Rhythm Pharmaceuticals is accelerating the development of Imcivree, a melanocortin 4 receptor (MC4R) agonist. First approved more than five years ago as a treatment for certain patients with inherited obesity, the drug is moving into another broader area with FDA approval for acquired hypothalamic obesity (HO).
Acquired HO, for which Imcivree is the first approved treatment, represents an “expanded way of thinking” about the weight-regulating MC4R pathway that Rhythm’s products target, chief scientific officer Dr. Alastair Garfield explained in a recent interview with Fierce.
Until now, all of Imcivree’s approved uses have centered on specific genetic causes. In HO, on the other hand, the MC4R pathway is impaired as a result of hypothalamic damage, such as a tumor or stroke, leading to weight gain and insatiable hunger (bulimia).
In 2020, Imcivree became the first drug to receive FDA approval for the treatment of obesity due to genetically confirmed POMC, PCSK1, or LEPR deficiencies. Two years later, monogenic obesity due to Bardet-Biedl syndrome was added to the label.
Garfield said the move outside of its core product of genetic diseases is “a bit of a turning point” for Rhythm and “a big shift in the market potential” for the drug.
In a press release, Rhythm said the number of patients with acquired HO in the United States is estimated to be approximately 10,000, based on numbers from the literature, tumor registries, and claims data. As part of the launch for this indication, Rhythm is focused on educating physicians and patients who may be affected by this disease. Garfield expects the drug’s indications to “grow a little bit,” but in terms of global patient spread, he believes the company “will be able to find patients wherever we go.”
Imcivree’s FDA approval was supported by Rhythm’s Phase 3 Transcend trial, which showed an average improvement in body mass index (BMI) change of 18.4% for Imcivree-treated patients. The average change in BMI from baseline was a 15.8% decrease in the treated group, compared to a 2.6% increase in BMI in the placebo group, according to the company.
“This is a transformational milestone for Rhythm and strengthens our commitment to providing meaningful treatments to patients with rare MC4R pathway diseases,” CEO David Meeker, MD, said in a company release.
The new label specifically allows the use of Imcivree to reduce excess weight and maintain weight loss over the long term in adult and pediatric patients 4 years of age and older with acquired HO.
Leerink analysts said in a note to clients that the agreement is a “significant label expansion” that strengthens the company’s leadership position in the genetic obesity field. The approval marks a “major inflection point” for Rhythm, the analysts wrote, noting that the company has “successfully transitioned from an R&D-stage biotech to a commercial-stage company with durable revenue prospects.”
Imcivree is Rhythm’s only commercial product and had 2025 sales of $194.8 million.
The FDA’s blessing on the acquired HO marks a welcome reprieve from the trial failure that Rhythm reported earlier this week, ending the company’s hopes of expanding into another subset of genetic obesity. Still, given how “crucial” the MC4R pathway is in defining body weight, “I think we have a lot more places to learn before our approach is most effective,” Garfield said. The executive spoke with Fierce Pharma before the latest results were released.
As it stands, Garfield said the potential for spread to Prader-Willi syndrome “is our number one concern.”
Obesity lessons
Rhythm entered the obesity space with its small genetics corner before Eli Lilly and Novo Nordisk largely carved out the market with their popular GLP-1 products for general obesity. When Lilly and Novo’s drugs became widely available a few years ago, Rhythm ultimately learned a “very valuable lesson,” Garfield said.
“We were worried we were going to be the proverbial damsel in distress,” Garfield said, drawing a picture of a small pharmaceutical company “tied to the railroad tracks when two bigwigs, Novo and Lily, came across us.”
Instead, Rhythm came to learn that “a rising tide lifts all boats,” Garfield said of how GLP-1 increased awareness and interest in obesity drugs.
Of course, that increased awareness requires more education about the difference between bulimia and general obesity, and a fight against the notion that all obesity is the same. But by further recognizing and proving that the MC4R mechanism works in the “right” population, Rhythm “could build a moat around patient populations,” Garfield said. In the future, he predicts obesity will become an “umbrella term” with a broad definition that includes clearly defined subsets.
