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CHICAGO — Patients with obesity with or without diabetes lost as much as 20% of body weight and showed reductions in A1c levels, after 1 year of treatment with the novel agent maridebart cafraglutide (MariTide), according to the results of a Phase 2 study.

However, virtually all patients experienced a gastrointestinal (GI) adverse event, leading as many as 27% to discontinue.

Study authors, led by Ania M. Jastreboff, MD, PhD, associate professor of endocrinology at Yale School of Medicine, New Haven, Connecticut, said that although GI events were common, a pharmacokinetics study undertaken simultaneously found that side effects could be mitigated through a dose escalation protocol.

The results of the study were presented at the American Diabetes Association (ADA) 85th Scientific Sessionsand published simultaneously in The New England Journal of Medicine.

MariTide is built on a monoclonal antibody backbone; the agent combines a glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist with a novel bispecific GLP-1 receptor agonist. The agent, which has a 21-day half-life, upregulates GLP-1 and downregulates GIP pathways to reduce body weight.

The researchers enrolled 592 people in the trial — 465 people with obesity (63% women; mean age, 48 years; mean BMI, 37.9), and 127 with obesity and type 2 diabetes (42% women; mean age, 55 years; mean BMI, 36.5).

Patients in the obesity-only cohort were assigned to placebo, a fixed monthly dose of maridebart cafraglutide (140 mg, 280 mg, or 420 mg), or a fixed dose (420 mg) every other month. Two groups within the cohort received escalating doses over 4 or 12 weeks to reach a maximum of 420 mg.

Patients in the obesity plus diabetes cohort were assigned to one of four fixed monthly dosing groups: placebo, 140 mg, 280 mg, or 420 mg.

At week 52 in the obesity-only group, for the intent-to-treat group, the mean percent reduction in body weight for those taking MariTide ranged from 12.3% (95% CI, -15.0 to -9.7) to 16.2% (95% CI, -18.9 to -13.5) compared with 2.5% (95% CI, -4.2 to -0.7) with placebo.

At 1 year, in the obesity plus diabetes group, those taking MariTide lost 8.4% (95% CI, -11.0 to -5.7) to 12.3% (95% CI, -15.3 to -9.2) of their body weight, compared to 1.7% (95% CI, -2.9 to -0.6) for those taking placebo.

People with obesity and diabetes taking the highest-dose of the drug (420 mg) lost an average 17% of body weight, Jastreboff, who is also director of the Y-Weight Yale Obesity Research Center, noted at a press briefing.

About a third of all study participants in the obesity-only group had prediabetes at baseline (an A1c of 5.7 to < 6.5), she said, adding that 70%-96% reverted to normal glycemia with MariTide vs 17% with placebo.

Importantly, the obesity-diabetes cohort had a baseline mean A1c of 7.9, and up to 87% of participants treated with MariTide across all doses achieved an A1c of < 6.5, she reported.

On average, the study drug was associated with a 2.2% reduction in A1c in the obesity plus diabetes cohort.

“This is impressive,” said Jastreboff. MariTide is promising in this group, but it’s not clear by what mechanism it is working, she said, adding, “I don’t think we know.”

GI Adverse Events

Virtually all participants reported GI adverse events, primarily nausea, vomiting, constipation, retching (dry heaves), and diarrhea. Patients were asked to describe symptoms using the MINVR (modified index of nausea/vomiting/retching). The incidence was higher in the no-dose-escalation groups.

Eight percent of the obesity cohort in a dose escalation group discontinued compared to 12%-27% in the no-dose-escalation groups.

Iin the obesity plus diabetes cohort with no-dose-escalation, 6%-16% of patients discontinued.

Study co-author, Donna Ryan, MD, professor emerita at Pennington Biomedical in Baton Rouge, Louisiana, told reporters that the results were to be expected for an early, phase 2 trial.

“We nailed efficacy,” she said. It appears “we’re going to get about 20% weight loss or more,” because participants had not reached a plateau at the end of the 52 weeks. But she added, “Clearly we had some work to do on gastrointestinal tolerability.”

With results in hand from the simultaneous pharmacokinetics studies, researchers are planning a dose escalation for the phase 3 trials.

“We are very excited about this molecule,” said Ryan. “We’re excited about that long half-life and the potential for monthly or even less frequent dosing.”

Tolerability is Key

Asked to comment by Medscape Medical News, Priya Jaisinghani, MD, clinical assistant professor in the Division of Endocrinology, Diabetes & Metabolism at New York University Grossman School of Medicine, New York City, said it will be interesting to see whether the trajectory of weight loss continues during the 72-week phase 3 study.

Jaisinghani said she also looks forward to seeing whether starting therapy at a lower dose and with a revised dose escalation schedule — as planned in phase 3 — “will significantly help reduce the incidence and severity of gastrointestinal adverse events, as well as overall discontinuation rates.”

Tolerability is key, she said. “Patients must be able to remain on therapy consistently to achieve meaningful and sustained outcomes.”

While some investors had expressed disappointment with initial reports about the amount of weight loss with MariTide, Jaisinghani said the concern is misplaced.

“It’s time we shift the conversation from focusing solely on the quantity of weight loss to also evaluating the quality of weight loss,” she said.

MariTide, also, for instance, “demonstrated a > 70% reduction in hsCRP [high-sensitivity C-reactive protein] in secondary outcomes, suggesting anti-inflammatory effects,” said Jaisinghani.

Amgen said in a press release that it expects to also start phase 3 studies for atherosclerotic cardiovascular disease, heart failure, and obstructive sleep apnea in 2025.

This study was supported by Amgen. Jastreboff disclosed that she is a consultant for Amgen, Biohaven Pharmaceuticals, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terns Pharmaceuticals, Weight Watchers International, and Zealand Pharma; and that she has stock options in IntelliHealth, State 4 Therapeutics, and Syntis Bio. Ryan reported that she is a consultant or speaker for AbbVie, Amgen, Altimmune, Astra Zeneca, Biohaven, Calibrate, Carmot Therapeutics, Currax, Eli Lilly, Epitomee Medical Limited, Nestle HealthCare Nutrition, Novo Nordisk, Regeneron, Structure Therapeutics, Tenvie, and Wondr Health. Jaisinghani disclosed that she receives consulting fees for Eli Lilly and Novo Nordisk.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.