Rhythm Pharmaceuticals just reported today that it had achieved positive results from its pivotal phase 3 TRANSCEND study evaluating the use of setmelanotide, a melanocortin-4 receptor [MC4R] agonist, for the treatment of patients with acquired hypothalamic obesity. This is a rare disorder whereby a patient has obesity due to damage to the brain. Specifically, the hypothalamus portion of the brain is impaired, which is not a good thing at all. That’s because this portion of the brain controls a person’s hunger, energy balance level, and satiety [feeling full].
This late stage study enrolled a total of 120 patients who were randomized 2:1 to receive either setmelanotide or placebo over a 52-week period. The primary endpoint of this study was looking for a statistically significant effect of drug versus placebo when looking at a measure of obesity known as Body Mass Index (BMI). The primary endpoint was met, in that the patients who took Rhythm’s drug achieved a -16.5% reduction from baseline (81 patients] compared to that of an increase in BMI for those who took placebo instead with +3.3%.
This is good news in terms of the regulatory front, because with the primary endpoint being met, this should give the company the ability to receive approval of setmelanotide for the treatment of these patients with acquired hypothalamic obesity. However, it also did have an impact on these patients lives and the reason why is because about 80% of patients in this trial who took the company’s drug ended up achieving a BMI reduction of 5% or more over the 52-week period.
This disorder is not ideal, because some type of damage that occurs to the hypothalamus, like a tumor or other damaging impact, has an effect on the ability for a patient to experience satiety. Thus, these patients suffer from hyperphagia (extreme state of hunger). The gist here is that with the hypothalamus being damaged, it leads to impaired MC4R signaling. This is bad because this protein is responsible for controlling a person’s hunger. The goal of setmelanotide is to restore functional signaling of this pathway, which leads to energy expenditure, a feeling of fullness and excellent hunger control.
As I indicated above, the primary endpoint being met leads to the ability for Rhythm to file for regulatory approvals, and that’s exactly what it intends to do. It will submit a New Drug Application of setmalanotide to the FDA and a Type II variatio request to the European Medicines Agency (EMA). The thing is that this company is already one step ahead of the game when it comes to using this drug to target rare obesity disorders. The reason why is because it has already received FDA approval of a IMCIVREE (setmelanotide injection) for the treatment of patients with rare genetic forms of obesity like: Bardet-Biedl syndrome (BBS) or Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency
Besides the fact that this company could expand its label to include this other rare form of obesity, there is something else far more important to note, which is first to market. In essence, if this drug is approved to treat patients with acquired hypothalamic obesity, then it will be the first one of its kind.
That’s because there are no therapies that have yet been approved to treat them. Taking it one step further, the company is hoping to expand its pipeline with a next-generation MC4R pathway drug, known as Bivamelagon (LB54640). The difference of this drug, compared to that of setmelanotide, is that it can be taken orally. The hope is that an oral drug can achieve superior efficacy compared to that of a drug that is given via subcutaneous injection like setmelanotide. Investors aren’t going to have to wait long to see if this oral drug can accomplish such a feat. That’s because the company is expected to announce top-line data from a phase 2 study using bivamelagon to treat acquired hypothalamic obesity patients in the 2nd half of 2025.
