Rivus Pharmaceuticals Unveils Preclinical Data for Muscle-Preserving Oral GLP-1 Agonist RV-8451 at ADA 2026
Key Insights
RV-8451 (search), a novel oral non-peptide GLP-1 receptor (search) agonist, demonstrated 9% body weight reduction and up to 20% fat mass loss in diet-induced obese non-human primates over 18 days while preserving lean mass.
In a head-to-head study versus orforglipron, RV-8451 (search) achieved similar overall weight loss (7%) but significantly greater fat loss (30% vs. 11%) and increased lean mass by 4% compared to a 6% decrease with orforglipron.
No drug-related gastrointestinal adverse events were observed in either preclinical study, addressing a key tolerability limitation of currently approved GLP-1 therapies.
Rivus Pharmaceuticals (search) presented promising preclinical data for its investigational oral GLP-1 receptor (search) agonist, RV-8451 (search), at the American Diabetes Association's 86th Scientific Sessions in New Orleans, LA. The findings, drawn from two independent studies in diet-induced obese non-human primates, suggest the novel small molecule may offer a differentiated profile in the increasingly competitive obesity (search) treatment landscape by delivering fat-selective weight loss while preserving lean muscle mass.
The data were featured in an oral presentation on June 5, 2026, delivered by Sol Collado, Ph.D., Executive Director of Drug Discovery at Rivus Pharmaceuticals (search), with a second poster presentation scheduled for June 8.
Monotherapy Results: Fat Loss Without Muscle Wasting
In the first preclinical study, DIO NHPs were treated with RV-8451 (search) for 18 days following a 7-day vehicle acclimatization period. The results showed a 53% reduction in daily food intake (p<0.05 from baseline) and a 9% reduction in body weight (p<0.05 from baseline). Critically, fat mass declined by up to 20% (p<0.05 from baseline), while lean mass showed no change as measured by DEXA scanning.
Beyond weight-related endpoints, the study also captured improvements in cardiometabolic markers, including reductions in plasma alanine transaminase (ALT), triglycerides, and total cholesterol. Notably, no drug-related gastrointestinal adverse events were observed throughout the treatment period.
Head-to-Head Comparison with Orforglipron
A second 28-day study directly compared RV-8451 (search) with orforglipron, an oral GLP-1 receptor (search) agonist in late-stage development. Both compounds produced similar overall weight loss of approximately 7%. However, the composition of that weight loss diverged sharply: RV-8451 achieved a 30% reduction in fat mass compared to an 11% reduction with orforglipron (p<0.05). More strikingly, lean mass increased by 4% in the RV-8451 group, whereas the orforglipron group experienced a 6% decrease in lean mass (p<0.05). As with the monotherapy study, no drug-related gastrointestinal adverse events were reported for RV-8451.
"We are excited to present preclinical obesity (search) data for RV-8451 (search), demonstrating the potential of our highly-differentiated, oral GLP-1 to deliver quality, muscle-preserving weight loss," said Shaharyar Khan, Ph.D., Chief Scientific Officer of Rivus Pharmaceuticals (search). "We are particularly encouraged by a head-to-head study versus orforglipron, showing RV-8451 resulted in similar weight loss with greater fat loss while preserving lean mass."
Addressing a Key Limitation of GLP-1 Therapies
The muscle-sparing profile of RV-8451 (search) targets a well-recognized shortcoming of currently approved GLP-1 receptor (search) agonists. According to Rivus, an estimated 20–40% of total weight lost with existing therapies comes from lean muscle mass, which can have negative implications for metabolic health and physical function. Furthermore, when treatment is discontinued, patients often rapidly regain weight — primarily as fat — potentially leaving body composition worse than before treatment initiation.
RV-8451 (search) is described by the company as the first muscle-preserving, oral non-peptide GLP-1 agonist. It is designed to deliver high-quality, fat-selective, and durable weight loss with convenient oral dosing.
Next Steps Toward the Clinic
Rivus Pharmaceuticals (search) is currently advancing IND-enabling studies for RV-8451 (search) and plans to submit an Investigational New Drug application in the first quarter of 2027, targeting a Phase 1 clinical trial in obesity (search). The company's broader pipeline includes HU6, a potential best-in-class oral therapeutic for MASH (search) currently in the Phase 2 AMPLIFY trial, reflecting Rivus's focus on developing oral medicines that incorporate energy expenditure modulation to improve cardiometabolic health.
Obesity (search) affects more than one billion people worldwide and remains a primary driver of cardiometabolic disease, underscoring the significant unmet need for therapies that can achieve meaningful weight loss without compromising muscle integrity.