Rhythm RM-718 Shows 11.6% BMI Reduction in Hypothalamic Obesity Trial

Rhythm Pharmaceuticals has reported preliminary efficacy and safety data from its ongoing Phase 2 clinical trial evaluating RM-718, an investigational once-weekly melanocortin-1 receptor (MC4R) agonist, in patients with acquired hypothalamic obesity (HO). After 16 weeks of treatment, patients receiving RM-718 experienced a mean 11.6% reduction in BMI from baseline, supporting the drug’s potential as a next-generation therapy for rare disorders involving the MC4R pathway.

The early findings also suggest that RM-718 may offer an improved tolerability profile by minimizing one of the most common adverse effects associated with MC4R agonists, hyperpigmentation.

MC4R Activation Targets a Major Driver of Hypothalamic Obesity

Hypothalamic obesity is a rare and severe disorder that develops after damage to the hypothalamus, most commonly following surgery, radiation therapy, or tumors such as craniopharyngioma. Injury to this brain region disrupts energy balance and appetite regulation, leading to uncontrolled hunger, rapid weight gain, and resistance to conventional weight-loss interventions.

RM-718 is an investigational once-weekly injectable agonist that selectively activates the melanocortin-4 receptor (MC4R), a key regulator of appetite and energy expenditure. Unlike earlier MC4R agonists, the molecule has been engineered to spare activation of the melanocortin-1 receptor (MC1R), which is associated with treatment-related skin hyperpigmentation.

Preclinical studies have shown that RM-718 reduces both body weight and hunger, supporting its continued clinical development.

Preliminary Phase 2 Results Show Meaningful BMI Reduction

The ongoing open-label Phase 2 study enrolled 11 patients with acquired hypothalamic obesity.

Among the seven participants who completed 16 weeks of treatment, RM-718 produced a mean BMI reduction of 11.6% from baseline.

Rhythm noted that these results are broadly consistent with efficacy previously observed for other MC4R-targeted therapies. The company reported that bivamelagon produced a mean BMI reduction of 10.1% after 14 weeks in seven patients receiving the 600 mg dose, while setmelanotide achieved a similar 10.1% BMI reduction after 16 weeks across 64 patients enrolled in Phase 2 and Phase 3 studies.

As of July 16, 2026, eight participants remained on active treatment, including two who had not yet reached the 16-week assessment.

Three participants discontinued the study. Two stopped treatment because of adverse events, specifically injection-site induration and nausea, while one patient withdrew during the extension phase.

Safety Profile Shows Limited Hyperpigmentation

RM-718 was generally well tolerated throughout the study.

The most frequently reported adverse events were injection-site reactions, nausea, and vomiting.

Only two mild cases of hyperpigmentation were observed, both confined to the injection site. No cases of generalized hyperpigmentation were reported, an encouraging finding given that pigmentation changes remain a known class effect of MC4R agonists.

The early safety profile supports the rationale behind developing an MC1R-sparing molecule that maintains therapeutic activity while reducing off-target pigmentation effects.

Company Sees Potential for a Next-Generation MC4R Therapy

David Meeker, M.D., Chair, President and Chief Executive Officer of Rhythm Pharmaceuticals, said the preliminary findings indicate that RM-718 has the potential to produce clinically meaningful BMI reductions in patients with acquired hypothalamic obesity.

He noted that the magnitude of weight reduction observed so far is comparable to that seen with both setmelanotide and bivamelagon at similar treatment durations. He also highlighted the limited occurrence of hyperpigmentation, with only two mild injection-site cases reported, suggesting that RM-718 may improve tolerability while preserving efficacy.

Path Forward

The Phase 2 trial remains ongoing, and additional patient follow-up will further define the durability of weight reduction and long-term safety of RM-718. If subsequent data continue to support its efficacy and favorable tolerability profile, the investigational therapy could expand Rhythm Pharmaceuticals’ portfolio of MC4R-targeted treatments for rare neuroendocrine diseases and provide another therapeutic option for patients living with acquired hypothalamic obesity.

Reference

Rhythm Pharmaceuticals Announces Preliminary Data from Phase 2 Trial that Showed RM-718 Demonstrated Positive Efficacy Signal in Acquired Hypothalamic Obesity – Rhythm Pharmaceuticals, Inc.