While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revamped management of type 2 diabetes and associated complications, most are available as peptide-based injectable medications. Non-peptide, small molecule-based GLP-1 RAs may offer key advantages, such as oral bioavailability and patient convenience with administration and dosing.

In the Saturday, June 21, symposium, Emerging Non-Peptide, Small Molecule GLP-1 Receptor Agonists—Can They Become Players?, experts explored the promising new frontier of non-peptide GLP-1 RAs, reviewing design considerations for small molecules in the context of GLP-1 receptor structure and function, the rapidly expanding clinical development pipeline for non-peptide agonists, and encouraging clinical evidence.

The session also included a first report of findings from the phase 3 randomized ACHIEVE-1 trial, which evaluated orforglipron, a non-peptide GLP-1 RA, as monotherapy in drug-naïve type 2 diabetes with inadequate glycemic management.

“Oral small-molecule non-peptide GLP-1 receptor agonists such as orforglipron, proven to substantially reduce A1C to the 6.5%-range and associated with meaningful weight loss and a safety profile consistent with the GLP-1 receptor agonist class, have, indeed, the potential to be widely accepted as much earlier therapy for type 2 diabetes,” said Julio Rosenstock, MD, Senior Scientific Advisor for Velocity Clinical Research, Director of Velocity’s site at Medical City Dallas, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center.

Dr. Rosenstock, who shared the first report of data from the ACHIEVE-1 trial, said that orforglipron led to A1C reductions of 1.2% to 2.1% and weight reductions of 3.7% to 10.0% in a phase-2 dose-response 26-week type 2 diabetes study. Based on these data, orforglipron clinical development programs for the management of type 2 diabetes and obesity are ongoing.

ACHIEVE-1 results were published simultaneously in the New England Journal of Medicine on June 21.

In addition to ACHIEVE-1, orforglipron is being investigated in type 2 diabetes combination with metformin (ACHIEVE-2) or an insulin (ACHIEVE-5), and being compared to oral semaglutide (ACHIEVE-3). Orforglipron is also being compared to insulin glargine in individuals with type 2 diabetes and living with obesity/overweight at increased cardiovascular risk in ACHIEVE-4.

In ACHIEVE-1, 559 participants with type 2 diabetes, with A1C levels >7% and ≤9.5% and a body mass index (BMI) of ≥23 who had not received any glucose-lowering treatments within 90 days of study enrollment were randomized to receive either orforglipron (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. The primary endpoint was change in A1C from baseline to week 40. Key secondary endpoints included proportion of patients achieving an A1C of <7% and <6.5%, change in fasting serum glucose (FSG), change in body weight, and change in lipid profiles.

The step-up dosing for orforglipron took place over four to 20 weeks, based on the dose.

Dr. Rosenstock shared data showing that orforglipron induced substantial A1C reductions, in the range of 1.3% to 1.6%, from a baseline of 8%, across dose levels. Notably, 65% of orforglipron-treated participants achieved an A1C of ≤6.5%. The FSG decreased as early as four weeks and was sustained over time.

Orforglipron induced a mean body weight loss of 7.9%, with the 36 mg dose, translating to approximately 17 pounds. Two-thirds of the orforglipron-treated patients achieved 5% weight loss, while one-third achieved 10% weight reduction.

The gastrointestinal safety profile of orforglipron was consistent with that for GLP-1 RAs overall, with very low rates of treatment discontinuation due to gastrointestinal side effects. No hepatic or pancreatic safety signals were seen.

Dr. Rosenstock shared translational perspectives comparing GLP-1 RA monotherapy in type 2 diabetes, stating, “Although comparisons between studies are suggestive and need to be validated in head-to-head randomized clinical trials,” data from ACHIEVE-1, PIONEER-1, and SUSTAIN-1 suggest that orforglipron and oral/injectable semaglutide induce similar improvements in in A1C and weight loss.

Denise Wootten, PhD, Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, Australia, reviewed the structure and signaling mechanism of GLP-1 receptors, the target for both peptide and non-peptide agonists.

Promoting insulin secretion in the pancreas, reducing food intake via its action in the brain, and delaying gastric emptying are the well-recognized effects that make the GLP-1 signaling pathway a validated clinical target for type 2 diabetes, Dr. Wootten noted.

The GLP-1 G protein-coupled transmembrane receptor undergoes a transformational change upon binding to the GLP-1 peptide hormone, enabling its activation and subsequent intracellular signaling. While some agonists can act on the GLP-1 receptor both at the membrane and after receptor internalization, others act only on the membrane-bound form.

“The complex signaling exhibited by the GLP-1 receptor gives rise to the concept of biased agonism,” Dr. Wootten explained. Biased agonism refers to how different signaling cascades can be activated, mediating varying combinations of physiological effects, by different agonists targeting the same receptor.

Dr. Wootten outlined challenges associated with peptide mimics of GLP-1: This class of agonists is generally not orally bioavailable, these agents are expensive, and they have limited stability, requiring a cold supply chain for storage and transport.

Non-peptide GLP-1 RAs can help address these disadvantages. However, Dr. Wootten explained, designing small molecules that can induce conformational changes akin to those potentiated by larger peptide GLP-1 mimics is challenging. Nevertheless, non-peptide molecules, based primarily on two structural ligand scaffolds, have advanced along the clinical development pipeline. These include compounds based on the scaffolds of danuglipron, which is no longer under clinical development due to liver toxicity concerns, and CHU-128, a close analog of orforglipron.

She said that while peptide agonists continue to dominate the field, promising new non-peptide agonists are progressing through clinical trials.

Tina Vilsbøll, MD, DMSc, Clinical Professor of Endocrinology and Head of Clinic at the Steno Diabetes Center, Denmark, reviewed clinical evidence for non-peptide GLP-1 RAs. She summarized the “life story” of GLP-1, a molecule known for 50 years, with the first GLP-1 RA approved for diabetes in 2005.

“There are over 200 different GLP-1−related therapeutic compounds in development, in preclinical and clinical settings,” Dr. Vilsbøll said. “It is incredible for a clinician to get these in the toolbox.” She highlighted the rapid expansion of non-peptide agonists, a dozen or more of which are currently under clinical investigation.

Dr. Vilsbøll reviewed data for non-peptide agonists that have moved to phase 3 studies: orforglipron, CX11 (VCT220), and HRS-7535. Phase 2 data for orforglipron, published in 2023,  showed that this first-in-class agonist was biased toward G protein activation versus recruitment of beta-arrestin and could be administered orally without food or water restrictions.

CX11, which has a shorter half-life than orforglipron, but high exposure and low peak-to-trough ratio, induced an average weight loss of 10% in 16 weeks in a phase 2 study, according to a poster presented at the 85^th Scientific Sessions. CX11 is being investigated in a phase 3 study of individuals living with obesity in China and in another phase 2 study of individuals living with obesity/overweight in the United States.

Dr. Vilsbøll discussed available phase 1 data for HRS-7535. This agonist is also being investigated in phase 2 and phase 3 studies (OUTSTAND-1 and OUTSTAND-2) in type 2 diabetes. She also highlighted phase 2 data for several other non-peptide GLP-1 RAs, including aleniglipron, RGT-075, RGT-076, AZD5004, and TERN-601.

Throughout her presentation, Dr. Vilsbøll called attention to “puzzling” and/or unresolved aspects of the clinical activity and deliverability of non-peptide GLP-1 RAs: The lack of food/water restrictions with these oral therapies; their impact on hepatic function, largely seen as a decrease in liver enzymes; potential circumvention of supply issues, although the manufacturing process still requires multistep synthesis; nausea as a side effect; and lowering of blood pressure.

On-demand access to recorded presentations from the 85^th Scientific Session will be available to registered participants following the conclusion of the meeting in Chicago, from June 25–August 25.