Rhythm Reports Positive Data with Setmelanotide in Additional Rare Obesities
January 26, 2021
Rare Daily Staff
Hoping to expand the indications for its use, Rhythm Pharmaceuticals reported positive proof-of-concept data from multiple cohorts in its phase 2 basket study evaluating setmelanotide in patients with severe obesity due to genetic variants in the melanocortin-4 receptor (MC4R) pathway, and a phase 3 study in Bardet-Biedle syndrome and Alström syndrome.
Setmelanotide, marketed as Imcivree, was approved by the U.S. Food and Drug Administration for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. It is the first-ever FDA approved therapy for these rare genetic diseases of obesity.
Rhythm plans to initiate a potentially registration-enabling phase 3 trial evaluating setmelanotide in patients with MC4R pathway deficiencies due to a variant in one of the two alleles in the POMC, PCSK1, or LEPR genes (HET obesity), as well as the SRC1 and SH2B1 genes.
Rhythm estimates, based on the response rates observed in its phase 2 basket study, together with the updated sequencing results that there are between 100,000 and 200,000 people with HET obesity or SRC1 or SH2B1 deficiency obesity in the United States who could potentially benefit from setmelanotide therapy.
“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,” said David Meeker, chair, president and CEO of Rhythm.
He noted that across the setmelanotide development program, patients who lost 5 percent or more weight in the first 12 to 16 weeks of therapy—the responder group—tended to go on to lose more weight over time.
“We believe these new data, coupled with our translational research and sequencing efforts, further validate our gene-selection strategy and support advancement into later-stage studies for certain genetic variants, as well as the expansion of our earlier-stage setmelanotide development program into as many as 31 additional MC4R pathway genes later this year,” he said.
The proof-of-concept interim data is from its ongoing phase 2 basket study of 65 individuals with one of three distinct rare genetic diseases of obesity: HET obesity due to a genetic variant in one of the two alleles of the POMC, PCSK1 or LEPR gene (HETs); obesity due to SRC1 deficiency (SRC1); and obesity due to SH2B1 deficiency (SH2B1).
The primary endpoint of the study is the percent of patients in each subgroup showing at least a 5 percent loss of body weight over three months with a mean reduction from baseline in body weight of -10.1 percent for the responder group. The analysis did not include 15 patients who withdrew early due to COVID-related issues, adverse events or were lost to follow-up. Also not included were data from 12 patients who remain ongoing but have not yet reached 12 weeks of therapy.
Four of 13 patients (30.8 percent) with obesity due to SRC1 deficiency achieved the primary endpoint with a mean reduction from baseline in body weight of -8.4 percent.
Nine of 17 patients (52.9 percent) with obesity due to SH2B1 deficiency achieved greater than 5 percent weight loss over 12 weeks of therapy with a mean reduction from baseline in body weight of -7.1 percent.
Setmelanotide was generally well tolerated in each of these rare genetic diseases of obesity. The most common treatment-emergent adverse events included mild injection site reactions, hyperpigmentation, and nausea and vomiting, which occurred early in the treatment course. There were no serious adverse events related to treatment with setmelanotide.
Rhythm is in discussions with the U.S. Food and Drug Administration to define a potential path for setmelanotide towards registration for these indications. Pending the outcome of these discussions, Rhythm plans to initiate a pivotal phase 3 trial evaluating setmelanotide in patients with HET obesity and SRC1 and SH2B1 deficiency obesities in the second half of 2021.
Rhythm also shared data from a predefined exploratory endpoint from the phase 3 trial evaluating setmelanotide in patients with Bardet-Biedle syndrome (BBS) and Alström syndrome that showed the impact of setmelanotide on BMI-Z scores for patients younger than 18 years old with BBS. The BMI-Z score, or BMI standard deviation score, represents the number of standard deviations from median BMI by child age and sex. In 16 patients younger than 18 with BBS, the mean BMI-Z score was reduced from 3.74 at baseline to 2.98 for a reduction of -0.76, or -24.5 percent.
Rhythm remains on track to complete regulatory submissions to both the FDA and European Medicines Agency for BBS in the second half of 2021. The company expects to determine next steps for Alström syndrome upon completing a full analysis of the final data from the phase 3 trial.
Photo: David Meeker, chair, president and CEO of Rhythm.

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