Rhythm Seeks to Test Setmelanotide in More Obesity Disorders This Year
Rhythm Pharmaceuticals has identified 31 additional genes whose mutations may be amenable to setmelanotide, its U.S.-approved therapy for genetic obesity disorders linked to the melanocortin-4 receptor (MC4R) pathway.
This discovery is the result of Rhythm’s sequencing efforts and precision approach that has been recently validated in a Phase 2 basket study (NCT03013543), leading to the identification of several new MC4R-related disorders with promising responses to setmelanotide.
“Leveraging our extensive scientific expertise and years of internal research, we have developed a process that allows us to identify new genes that may be responsive to setmelanotide and to quickly advance them into our Basket Study for clinical evaluation,” Alastair Garfield, PhD, Rhythm’s vice president and head of translational research, said in a press release.
“Based on our success across a range of genes with strong and very strong pathway relevance, we look forward to potentially expanding our clinical development program into patients with an additional 31 pathway genes later this year,” he added.
The company plans to discuss with the U.S. Food and Drug Administration (FDA) its plan to launch a similar Phase 2 basket study to test the therapy in these potential new indications.
Future plans for this and other trials, as well as a detailed description of the company’s precision approach, were recently shared at Rhythm’s virtual R&D event, held Jan. 26.
The company aims “to change the paradigm for the treatment of rare genetic diseases of obesity,” David Meeker, MD, Rhythm’s chairman, president, and CEO, said in the webcast.
Prior to Rhythm’s sequencing efforts, these patients were “lost in the system,” with no specific testing or treatment, Meeker said. Investigating these rare diseases was even more challenging as society and healthcare professionals tend to think that all obesity can be resolved with an “eat less and exercise more” approach.
Rhythm’s approach is not to “try and tackle all obesity,” but to focus on obesity associated with mutations in the MC4R pathway, which controls hunger and satiety (feeling full), added Murray Stewart, MD, Rhythm’s chief medical officer, during the webcast.
Given as an under-the-skin injection, setmelanotide was designed to lessen hunger and promote weight loss by activating the MC4R pathway, which is deficient in this subset of obese patients.
The therapy was approved in the U.S. under the brand name Imcivree in November 2020 for patients, 6 and older, with obesity due to POMC, PCSK1, or LEPR deficiency — all MC4R-related obesities. A similar application is currently being reviewed by the European Medicines Agency, with a decision expected later this year.
In the webcast, Stewart stated that Rhythm’s precision approach to identify genetically obese patients, who may respond to setmelanotide, comprises three steps. The first is to identify children with early-onset severe obesity (beginning at age 2 or older) and who are “hungry all the time.”
Then, these patients will undergo genetic testing to confirm the presence of MC4R pathway mutations, which will be classified according to the American College of Medical Genetics (ACMG). The five classifications are: benign (not contributing to the disease), likely benign, of uncertain significance, likely pathogenic, and pathogenic — which means disease-causative.
Each indication is “defined by the dysfunction of a gene, and it is only ever going to be as successful as the evidence that ties that gene to the MC4 receptor pathway and to human obesity,” Garfield said.
Similar to the ACMG classification, Rhythm also ranks these potential genes on the strength of their association to the MC4R pathway, based on external published data and the company’s internal research.
Patients carrying “likely disease-causative” or “disease-causative” mutations in genes with strong or very strong MC4R relevance are then considered for a three-month setmelanotide trial.
This type of trial has been proved to be sufficient to distinguish responders from non-responders based on the achievement of at least 5% weight loss in adults and clinically relevant drops in BMI-Z scores in children.
BMI-Z scores include standard deviations from the normal median body-mass index by child age and sex, thereby correcting for weight gain associated with normal growth.
Previous data from Phase 2 and 3 trials showing setmelanotide’s benefits in a number of obesity disorders highlight that Rhythm’s “underlying approach to the rationalized selection of genes in the MC4R pathway … is working,” Garfield said.
By applying its proprietary approach to the largest known genetic obesity database of approximately 37,500 individuals, the company has so far identified 113 genes with potential ties to the MC4R pathway.
People with mutations in five such genes have already been shown to respond to setmelanotide in a previous Phase 2 basket trial, and these responses are set to be confirmed in an upcoming Phase 3 trial.
The company also plans to test setmelanotide in obese individuals with mutations in 31 additional genes with strong and very strong evidence of MC4R pathway relevance in an upcoming basket study.
The study’s design will need to be discussed with the FDA, but Rhythm expects that, initially, all participants will receive an injection of setmelanotide once a day.
Patients showing at least 5% weight loss after three months will be randomly assigned to setmelanotide or a placebo for a specific period of time. Continuous treatment is expected to result in further weight loss, while switching to placebo is expected to drive weight gain, which may be rescued by switching these patients back to setmelanotide, Stewart said.
The remainder 77 genes currently ranked as weakly or moderately relevant on Rhythm’s list will continue to be evaluated in preclinical studies to clarify their potential “in such ways that may elevate them to the strong and very strong [categories] with further scientific data,” Garfield said.
“We will be working hard on these genes and continue to populate our master gene list and bring new indications forward,” he added, noting that “the expansion of our DNA sequencing database is absolutely critical to driving forward our agenda, both in terms of research, identifying patients, and building the community.”
Stewart also discussed other trial plans for this year, including the launch in the first half of the year of a Phase 2 study in people with hypothalamic obesity due to brain tumors. Notably, the hypothalamus is a brain region that controls weight, among other processes.
In the second half of 2021, the company also plans to launch a setmelanotide trial in children (2–6 years of age) with these rare genetic obesity disorders, to expand setmelanotide’s indication to younger patients, since early treatment is key.
Based on previous data suggesting that a weekly formulation of setmelanotide is as effective and safe at promoting weight loss in healthy obese individuals as its daily formulation, Rhythm plans to launch a study of this weekly formulation, which may potentially support a future application to regulators.