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ORLANDO -- Novel dual GLP-1 and glucagon agonist pemvidutide reduced weight and lipids with somewhat less muscle loss than expected, the phase II MOMENTUM trial showed.

Weight lost over 48 weeks ranged in a dose-dependent manner from 10.3% with the 1.2 mg weekly dose to 15.6% with the 2.4 mg weekly dose (P<0.001 vs placebo for all), reported Louis Aronne, MD, of Weill Cornell Medicine in New York City.

And the mean 32.2 lb shed likely wasn't the plateau level, as trajectory curves continued downward at the 48 week mark, he said at the American Diabetes Association (ADA) annual meeting.

Pemvidutide reduced LDL cholesterol by 6.2% to 11.2% and triglycerides by 21.7% to 34.9%, all statistically significant differences from placebo.

In a subset of patients who got MRI scans to check for composition of the weight loss, 21.9% of the weight shed was lean mass, which Aronne noted compares favorably with the 25% expected from weight loss overall and up to 40% seen with incretin therapies.

The vast majority of individuals with obesity have comorbid conditions, including metabolic dysfunction-associated steatohepatitis in some 30%.

Pemvidutide was designed with a dual target to impact the gastrointestinal (GI) system and brain via GLP-1 to reduce appetite, inflammation, and gastric emptying as well as have direct impacts on the liver via glucagon to increase lipolysis, fat mobilization, and energy expenditure, Aronne said.

The trial was one of some 20 different clinical trials with investigational weight loss agents at the conference in an "explosion of revolutionary obesity treatments," noted Robert Gabbay, MD, PhD, of the Joslin Diabetes Center in Boston and chief scientific and medical officer of the ADA.

"If two hormones are good, maybe two different hormones, maybe three hormones, and there's one preclinical of four different hormones, and maybe we can make it into a pill and maybe we can do it as a monthly injection -- almost every permutation you can think of," he said, which may help in targeting different patient populations.

"After many years in the desert, [we're] finally having some effective therapies that can really make a significant impact," he added.

And like the liver benefits with pemvidutide, other agents are expanding the view on what these therapies can do. On the first day of the ADA meeting, for example, the phase III SURMOUNT OSA trials showed GLP-1 receptor agonist tirzepatide (Zepbound) improved symptoms of moderate-to-severe obstructive sleep apnea in obesity, regardless of positive airway pressure use.

Pemvidutide was designed for longer half-life with potential for not needing titration. The MOMENTUM trial was designed to test this by randomizing 391 patients to placebo or one of three pemvidutide dose groups: 1.2 mg weekly or 1.8 mg weekly with no titration, or 2.4 mg weekly with rapid titration up from 0.6 mg over 4 weeks.

The trial was not a diabetes trial, as HbA1c had to be 6.5% or lower and fasting glucose 125 mg/dL or less. Participants needed to have a prior unsuccessful weight loss attempt and a BMI of 30 or as low as 27 if there was history of cardiovascular disease, hypertension, dyslipidemia, prediabetes, or obstructive sleep apnea.

Of the pemvidutide-treated patients, 74% completed the 48 weeks of treatment, consistent with many phase II trials of anti-obesity medications, Aronne noted. Patients who couldn't tolerate the drug discontinued it, without provision for back titration.

He called the drug very well tolerated, noting stable fasting glucose and HbA1c in this nondiabetic population, no clinically meaningful impact on heart rate, and small decreases in blood pressure.

About 16% of the patients in the two higher pemvidutide dose groups stopped due to drug-related adverse events, largely GI in nature. In those groups, about 52-60% had nausea, 27% reported vomiting, 10-18% had diarrhea, and 13-23% had constipation. The only serious adverse event was one case of vomiting.

Cardiac adverse events were similar across treatment groups.

Session moderator Ildiko Lingvay, MD, MPH, of UT Southwestern Medical Center in Dallas, called the concept interesting but expressed concern about the high incidence of nausea in the two higher-dose groups.

Aronne noted he recommended to the drug developer that they use other titration algorithms or back titration, perhaps starting patients at 1.2 mg to see how they do and if necessary increase to 1.8 and ultimately to 2.4 mg.

One audience member laughed, saying that this sounded an awful lot like dose titration.

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