Treatment with once-monthly subcutaneous injections of maridebart cafraglutide (MariTide), a novel first-in-class molecule that exhibits glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor antagonism, induced substantial weight reduction in a phase 2 clinical trial of adults living with obesity, with or without type 2 diabetes.

These topline efficacy results were shared at the symposium, Once-Monthly MariTide for the Treatment of Obesity in People with or without Type 2 Diabetes—A 52-Week Phase 2 Study, on Monday, June 23, at the 85^th Scientific Sessions.

“By 2023, the global prevalence of obesity is expected to be 1 billion,” said Ania M. Jastreboff, MD, PhD, Associate Professor of Endocrinology at Yale University School of Medicine, Director for the Yale Obesity Research Center, and Co-Director of the Yale Center for Weight Management. “One billion is not just a number, it is 1 billion people. It’s our fathers, neighbors, daughters—it’s all of us.”

Dr. Jastreboff said that, given the chronic nature of obesity, sustainable options that reduce treatment barriers are needed for individuals living with obesity, and a once-monthly treatment for obesity could be part of the solution to overcome these barriers.

Randy J. Seeley, PhD, the Henry King Ransom Professor of Surgery and Director of the Michigan Nutrition Obesity Research Center at the University of Michigan’s Neuroscience Institute, reviewed the structure, mechanism of action, and preclinical/early clinical evidence for MariTide.

Tirzepatide is currently the only dual agonist of GLP-1/GIP receptors approved for an obesity indication. Tirzepatide, like single GLP-1 receptor agonists (RAs), is a peptide-based therapy. MariTide, on the other hand, is a large molecule with two components: a monoclonal antibody targeting GLP-1 receptors, coupled to peptide GIP RA molecules.

Speaking about the rationale for the once-monthly dosing approach for MariTide in the phase 2 study, Dr. Jastreboff highlighted the long half-life of MariTide, around 21 days, a duration that is three times that of any GLP-1/GIP therapies with U.S. Food and Drug Administration (FDA) approval.

The phase 2 study included two parts and two cohorts. In part 1, participants received different doses of MariTide, with or without dose escalation, for 52 weeks. The efficacy, safety, and tolerability results from part 1 were presented at the symposium.

In part 2, which is ongoing, maintenance dosing approaches and durability of MariTide treatment are being evaluated.

The first cohort enrolled adults living with obesity, defined as having a body mass index (BMI) ≥30 kg/m² or BMI ≥27 kg/m² with one or more weight-related complication, who had one or more unsuccessful attempt at weight loss via diet and exercise, and had an A1C <6.5%. Patients received either placebo, one of three fixed once-monthly doses of MariTide, a high dose of MariTide once every other month, or one of two dose-escalation schemes of MariTide.

Across all treatment arms, MariTide induced significant weight loss, ranging from 16.3%–19.9% reduction, compared to 2.6% with placebo. Notably, the weight loss with MariTide had not yet reached a plateau at the end of the 52-week study period.

Prespecified cardiometabolic measures also improved, including A1C, blood pressure, and lipids.

Dr. Jastreboff said that the most common MariTide-associated side effects were gastrointestinal, mostly mild to moderate.

Harold Bays, MD, Medical Director and President of the Louisville Metabolic and Atherosclerosis Research Center, shared results from the second cohort, comprising adults living with obesity as well as type 2 diabetes, the latter defined as having an A1C ≥7% and ≤10%. The participants included those receiving treatment with diet and exercise or on stable medical therapy with metformin, a sulfonylurea, with or without a sodium-glucose cotransporter-2 (SGLT2) inhibitor as single-agent or combination therapy.

Participants in the second cohort of the phase 2 study of MariTide were randomized to either placebo or one of three fixed doses of MariTide. MariTide induced weight loss, ranging from 12.1%–17%, in individuals living with obesity and type 2 diabetes, compared to a 1.4% reduction with placebo.

Overall, the highest MariTide dose resulted in the highest attainment of weight reduction thresholds. With the highest dose of MariTide, nearly all participants achieved ≥5% (99%) and ≥5% (94%) weight loss, with over two-thirds (67%) and nearly one-third (32%) achieving ≥15% and ≥20% reduction in body weight.

Notably, participants who received MariTide treatment had improved A1C levels, with up to a 2.2% reduction of A1C at 52 weeks, from a mean baseline A1C of 7.9%. Moreover, up to 87% of MariTide-treated patients achieved A1C of ≤6.5%.

In both cohorts, there was a high rate of treatment discontinuation, especially discontinuation due to gastrointestinal adverse effects. To address these tolerability challenges, the investigators applied the lessons learned from the phase 2 study to a phase 1b low-dose initiation study of MariTide in adults without clinically significant findings other than overweight or obesity.

Of the three MariTide dose escalation schemes in the phase 1b trial, the lowest starting dose (21 mg) was associated with the lowest incidence of gastrointestinal adverse effects, compared to the higher doses. All gastrointestinal adverse effects lessened over time once the dose exceeded 70 mg, suggesting that dose-escalation schemes that include multiple steps between 21 mg and 70 mg may help mitigate gastrointestinal adverse effects, especially nausea.

Based on these data, a multistep dose-escalation scheme for MariTide is planned for the MariTide phase 3 clinical program.

“The MariTide Phase 3 program represents the opportunity to bring monthly or less frequent treatment with MariTide to patients with obesity as well as patients with obesity and type 2 diabetes,” said Donna H. Ryan, MD, Professor Emerita at the Pennington Biomedical Research Center.

Julio Rosenstock, MD, Senior Scientific Advisor for Velocity Clinical Research, Director of Velocity’s site at Medical City Dallas, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, who provided an independent perspective on the MariTide trials, agreed overall with Dr. Ryan’s take-home message.

Dr. Rosentsock emphasized, “Start low and go slow,” as the core mantra for optimizing dosing approaches for GLP-1 medications.

The results of the MariTide phase trial were published in the New England Journal of Medicine, concurrent with the symposium.

On-demand access to recorded presentations from this session will be available to registered participants of the 85^th Scientific Sessions through August 25.