From the recent newsletter “CLINUVEL is obliged to be at the forefront of this wave of attention to melanocortin 1 receptor (MC1R) function, melanocyte biology and proopiomelanocortin (POMC). The present status of melanocortins is positive as the environment has been primed and is ready to accept a once-so-alien concept.” With Wolgen talking about competitors and the growing interest in melanocortins stimulated by Clinuvel’s success I thought I would write a comparison of what I think is the closest melanocortin.
The drug is setmelanotide, and the company is Rhythm pharma. RYTM (NASDAQ) listed October of this year. It currently has a market cap of $972 million (Clinuvel $360 million).
Rhythm are aiming to demonstrate efficacy in the treatment of rare genetic disorders of obesity. Setmelanotide development efforts are initially focused on six genetic disorders of obesity—Pro-opiomelanocortin (POMC) deficiency obesity, leptin receptor (LepR) deficiency obesity, Bardet-Biedl syndrome, Alström syndrome, POMC heterozygous deficiency obesity, and POMC epigenetic disorders—for which there are currently no effective or approved treatments.
Proof of concept has been demonstrated in Phase 2 clinical trials in POMC deficiency obesity, LepR deficiency obesity, and Bardet-Biedl syndrome—three genetic disorders of extreme and unrelenting appetite and obesity—in which setmelanotide dramatically reduced both weight and hunger. The U.S. Food and Drug Administration (FDA), has acknowledged the importance of this preliminary clinical evidence by granting setmelanotide breakthrough therapy designation for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway, which includes both POMC deficiency obesity and LepR deficiency obesity, enabling an expedited path to approval of setmelanotide for these two indications. In addition, the FDA has granted orphan drug designation for setmelanotide for the treatment of POMC deficiency obesity.
The phase 2 findings were published on July 21, 2016 in The New England Journal of Medicine, and the accompanying editorial described the trial as demonstrating impressive hunger reduction and weight loss as well as improved insulin sensitivity. Afamelanotide phase 3 trials were published in NEJM and long term observation in clinical use have also been published.
Rhythm claims that setmelanotide is a MC4R agonist but skin darkening due to MC1R activity is universally reported. There are also many animal studies which report MC4R activation by afamelanotide. Both drugs are non selective but how close they are in function is not able to be determined. Personal communication with Clinuvel trial participants confirms appetite suppression as a clinical effect but this does not seem to be well reported as a side effect.
Setmelanotide has been administered to only a handful of patients and therefore the safety data compared to afamelanotide is very significantly less. Afamelanotide being first in class and very similar in function has likely done a lot of the hard work for Rhythm.
Setmalanotide is currently administered as a daily injection. Clinuvel has a patent for a slow release implant, this may not be useful for hunger suppression anyway as there is not detectable drug in the plasma after 10 days. (Scenesse probably works for 50-60 days in EPP patients because of the antioxidant effect of melanin itself.) Rhythm is currently investigating a slow release depot to avoid the need for daily injections. This trial is being done on non genetic obese patients, if these results are successful an enormous off label indication is opened up (obesity epidemic). A fairly astute choice to trial the new delivery system on such a group!
So despite limited clinical data for safety or efficacy and no phase 3 trials and also requiring daily injections Rhythm has a market cap almost 3 times that of Clinuvel’s. 2 drugs that probably do much the same thing, one is a weight loss drug improving insulin sensitivity that gives you a tan as a side effect the other provides a “dermal umbrella” to prevent pain for a few patients that governments do not want to pay for.
This story hasn’t played out yet and setmelanotide may fall over for lots of reasons but given the excellent safety profile of afamelanotide and the very promising clinical data with setmelanotide, the obesity epidemic, a seemingly switched on management and a US listing I am backing this one. I think Clinuvel shareholders have paid a very high price for being first in class and also the mistakes of Clinuvel management.
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