Marlene Busko
October 31, 2023
With nutrient-stimulated hormone therapies for obesity in phase 3 trials, and activin-receptor inhibitors the next upcoming drug class, highly effective treatments for obesity are on the horizon.
“We are at a watershed [moment] brought on by the recent introduction of highly effective antiobesity medications,” said Ania M. Jastreboff, MD, PhD, in a lecture at ObesityWeek.
Jastreboff, from Yale University and the Yale Center for Weight Management, New Haven, Connecticut, provided an overview of the many nutrient-stimulated hormone-based antiobesity therapies in late phases of development — including dual and triple therapies with glucagon-like peptide 1 receptor agonists (GLP-1 RAs), glucose-dependent insulinotropic polypeptide (GIP) agonists, glucagon, and amylin.
“I’ve shown you all of these agents that clearly produce substantial weight reduction,” she said. “The fact that these nutrient-stimulated, hormone-based therapies are not all the same is a good thing,” she stressed, because “it’s not likely that everyone will respond to each of these, and they are likely to respond differently.”
She then briefly touched on activin receptor inhibitors —”the next [medication] class that I think will be up and coming,” she speculated.
“Beyond (just) weight reduction,” Jastreboff concluded, clinicians “need to focus on optimizing health as we are treating obesity.” Clinicians need to consider the patient’s severity of obesity, overall health, and metabolic profile, and match the obesity treatment to the patient. They also need to consider the rate of weight reduction, potential bone loss, vitamin deficiencies, muscle loss and function, and side effects, and be mindful of affordability, bias, and stigma.
Looking Forward to Multiple Options
W. Timothy Garvey, MD, from the University of Alabama at Birmingham, told Medscape that clinicians treating patients with obesity are looking forward to the decision from the US Food and Drug Administration (FDA) about tirzepatide (Mounjaro), expected by year’s end. Tirzepatide “is really the best medicine that we have for diabetes in terms of A1c control without much hypoglycemia,” he said, “and also the best medicine for treating obesity in patients with diabetes.”
A recent study found that people with type 2 diabetes who adhered to their tirzepatide regimen achieved a 15% weight loss from their baseline after 40-42 weeks, as reported by Medscape Medical News.
Garvey added that he is also looking forward to drugs in development like survodutide (a GLP-1/glucagon agonist) and orforglipron (a small oral daily nonpeptide GLP-1 RA). “Orforglipron wouldn’t have to be refrigerated,” he noted, and it “could be cheaper to manufacture, might be preferred over subcutaneous medication by some people, and it showed pretty good efficacy in early studies.”
Retatrutide, a triple agonist (GLP-1/GIP/glucagon) and CagriSema (cagrilintide plus semaglutide) showed “pretty impressive weight loss in early studies,” Garvey said. “We’re optimistic.”
Also invited to comment, Sean Wharton, MD, PharmD, Wharton Medical Clinic and York University, Toronto, Canada, told Medscape that the recent developments in antiobesity medications are “so exciting that it’s difficult to make direct comments,” since “maybe there will be something bigger, or maybe something will go wrong with these molecules and we’ll have to back-step.”
Further studies are needed, he added, to determine outcomes in patients who reduce their intake to half or three quarters of a dose, or who transition to intermittent therapy.
Nutrient-Stimulated, Hormone-Based Antiobesity Medications
Here’s a status overview of the nutrient-stimulated hormone-based medications already approved and on the horizon:
Semaglutide. The GLP-1 RA semaglutide (Ozempic), was approved by the FDA for type 2 diabetes in 2017. In June 2021, the FDA approved the use of semaglutide (Wegovy) for obesity.
Topline results from the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) cardiovascular outcome trial showed that in individuals with obesity without type 2 diabetes, semaglutide led to a 20% reduction in major cardiovascular events, Jastreboff noted, adding that full results will be presented at the American Heart Association meeting on November 11.
Tirzepatide . In May 2022, the FDA approved tirzepatide (Mounjaro), a GIP/GLP-1RA, for type 2 diabetes, and a decision about the use of tirzepatide for obesity is expected by year’s end.
The full results of the phase 3 SURMOUNT-3 trial were presented at Obesity Week (just after this session), as reported by Medscape Medical News.
And the full results of the phase 3 SURMOUNT-4 trial of tirzepatide for obesity were presented at the European Association for the Study of Diabetes meeting, Jastreboff noted. At 88 weeks, in the continued tirzepatide group, average weight reduction was 26%, absolute weight reduction was 62 lb (28.1 kg), and >50% of individuals achieved ≥25% weight loss.
The phase 3 SURMOUNT MMO trial of morbidity and mortality with tirzepatide in obesity is estimated to be completed in 2027.
Cagrilintide . In a phase 2 trial of the amylin analog cagrilintide in patients with obesity, more than half of participants lost at least 10% of their weight at 26 weeks.
CagriSema. In a phase 1b trial of the amylin analog/GLP-1 RA combination of cagrilintide/semaglutide (CagriSema), average weight reduction at 20 weeks was 17.1%. The estimated primary completion dates of phase 3 trials of CagriSema, REDEFINE 1 (obesity), REDEFINE 2 (obesity and type 2 diabetes), and REDEFINE 3 (obesity and established cardiovascular disease), are 2025, 2024, and 2027, respectively.
Survodutide . Findings from a phase 2 trial of the glucagon/GLP-1 RA survodutide were presented at the American Diabetes Association (ADA) meeting in June. With 46 weeks of treatment, the average weight reduction was 18.7%, and up to 40% of participants lost at least 20% of their body weight.
Survodutide is being studied in the phase 3 SYNCHRONIZE trials.
Retatrutide . Phase 2 findings of 12-mg weekly of the GIP/GLP-1/glucagon triple hormone receptor agonist retatrutide were also presented at ADA. On average, at 48 weeks, the placebo group lost 2.1% of their weight and the retatrutide group lost 24.2% of their weight, with an average absolute reduction of 58 lb (26.3 kg). At the highest dose (12 mg), 9 out of 10 individuals lost ≥10%, nearly two thirds lost ≥20%, and a quarter lost ≥30% of their weight, at 48 weeks.
With the two highest doses of retatrutide, 100% of participants lost ≥5% of weight, Jastreboff reported, adding “I’m not sure how many other times I will ever be able to say ‘100%’ in any scientific presentation.”
TRIUMPH phase 3 studies of retatrutide are ongoing.
“All the agents I’ve spoken about thus far are once-weekly injectable,” Jastreboff said, turning her attention to oral drugs.
Oral semaglutide (Rybelsus) is already FDA-approved for type 2 diabetes. The phase 2 OASIS trial results presented at ADA showed that participants with obesity who received 50 mg daily of the oral medication had an average weight reduction of 17.4% at 68 weeks, which is comparable to the 16.9% weight reduction with subcutaneous semaglutide 2.4 once weekly. More than a third of patients receiving the treatment lost ≥20% weight at 68 weeks.
The phase 3 OASIS study of oral semaglutide in obesity is ongoing.
Orforglipron . Phase 2 data of the small molecule oral GLP-1 RA orforglipron presented at ADA showed that participants with obesity had up to a 14.7% body weight reduction at 36 weeks. Nearly half of participants lost ≥15% of their body weight at 36 weeks.
The phase 3 ATTAIN study of orforglipron in obesity is ongoing.
AMG133 . In a phase 2 trial, participants with obesity who received the monthly GIP receptor antagonist/ GLP-1 receptor agonist AMG133 (Amgen) had an average weight reduction of 14.5% at just 12 weeks.
Activin Receptor Inhibitors
Bimagrumab. This drug is a monoclonal antibody activin receptor inhibitor that binds to activin type II receptors. In a phase 2 study in 58 individuals with type 2 diabetes and obesity who received monthly medication or placebo, participants receiving bimagrumab lost 20.5% of fat mass and gained 3.6% of lean mass at 48 weeks, and the most common adverse events were mild diarrhea and muscle spasm.
Bimagrumab and semaglutide for obesity are being studied in BELIEVE, an ongoing phase 2b study. Topline results are anticipated by the end of 2024.
Taldefgrobep . The fusion protein taldefgrobep binds active myostatin. A phase 2 study of taldefgrobep for obesity is planned to start in 2024.
Jastreboff is on the scientific advisory board for Amgen, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk, and has received research support form Novo Nordisk, Eli Lilly, Rhythm, and NIH/NIDDK.
ObesityWeek. Presented October 15, 2023.
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