Rhythm Pharma Drug Lowers BMI in Rare Form of Obesity Rooted in a Dysregulated Brain Pathway

Before GLP-1 agonists became the blockbuster obesity drugs many people know and use today, Rhythm Pharmaceuticals was researching molecules that take a similar approach but for a different target. The biotech’s drug, Imcivree, has FDA approvals for two rare forms of obesity. Preliminary data from a pivotal test in yet another type position the drug to continue Rhythm’s pipeline-in-a-product strategy.

The Imcivree data announced Monday are from a Phase 3 test in hypothalamic obesity. Rhythm said its once-daily injectable drug met the trial’s main goal by leading to statistically significant and clinically meaningful reduction in body mass index (BMI) compared to a placebo. Full results will be presented at a future medical meeting. But based on the preliminary results so far, Boston-based Rhythm said it plans to submit applications to U.S. and European regulators in the third quarter of this year seeking to expand Imcivree’s approval to hypothalamic obesity.

Whereas GLP-1 drugs are peptides engineered to hit receptors for gut hormones, Rhythm’s drug is a peptide engineered to bind to and activate targets in the brain. Imcivree is specifically designed to target melanocortin-4 receptor (MC4R), a receptor found primarily in the hypothalamus, a region of the brain that produces hormones that regulate various bodily functions. The MC4R pathway regulates hunger and energy expenditure.

Cancer patients can develop obesity after surgery or radiation to treat brain tumors. These treatments can damage the hypothalamus, disrupting the MC4R pathway. By binding to and activating the MC4 receptor, Rhythm’s engineered peptide is intended to restore signaling in this pathway.

The preliminary results announced Monday are from a Phase 3 test that enrolled 120 participants, adults and children. The company said that after one year of treatment, Imcivree led to a 15.5% reduction in BMI compared to a 3.3% increase in the placebo group. Rhythm added that no new safety signals were reported. Side effects reported in previous tests of the drug include sexual dysfunction, hypersensitivity, and depression and suicidal ideation. In the latest study, Rhythm said no serious adverse events were reported that led to discontinuation of the study drug.

“These data are highly clinically meaningful, offering hope that a new targeted therapy may become available for patients — both adults and children — living with acquired hypothalamic obesity,” Dr. Susan Phillips, a pediatric endocrinologist at Rady Children’s Hospital-San Diego and professor of pediatrics at the UC San Diego School of Medicine, said in a prepared statement included in Rhythm’s announcement of the latest Imcivree results.

Imcivree’s initial FDA approval in 2020 covered chronic weight management caused by three rare protein deficiencies that impair the MC4 receptor pathway. In 2022, the Rhythm drug expanded its approval to Bardet-Biedl syndrome, a rare disease that leads to insatiable hunger. Both indications are genetically driven.

An approval of Imcivree in hypothalamic obesity would be the first for this drug in an acquired form of obesity. It could also potentially become the first approved treatment for this specific type of obesity. Rhythm estimates between 5,000 and 10,000 patients in the U.S. are living with hypothalamic obesity; the company believes the disorder’s prevalence in Europe is similar. That’s larger than patient populations served by Imcivree in its two currently approved indications, giving Rhythm the opportunity to further grow revenue. For 2024, the biotech reported $130.1 million in product sales, a 68% increase compared to the prior year.

Rhythm is not the only biotech developing a hypothalamic obesity drug. The lead drug candidate of Aardvark Therapeutics is a small molecule designed to block TAS2 receptors in the gut. This drug is currently in Phase 3 testing in Prader-Willi syndrome, a rare metabolic disorder that leads to insatiable hunger (the first FDA approval in Prader-Willi was awarded last month to Soleno Therapeutics). Aardvark also plans to develop its drug for hypothalamic obesity. Those plans will be supported in part by Aardvark’s IPO, which raised $94 million in February.

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