FDA-approved Setmelanotide Shows Promise in More Genetic Obesity Disorders

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Three months of treatment with setmelanotide, an approved therapy for genetic obesity disorders, led to clinically meaningful body weight loss in adolescents and adults with additional diseases linked to the melanocortin-4 receptor (MC4R) pathway, data show.

These interim data, from a Phase 2 basket trial, highlight setmelanotide’s potential for treating so-called heterozygous (HET) obesity — caused by mutations in only one copy of the POMC, PCSK1, or LEPR genes — as well as SRC1 deficiency, and SH2B1 deficiency, according to Rhythm Pharmaceuticals, the therapy’s developer.

“This is an exciting moment for Rhythm as we enter a new frontier in the treatment of rare genetic diseases of obesity,” David Meeker, MD, Rhythm’s chair, president and CEO, said in a press release.

“These new data show that setmelanotide led to meaningful weight loss in approximately 30 percent to greater than 50 percent of treated patients with genetic variants in the MC4R pathway across multiple genes,” Meeker said.

Rhythm plans to confirm these positive findings in a Phase 3 trial expected to be launched in the second half of 2021, pending discussions with the U.S. Food and Drug Administration (FDA).

The Phase 2 results, along with Phase 3 data from pediatric patients with Bardet-Biedl syndrome (BBS) — another MC4R-related genetic obesity disorder — were recently presented at a Rhythm’s virtual R&D event, held online Jan. 26.

Setmelanotide works by activating the MC4R pathway, which controls hunger and satiety (feeling full) and is deficient in people with rare genetic obesity disorders. Such disorders including those caused by mutations in the POMC, PCSK1, LEPR, SRC1, and SH2B1 genes, as well as BBS, Alström syndrome, and Smith-Magenis syndrome.

Given as an under-the-skin (subcutaneous) injection, the therapy is intended to lessen hunger and promote weight loss in obese patients.

Setmelanotide was approved in the U.S. in November 2020, as the first treatment available for patients ages 6 and older with obesity due to POMC, PCSK1, or LEPR deficiency. It is expected to be commercially available — under the brand name Imcivree — in the upcoming months, Meeker said during the event.

The international, Phase 2 basket study (NCT03013543) is evaluating setmelanotide’s safety and effectiveness in a number of other rare obesity disorders related to problems in the MC4R pathway.

Participants receive an injection of setmelanotide (doses from 1–3 mg depending on age group) once a day. The trial’s main goal is to assess the proportion of patients in each disease subgroup achieving at least a 5% weight loss over three months. After treatment in this phase, the participants can choose to enter a long-term extension study (NCT03651765).

This 5% reduction is considered clinically significant as it is linked to positive changes “in terms of other metabolic parameters, and morbidity, and ultimately, mortality,” said Murray Stewart, MD, Rhythm’s chief medical officer.

It also is “sustained over a year,” he said in the webcast. 

Thus far, the setmelanotide development program has shown that “patients who lost 5 percent or more weight in the first 12 to 16 weeks of therapy — our responder group — tended to go on to lose more weight over time,” Meeker said in the release.

In the webcast, Stewart presented data from a total of 65 people with severe obesity due to HET deficiencies (35 patients), SRC1 deficiency (13 patients), and SH2B1 deficiency (17 patients). All had completed three months of treatment as of December 2020.

The patients’ ages ranged from 12 to 68 years, with a mean of 30 to 39 years, depending on their deficiency. There were six adolescents in the HET obesity group, five in the SH2B1 group, and four in the SRC1 group.

The results showed that 12 HET obesity patients (34.3%) achieved at least 5% weight loss, with a mean body weight reduction of 10.1%, compared with 0.4% weight loss among non-responders.

According to Stewart, participants carrying disease-causative or likely disease-causative mutations in the POMC, PCSK1, or LEPR genes — or the known N221D mutation in the PCSK1 gene — more commonly met the main goal than those carrying mutations of unknown significance.

Notably, responders also showed a nearly twofold greater reduction in hunger relative to non-responders.

In turn, four SRC1 deficiency patients (30.8%) and nine participants with SH2B1 deficiency (52.9%) attained a weight loss of at least 5%, with a mean drop of 7.1–8.4%, compared with a 0.3–1.5% reduction among non-responders.

“The positive interim data in these new patient [groups], while representing diseases which are individually rare, expand our estimates of the potential of setmelanotide to serve a far larger cumulative patient population than has been examined to date,” Meeker said in the release.

Based on the latest analyses, the company now estimates there are between 100,000 and 200,000 potentially setmelanotide-responsive people with these three rare genetic obesity disorders in the U.S alone, officials said in the webcast.

“These data increase our confidence in setmelanotide’s potential as a precision medicine for patients with a range of MC4R pathway variants and reinforce our commitment to working with urgency to maximize setmelanotide’s reach,” Stewart said in the release.

Rhythm will now discuss with the FDA its preliminary plan to launch a confirmatory, placebo-controlled Phase 3 trial to confirm these positive data in a larger number of patients — likely up to a total of 200.

“The primary [goal] will be at six months, but we’ll also be following patients for a year to ensure we’ve got a year’s worth of data, and we hope to be able to transfer the placebo patients onto active therapy,” Stewart said in the webcast.

The company also presented additional data from the confirmatory Phase 3 trial (NCT03746522) of setmelanotide in people with BBS and Alström syndrome. In people with Alström, the trial’s initial data had demonstrated only trends toward weight and hunger reductions.

However, the study met its main and secondary goals among the BBS group, with significant drops in body weight and hunger, those previous results had shown.

The new results concerned setmelanotide’s weight effects in 16 pediatric BBS patients. Three of the children were younger than 12, Stewart said in the webcast, and 13 were between ages 12 and 17 years.

The effects of the therapy were evaluated with the body mass index BMI-Z score. This score includes standard deviations from the normal median BMI by child age and sex, thereby correcting for the fact that “a child or adolescent may be growing in height, and therefore would be expected to gain weight,” Stewart said in the release.

One year of setmelanotide treatment in the children and adolescents with BBS was found to result in statistically significant and clinically meaningful reductions in BMI-Z scores.

Rhythm said its plans remain on track to file applications in the second half of 2021 with both the FDA and the European Medicines Agency to seek setmelanotide’s approval for BBS.

Regarding Alström syndrome, the company’s next steps will be determined upon a full analysis of the Phase 3 trial’s final data, expected to be ready by March, the scientists said.

“There is a clear signal in Alström,” Meeker said. But thus far, only 10 Alström’s patients have been treated with the therapy, making it difficult to get clinically significant results, he said.

“As with many of these genes, not every patient may respond,” Meeker added. He said the company is looking into its alternatives.

“We’re not gonna give up on Alström,” he said.

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