Treatment with setmelanotide continues to provide significant weight loss at two years in six of nine patients with Bardet-Biedl syndrome (BBS) taking part in an ongoing Phase 2/3 basket trial. Also, five patients have experienced a significant decrease in hunger.
As of August, the mean weight reduction in the basket trial was 22.2%. Of three subjects with Alström syndrome, one has shown a 20% weight loss and a 25% reduction in the hunger score, another did not lose weight but showed a 38% decrease in hunger and improved diabetes control, and the third patient achieved 6% weight loss with no change in hunger. All three plan to stay on setmelanotide in the long-term extension study.
The trial (NCT03013543) is called a basket study because it is testing one therapy in various conditions linked to the melanocortin-4 receptor (MC4R) pathway. Mutations in genes along this pathway, such as POMC, PCSK1, LEPR and MC4R, are common causes of genetic obesity.
Setmelanotide is a MC4R agonist intended to restore MC4R pathway function. The U.S. Food and Drug Administration granted setmelanotide breakthrough therapy designation to treat obesity that’s caused by MC4R pathway mutations. Recently, the Committee for Orphan Medicinal Products, an arm of the European Medicines Agency, favored naming setmelanotide an orphan medicine to treat BBS.
The one-year basket study is evaluating the therapy in patients, 12 and older, with severe obesity and hyperphagia, or excessive food cravings. The medication is given once daily via subcutaneous (under-the-skin) injection.
Initially, the target indications were POMC deficiency, LEPR deficiency, BBS, and Alström syndrome. But at a recent R&D event in New York City, Rhythm announced the inclusion of four additional rare genetic obesity disorders in its study: SRC1 deficiency, SH2B1 deficiency, MC4R deficiency, and Smith-Magenis syndrome, all of which involve the MC4R pathway.
Enrollment is ongoing at locations across the U.S. and in Europe; details are available here.
“We look forward to evaluating setmelanotide in these indications in the months and years ahead,” Alastair Garfield, PhD, Rhythm’s vice president of translational research and development, said in a news release. “We are also committed to continuing to probe the numerous other MC4R pathway genes that may be implicated in rare genetic disorders of obesity and may provide additional opportunities for setmelanotide.”
The company also presented updated data on the prevalence of MC4R-driven obesity disorders in the U.S. As of June 2019, Rhythm collected samples from 13,567 patients with severe obesity, and found 1,584 individuals (11.7%) with a rare variant of the MC4R pathway. These patients may be eligible for the basket study or other Phase 3 trials.
Also, the genetic tests identified 29 cases of POMC or LEPR deficiency, currently addressed in two pivotal Phase 3 trials of setmelanotide (NCT02896192 and NCT03287960). Top-line results are expected by the end of the year.
Rhythm’s genetic test results are consistent with its clinical epidemiology estimates of 100–500 POMC deficiency and 500–2,000 LEPR deficiency patients living in the U.S. The findings are also in line with prior estimates of more than 20,000 living with obesity and carrying mutations on one copy of the POMC, PCSK1, or LEPR genes.
The company estimates that 23,000 patients have SRC1 deficiency, more than 24,000 have SH2B1 deficiency, over 10,000 have MC4R deficiency, and more than 2,400 have Smith-Magenis syndrome in the U.S.
“We believe we may have identified nearly one-third of the estimated BBS and Alström patients living in the U.S., providing a foundation as we continue to enroll our pivotal Phase 3 trial in BBS and Alström syndrome, and begin to build the infrastructure to support the potential commercialization of setmelanotide in these indications,” said Nithya Desikan, chief commercial officer at Rhythm.
Keith Gottesdiener, MD, the company’s CEO, commented: “In collaboration with partners, patients, and health care providers, Rhythm is advancing toward our goal of changing the paradigm for rare genetic disorders of obesity.”
“Through these initiatives, we aim to provide patients with severe obesity and unrelenting hunger a potential new therapeutic option, and to equip physicians and caregivers with the knowledge and resources to better manage these disorders.”
A replay of Rhythm’s recent webcast of its R&D event can be found here.