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A once-monthly injectable weight management agent safely induced durable weight loss in a phase I human trial.

At the highest dose tested, patients with overweight or obesity lost 14.5% of their body weight by day 85, Murielle Véniant, PhD, of Amgen Research in Thousand Oaks, California, and colleagues reported in .

And at 150 days following the last dose, this high-dose group maintained a weight loss of 11.2% from baseline.

The first-in-class investigational compound maridebart cafraglutide, known as MariTide and previously as AMG 133, acts as an inhibitor of the gastric inhibitory polypeptide receptor (GIPR) and an activator of glucagon-like peptide 1 (GLP-1) receptor.

"The combination of an anti-GIPR monoclonal antibody ... and a GLP-1RA has been shown to mediate more pronounced weight loss than either agent alone in preclinical obesity models," the researchers wrote. They explained that because the compound has a longer half-life than other similar agents on the market, the dosing intervals are able to be extended while still maintaining most of the weight loss.

Current GLP-1 receptor agonists on the market for weight-loss like semaglutide (Wegovy) and tirzepatide (Zepbound) are injected once weekly and have shown weight regain after discontinuation.

The new findings build upon , which developer Amgen announced back in December 2022. A total of 49 patients got a single dose of progressively higher dosages across the cohort, starting at 21 mg and reaching up to 840 mg to monitor safety. Another 26 got three doses of 140 mg, 280 mg, or 420 mg subcutaneously administered every 4 weeks (days 1, 29, and 57).

All participants in the 140- and 280-mg groups and the placebo group received all three scheduled doses, as did four of eight participants in the 420-mg group; the others in the high-dose group withdrew from the study after reporting mild gastrointestinal-related adverse events.

Typical of any GLP-1 agonist containing compound, the most common adverse events were gastrointestinal related. The most common event was nausea, which all of the highest dose group experienced and nearly all of the two lower doses experienced. The majority of all dose groups also experienced vomiting. There were also a few reports of diarrhea, constipation, and dyspepsia across the active treatment groups. However, most events were mild and resolved within 48 hours.

Because of the high frequency of withdrawal in the 420-mg group, the researchers suggested that "intra-patient dose-escalation-based regimens may offer a future advantage in decreasing the first-dose effect seen with AMG 133."

Across all three multi-dose groups, substantial weight loss was recorded as early as the first week of treatment. Mean percent body weight change averaged as follows:

• With the 420-mg dose, -4.9% at day 7 and -14.5% at day 85
• With the 140-mg dose, -2.0% at day 7 and -7.4% at day 78
• With placebo, 0.04% at day 7 and 1.5% at day 85

This body weight reduction was maintained through day 70 after the third dose in each of the three multiple dosing groups.

Beyond body weight reduction, active dose groups had a similar patterns of reductions in BMI. Also, fasting glucose decreased from baseline in a dose-responsive manner at days 29 and 85 for all maridebart cafraglutide-treated patients but remained the same in placebo. While the lowest and highest dose groups saw dose-dependent decreases in waist circumference, there were fluctuations in waist circumference in the 280-mg dose group.

While none of the participants had diabetes at baseline (average baseline HbA1c ranged from 5.5% to 5.6%), HbA1c decreased in all three dose groups by day 85 then trended toward baseline during the safety follow-up period at day 207.

topline data from the phase II study of maridebart cafraglutide is expected later this year. That trial enrolled adults with overweight or obesity, with or without type 2 diabetes.

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