Novel GLP-1/GIP formula finishes strong in phase II obesity, T2D trial

In part 1 (dose ranging with and without dose escalation) of the phase II MariTide study, significant weight reduction and robust glycaemic improvement were achieved with maridebart cafraglutide (MariTide) – the first, long-acting, GIPR* antagonist and GLP-1R** agonist – in individuals with obesity or overweight and type 2 diabetes (T2D).

“Obesity is a chronic disease. Sustainable options that reduce treatment barriers are needed for patients with obesity. Once-monthly treatment options for obesity may be part of the solution to overcome these barriers,” said Professor Ania Jastreboff from the Yale School of Medicine, New Haven, Connecticut, US, during a late-breaking symposium at ADA 2025.

“We have very highly effective once-weekly options – that is, 52 injections a year. But let’s imagine a world where you have 12, or maybe fewer, injections a year – just once a month, or less frequently,” Jastreboff said.

The study was divided into two cohorts: Cohort A comprised participants with obesity, while cohort B included individuals with obesity and T2D. [ADA 2025, abstract CT-SY43-1.5]

Cohort A: Obesity

Cohort A included 465 patients (mean age 47.9 years, 62.8 percent women, 22.2 percent Asian). The mean body weight was 107.4 kg, mean BMI 37.7 kg/m², and mean HbA_1c 5.5 percent. Participants were randomized to seven groups: four no-dose-escalation (no-DE) arms, two DE arms, and a placebo arm.

In the no-DE subset, participants received one of four monthly fixed doses of placebo, MariTide 140, 280, or 420 mg, or MariTide 420 mg every other month. MariTide DE was either for 4 weeks (starting with two 70-mg doses) or 12 weeks (starting with 70 mg [week 0–4], 140 mg [4–8], and 280 mg [8–12]), followed by 420 mg monthly.

Per the efficacy estimand (on treatment), MariTide recipients showed up to about 20 percent average weight loss at 52 weeks. In the placebo arm, the average weight loss was only 2.6 percent.

“The weight reduction efficacy [with MariTide] was not impacted by [DE and] was numerically similar across treatment arms irrespective of dose,” said Jastreboff. “[Moreover,] the weight reduction curve had not reached a plateau at 52 weeks for MariTide-treated groups.”

Anthropometric, cardiometabolic parameters

From a mean baseline waist circumference (WC) of 115.2 cm (45.4 inches), placebo recipients only shed 3.6 cm off their waist by week 52. With MariTide, the WC reductions fell between 14.6 cm (4-week DE) and 16.8 cm (12-week DE). “The WC reduction was more than 4.5 times greater with MariTide than with placebo. The 16.8-cm loss is equivalent to ~6.8 inches. According to a [certain] belt buckle scale, this is about seven belt buckles,” Jastreboff lightly remarked.

MariTide recipients lost more fat mass (between 26.2 percent and 36.8 percent) than lean mass (between 8.6 percent and 11.6 percent). Of note, the lean mass loss accounted for ~30 percent of the weight lost, noted Jastreboff.

All MariTide dose groups had HbA_1c reductions of 0.4 percent. In participants who had prediabetes at baseline, 70–96 percent reverted to normoglycaemia (HbA_1c <5.7 percent) with MariTide as opposed to 17 percent with placebo.

There were also greater improvements in systolic and diastolic blood pressure (BP), as well as all lipid levels, across all MariTide groups vs placebo.

Safety, tolerability

In addition to the standard (unsolicited) reporting of adverse events (AEs), this study used the M-INVR***, a patient-reported outcome tool used in chemotherapy trials to evaluate the incidence, duration, and frequency of nausea, vomiting, and retching, noted Jastreboff. M-INVR was administered daily for 7 days after each dose up to week 12.

“M-INVR is a more rigorous way to assess tolerability than standard AE reporting conventionally used in obesity trials, and it may introduce ascertainment bias. But again, this is the first trial to do this, and I think, in a phase II trial, it really informs about tolerability,” she explained.

The most common adverse events (AEs) were gastrointestinal (GI), mostly mild to moderate, and occurred with higher frequency in the no-DE arms. The incidences of MariTide discontinuation due to GI AEs were lower in the DE vs no-DE arms (~10 percent vs ~20 percent).

Looking at the nausea and vomiting events with the four highest MariTide doses, most were experienced with the first dose, and the incidence markedly dropped with each subsequent dose.

Cohort B: Obesity and T2D

Cohort B included 127 patients (mean age 55.1 years, 42 percent women, 24.4 percent Asian). The mean body weight was 103.9 kg, mean BMI 36.5 kg/m², and mean HbA_1c 7.9 percent. Participants were randomized to either placebo or one of three monthly MariTide fixed doses (140, 280, or 420 mg).

On treatment, the highest MariTide dose was associated with the greatest percent reduction in body weight (17 percent). With the two lower MariTide doses, 12 percent weight loss was achieved. Placebo yielded only a 1.4-percent weight reduction.

WC dropped with all MariTide doses, the greatest being with the highest dose (16.8 cm), noted Dr Harold Bays from the University of Louisville School of Medicine, Louisville, Kentucky, US, during his presentation at ADA 2025. “MariTide also reduced percent body fat, with less than 1/3 of the total weight reduction being lean mass reduction.”

The HbA_1c reductions with MariTide ranged between 1.9 percent and 2.2 percent, as opposed to 0.1 percent with placebo. What is more, nearly 90 percent of MariTide recipients achieved HbA_1c ≤6.5 percent irrespective of dose.

MariTide reduced fasting plasma glucose without increasing fasting serum insulin. Of note, there were variable increases in LDL-C and decreases in systolic BP, Bay added.

As in cohort A, the most frequent AEs in cohort B were GI-related, the most common being vomiting and nausea.

Long half-life, dual mechanism of action

In summary, MariTide is a novel antibody-peptide conjugate with a dual mechanism of action and a very long half-life (21 days). “This is three times longer than any [FDA-approved] therapy we currently have for obesity treatment … The backbone of this monoclonal antibody enables this longer half-life, which supports monthly or less frequent administration,” Jastreboff said.

“A monthly or less frequent treatment will be a defining advance for the obesity field, and [MariTide] could be that molecule. Less frequent administration may mitigate treatment burden, improving long-term adherence, thus providing the opportunity to optimize health outcomes for people living with obesity,” she continued.

Among patients living with obesity and T2D, similar patterns of benefit were observed. However, Bay stressed that the challenge would be the side effects. Considering the AEs and the lack of DE in cohort B, these questions come to mind: “Is there an alternative way to administer the drug? Are there different dosing schemes that could … retain the weight [and] HbA_1c reductions yet allow people to have less frequent side effects?,” he noted.

Ninety-four percent of eligible patients opted to participate in part 2 of the trial, which will determine the maintenance dosing approaches and durability of MariTide.