Near 15% Weight Loss With Novel Oral GLP-1 RA in Phase II Obesity Trial

SAN DIEGO -- Orforglipron, an investigational nonpeptide GLP-1 receptor agonist, helped people with obesity lose a significant amount of weight in a phase II trial.

Tested at four once-daily doses -- 12, 24, 36, or 45 mg -- patients on orforglipron lost between 8.6% to 12.6% of body weight compared with a 2% change seen in placebo by week 26, achieving the primary endpoint, reported Sean Wharton, MD, PharmD, of Wharton Weight Management Clinic in Toronto, and colleagues.

Also achieving the trial's secondary endpoint, those on orforglipron lost up to an average 14.7% of body weight by week 36:

• 12-mg dose: -9.4% drop, -9.8 kg drop (21.6 lbs)
• 24-mg dose: -12.5%, -13.6 kg (30.0 lbs)
• 36-mg dose: -13.5%, -14.2 kg (31.3 lbs)
• 45-mg dose: -14.7%, -15.4 kg (34.0 lbs)
• Placebo dose: -2.3%, -2.4 kg (5.3 lbs)

The findings were presented at the American Diabetes Association (ADA) Scientific Sessions and simultaneously published in the New England Journal of Medicine.

"Here's the good news, it [orforglipron] can be taken without restriction of food, water, or other medications," Wharton pointed out in the ADA presentation. Patients in this trial took the agent or matching placebo every morning without meal-time restrictions. He added that at the 36-week mark, the slope of weight loss still hadn't plateaued, suggesting that these patients could achieve even more weight loss than what was seen here.

All patients in this trial were free of diabetes at baseline (an HbA1c below 6.5%). "My hope is that this becomes a pre-diabetes medication," he said.

When asked about weight regain, Wharton noted that he expects weight regain to happen if the agent is stopped. "I don't expect patients to stop an effective intervention that's actually helping [them]," he stated.

Two GLP-1 receptor agonists on the market today are currently FDA approved for weight management, though both are injectable: once-daily 3.0 mg liraglutide (Saxenda) and once-weekly 2.4 mg semaglutide (Wegovy). In the STEP 1 trial of Wegovy, patients with obesity lost an average 14.9% of baseline body weight after 68 weeks of treatment when it was added to lifestyle intervention, which is a similar weight loss to what was seen here with the maximum orforglipron dose.

Wharton pointed out in the current trial, patients were provided with education about healthy eating and exercise, but there were no mandatory lifestyle intervention goals. In the Wegovy trial, participants were encouraged to achieve a 500 kcal deficit per day paired with a goal of 150 minutes of physical activity per week.

While only 9% of placebo patients achieved at least a 10% weight reduction by 36 weeks, this was achieved by 46% (12-mg group) to 69% (45-mg group) of orforglipron patients. Between 22% (12-mg group) to 48% (45-mg group) were able to achieved at least a 15% body weight reduction by the end of the trial versus only 1% of placebo.

The 45-mg group also achieved a 13.6 cm drop in waist circumference versus a 4 cm drop seen in placebo, plus a 5.5-point reduction in BMI compared with a 0.9-point drop in placebo.

Beyond just body weight benefits, orforglipron was also associated with significant improvements in systolic blood pressure (up to 10.5 mmHg drop vs 1.8 mmHg drop with placebo at week 36). There were no differences in diastolic blood pressure, however.

Those on orforglipron treatment also saw improvements in fasting lipids including triglycerides, total cholesterol, HDL cholesterol, non-HDL cholesterol, LDL cholesterol, and very-LDL cholesterol.

As expected with a GLP-1 receptor agonist, gastrointestinal adverse events were most common, including nausea, vomiting, constipation, and diarrhea. Wharton noted these were more common during the dose escalation phase and led to discontinuation of 10-17% of orforglipron groups. "These findings suggest that lower starting doses and slower dose escalation are indicated for reducing gastrointestinal events and reaching the target dose; this is the concept used for injectable GLP-1 receptor agonists," the researchers suggested.

Also consistent with the GLP-1 class, there was a small increase in pulse rate (up to +7.4 bpm with orforglipron vs -1.8 bpm for placebo).

Among the 272 participants in the trial, the average baseline body weight was 108.7 kg and BMI was 37.9.

Also Works in T2D

Orforglipron succeeded in another phase II trial tested in patients with type 2 diabetes, with results presented at the ADA meeting and simultaneously published in The Lancet.

Here, patients on orforglipron saw a drop in HbA1c by up to 2.1% by week 26 of treatment compared with a 0.43% drop in placebo -- achieving statistical superiority -- and -1.1% drop in those treated with dulaglutide (Trulicity 1.5 mg once-weekly), found Juan P. Frias, MD, of Velocity Clinical Research in Los Angeles, and colleagues.

Once-daily doses of 3 mg, 12 mg, 24 mg, 36 mg, and 45 mg orforglipron were tested in this trial. Similarly, orforglipron was administered without food or water restrictions. Unlike the obesity trial, these participants were also treated with diet and exercise, with or without metformin.

This trial "establishes this novel and highly effective small molecule GLP-1 receptor agonist 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," stated Michael A. Nauck, MD, of Ruhr-University Bochum in Germany, and Michael Horowitz, PhD, of Royal Adelaide Hospital in Australia, in an accompanying comment.

This type 2 diabetes population also reaped weight benefits, dropping as average 10.1 kg (22.3 lbs) by 26 weeks versus 2.2 kg (4.9 lbs) and 3.9 kg (8.6 lbs) drops with placebo and dulaglutide, respectively.

Similar to the weight loss trial, the most common adverse events reported were gastrointestinal, occurring in up to 70.4% of those on orforglipron (mild to moderate in severity) versus 18.2% with placebo and 34.0% with dulaglutide. Nauck and Horowitz suggested future studies of GLP-1 receptor agonist better quantify gastrointestinal symptoms using validated measures, instead of "an unstructured self-report method" used in the current study.

In addition, three orforglipron patients and one dulaglutide patient experienced hypoglycemia (glucose below 54 mg/dL), although there were no reports of severe hypoglycemia. One death occurred in the placebo group, deemed not related to the study drug.

The 45-center trial enrolled 383 patients, 59% men, with an average age of 58.9, HbA1c of 8.1%, and BMI 35.2.

Developer Eli Lilly said its now investigating this agent for chronic weight management in the phase III ATTAIN clinical program and for type 2 diabetes in the phase III ACHIEVE clinical program.