reductions of 9.4% to 14.7% with orforglipron versus 2.3% with placebo.

The proportion of patients achieving weight loss of at least 10% by week 36 was 46% to 75% with orforglipron, compared to 9% with placebo.

As with other GLP-1 agonists, the most commonly reported adverse events were gastrointestinal, mostly mild to moderate, occurring primarily during dose escalation and leading to discontinuation in 10% to 17% across doses.    

Superiority Compared With Dulaglutide in Type 2 Diabetes

The phase 2 study in type 2 diabetes was a 26-week, double-blind, multicenter trial that randomized 383 adults with an A1c of 7.0%-10%, with or without taking metformin, to orforglipron doses of 3 mg, 12 mg, 24 mg, 36 mg, or 45 mg or placebo once daily, or dulaglutide 1.5 mg subcutaneous once weekly as an active comparator. There were no food or water restrictions.

Overall baseline A1c was 8.1% and BMI was 35.2 kg/m². At week 26, mean change in A1c was a reduction of up to 2.0 percentage points for the 36-mg orforglipron dose (–2.10%), compared with a 0.4-point drop for placebo (–0.43%) and –1.10% with dulaglutide. All orforglipron doses were significantly better than placebo in A1c lowering, while doses of 12 mg or greater were superior to dulaglutide.   

Mean bodyweight at 26 weeks dropped by up to 10.1 kg (22.2 lb) with orforglipron versus 2.2 kg (4.8 lb) for placebo and 3.9 kg (8.6 lb) with dulaglutide.

As in the obesity trial, mild to moderate gastrointestinal events were common, occurring in 44.1% to 70.4% of those taking orforglipron versus 18.2% with placebo and 34.0% with dulaglutide.

Frias told Medscape Medical News that the gastrointestinal events “are pretty typical in phase 2 GLP-1 [agonist] studies, as you have to escalate [the dose] rapidly. This was also seen with tirzepatide. Generally, the lower the start, the slower the escalation, the less the GI problems. These studies will be used to come up with the dose escalation scheme for phase 3.”

In an editorial accompanying Frias’s study published in The Lancet, Michael A. Nauck, MD, University Medicine Greifswald, Germany, and Michael Horowitz, MB, BS, PhD, of Royal Adelaide Hospital, Australia, agree.

“The outcomes of slower versus more rapid increase in the titration of the higher doses [of orforglipron] reported by Frias and colleagues provide insight into this optimization process for phase 3 trials,” they note.

And they observe that compared with other preliminary results for other oral GLP-1 receptor agonists in early development, “Frias and colleagues now present a much larger phase 2 study with an appropriate duration, which allows for a more detailed comparison with peptide-based GLP-1 receptor agonists.”

The new study, they add, “establishes this novel and highly effective small molecule GLP-1 receptor agonist [orforglipron] as a potentially competitive alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the added advantage of requiring less burdensome precautions to achieve satisfactory bioavailability after oral administration,” they conclude.

The ACHIEVE phase 3 program “will further characterize the therapeutic potential of this oral GLP-1 receptor agonist,” says Lilly in a statement.

The studies were funded by Eli Lilly. Frias has reported receiving research funding, consulting fees, speaker fees, travel support, and/or advisory board participation fees from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, Ionis, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, Sanofi, Altimmune, Carmot Therapeutics, Echosens, Merck, and Gilead. He is on the board of directors for T1D Exchange. Wharton has reported being a speaker, advisor, and/or researcher for Bausch and Lomb, Biohaven Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Patorno has reported no relevant financial relationships.

ADA 2023. Obesity data were presented on June 23, 2023.

N Engl J Med. Published online June 23, 2023. Full text

Lancet. Published online June 23, 2023. Full text

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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