Imcivree (Setmelanotide) Becomes 1st Treatment Approved in US for 3 Rare Obesity Disorders

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by Marta Figueiredo |

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The U.S. Food and Drug Administration (FDA) has approved Imcivree (setmelanotide) as the first-ever treatment for people, 6 and older, with POMC deficiency, PCSK1 deficiency, and LEPR deficiency, three rare genetic obesity disorders.

The company expects that Imcivree will be available to eligible patients in the U.S. in the first months of 2021.

“Our first new drug approval is a major milestone … and we look forward to delivering on the promise of Imcivree for patients suffering with obesity due to POMC, PCSK1 or LEPR deficiency,” David Meeker, MD, chair, president, and CEO of Rhythm Pharmaceuticals, the therapy’s developer, said in a press release.

The approval includes patients whose conditions have been genetically confirmed by the presence of disease-causative, likely damaging, or uncertain-effect mutations in the POMCPCSK1, and LEPR genes.

All three genes are involved in the melanocortin-4 receptor (MC4R) pathway, which is responsible for controlling hunger, energy balance (how many calories we consume, and how many we burn), and consequently body weight.

As an activator of the MC4R pathway, Imcivree is designed to restore the pathway’s activity, potentially lessening hyperphagia, or insatiable hunger, and helping these patients lose weight. The therapy is given daily via under-the-skin injections.

“With Imcivree, we are advancing a first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the [MC4R] pathway,” Meeker added.

Many patients and their families face “an often burdensome stigma” associated with severe obesity, said Jennifer Miller, MD, pediatric endocrinologist at University of Florida Health. Caregivers often lock cabinets and refrigerators and significantly limit social activities to control disruptive food-seeking behavior, she added.

“This FDA approval marks an important turning point, providing a much needed therapy and supporting the use of genetic testing to identify and properly diagnose patients with these rare genetic diseases of obesity,” Miller said.

A similar marketing authorization application is currently being reviewed by the European Medicines Agency.

The FDA approval was based on one-year data from the largest Phase 3 trials conducted to date in obesity due to POMC/PCSK1 deficiency (NCT02896192) or LEPR deficiency (NCT03287960).

Top-line results from 21 participants showed that Imcivree resulted in at least a 10% weight loss in 80% of POMC/PCSK1 deficiency patients and in 45.5% of those with LEPR deficiency, meeting the main goal of both trials.

Over the course of one year, participants with POMC/PCSK1 deficiency lost a mean of 31.9 kilograms (70.2 pounds), while those with LEPR deficiency lost a mean of 16.7 kilograms (36.8 pounds).

The therapy also led to a 25% or greater hunger reduction in more than half of the participants and a drop in body mass index (BMI) — by 22.3% to 49.2% in patients with POMC/PCSK1 deficiency and by 10.6% in those with LEPR deficiency.

Notably, in both trials, participants’ weight and hunger levels increased during the one-month period in which they were switched to a placebo, and dropped again once they restarted Imcivree treatment.

The therapy was generally safe and well-tolerated, with no reports of treatment-related serious adverse effects or deaths in any of the trials. The most common adverse events were injection site reaction (96%), darkening of the skin (78%), and nausea (56%).

Still, its prescribing information contains warnings about possible sexual arousal disturbances, depression and suicidal thoughts, skin darkening, and darkening of pre-existing moles.

Imcivree’s recommended starting daily dose is 1 mg (0.1 mL) for children 6 to 12 years old, and 2 mg (0.2 mL) for older patients. The doses can be reduced to 0.5 mg or increased up to 3 mg, depending on the patient’s tolerability and age.

According to the label, if a patient does not lose at least 5% of body weight or 5% of BMI after 12 to 16 weeks of treatment, Imcivree should be discontinued as it is unlikely that clinically meaningful weight loss will be achieved and maintained with continued treatment.

“We know that not all obesity is the same, and genetic testing plays a key role in enabling physicians, patients and families to understand the underlying cause of certain severe obesities,” said Murray Stewart, MD, Rhythm’s chief medical officer.

“In addition to POMC, PCSK1 and LEPR genes, we are continuing our efforts to identify further genes and populations to evaluate the potential for setmelanotide to address the insatiable hunger and early-onset severe obesity that characterize these diseases,” he added.

Rhythm is testing the therapy in other obesity disorders linked to the MC4R pathway, including Bardet-Biedl syndrome and Alström syndrome in a Phase 3 trial (NCT03746522), as well as SRC1, SH2B1, and MC4R deficiency, and Smith-Magenis syndrome in a basket Phase 2 trial (NCT03013543).

Data about Imcivree’s safety and effectiveness in people with Bardet-Biedl and Alström syndromes is expected later this year or in the beginning of 2021, while such information in other conditions is anticipated in early 2021. The Phase 2 trial is still enrolling patients at sites across the U.S., Canada, and Europe; more information is available here.

Setmelanotide received the FDA’s breakthrough therapy and the EMA’s priority medicines designations for the treatment of MC4R-associated genetic obesity disorders. It was also granted orphan drug designation by both agencies and rare pediatric disease designation by the FDA for POMC/PCSK1 and LEPR deficiency obesities.

These designations are meant to accelerate the therapy’s development by providing support and financial benefits. They also ensure marketing exclusivity for a period of time (seven years in the U.S. and 10 years in Europe) if granted regulatory approval.

The approval also earned Rhythm a priority review voucher that can be redeemed to receive priority review for any subsequent marketing application, or be sold or transferred to other companies.

The company is also working on a new weekly formulation of setmelanotide, for which trial data so far suggest it is as safe and effective in promoting weight loss as the approved daily formulation.

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