Setmelanotide Phase 2 Study for Hypothalamic Obesity Published in The Lancet

On April 29, 2024, Rhythm Pharmaceuticals, Inc. disclosed the findings from its Phase 2 study evaluating setmelanotide for hypothalamic obesity, a rare severe form of obesity, in the peer-reviewed journal The Lancet Diabetes & Endocrinology. This particular type of obesity emerges after damage to the brain's hypothalamic region, often following the removal of specific brain tumors like craniopharyngioma or astrocytoma. The damage disrupts the melanocortin-4 receptor (MC4R) pathway, which is crucial for managing hunger and weight.

Led by Dr. Christian Roth of the Seattle Children’s Research Institute, the study is pioneering in investigating setmelanotide as a potential targeted treatment for hypothalamic obesity. The hallmark of this condition includes severe, rapid weight gain and an abnormal increase in hunger. The trial showed a consistent decline in both body weight and hunger among participants who adhered to the treatment regimen.

Rhythm Pharmaceuticals enrolled 18 patients in an open-label, 16-week Phase 2 trial. Participants, either within the 6 to <18 years age group with a BMI ≥95th percentile or adults with BMI ≥35 kg/m2, received setmelanotide, aiming to reduce their BMI by at least 5%. Daily hunger levels self-reported by the patients were also analyzed. The results were impressive: 89% of the participants met the primary endpoint by reducing their BMI by at least 5%, while 78% reduced their BMI by 10% or more. On average, the BMI fell by 15% from the initial measurement.

Specifically, in the pediatric subgroup, there was a mean reduction in BMI Z score by 1.3 points from the start to week 16. Furthermore, the average hunger score among patients over 12 years of age dropped from 6.6 to 3.7, translating to a 45% reduction.

The publication also features early data from a long-term extension of the Phase 2 study, initially presented at ObesityWeek® 2023. Over one year of setmelanotide treatment, patients had an average BMI reduction of around 26%.

Moreover, setmelanotide was generally well-tolerated throughout the study. Most common adverse events (AEs) included nausea, skin hyperpigmentation, vomiting, and COVID-19 among others. No new safety concerns emerged during the extended trial period. However, two patients discontinued due to adverse events. Rhythm Pharmaceuticals noted that the screening for the pivotal Phase 3 trial of setmelanotide in hypothalamic obesity had been completed, and results are anticipated in the first half of 2025.

Rhythm Pharmaceuticals continues to champion setmelanotide, marketed as IMCIVREE®, for managing chronic weight in patients with POMC, PCSK1, or LEPR deficiency from genetic testing or diagnosed with Bardet-Biedl syndrome (BBS). The drug is approved by the FDA, the European Commission (EC), and the UK’s MHRA for relevant indications in specific obesity-related conditions, with ongoing expansion of its clinical program to investigate further uses of setmelanotide and other MC4R agonists.

Setmelanotide has achieved significant progress in managing obesity due to genetic deficiencies, marking a crucial step forward in treating rare neuroendocrine disorders.