Some of our readers may have read a post on social media about RM-493 (setmelanotide) as an injectable medication to control appetite.  Rhythm Pharmaceuticals relayed results from a recent research report in the July 21, 2016 issue of the New England Journal of Medicine about setmelanotide’s impressive effects in an ultra-rare genetic appetite disorder called POMC deficiency.  POMC (pro opiomelanocortin) is one of  the anorexigenic hormone pathways that make you feel full – other hormones in this pathway include melanocortin 4 (MC4), melanocyte stimulating hormone (MSH), insulin, glucagon and leptin.   By contrast, orexigenic hormones make you feel hungry and include  ghrelin, agouti-related peptide (AGRP), and neuropeptide Y (NPY).  POMC deficiency is an exceptionally rare cause of obesity occurring in less than 1 in 1 million due to a defect in chromosome 2p23.3 – there are 10 known cases worldwide.  POMC deficiency is characterised by infants with red hair, adrenal gland crisis, and obesity.   Peter Kuhnen and colleagues studied the effects on weight control of setmelanotide in two individuals with POMC deficiency.   Over a 42 week period, the first patient lost 51 kg; the second patient lost 20.5 kg over three months (see Figure 1)!  Both patients also reported decreased hunger scores.  Side effects included dry mouth, injection site pain, skin colour change from red to brown, sadness, fatigue and “emptiness”. These results in a small study showed dramatic weight loss (with few adverse side effects) by restoring function of the MC4 receptor in the POMC-MC4-MSH pathway. This pathway is involved in other obesity syndromes such as leptin deficiency and prohormone convertase deficiency, and by implication, PWS.   

As you might imagine, the potential benefits in PWS are tantalising.  And to this effect, we are pleased to read from the clinicaltrials.gov website that Rhythm Pharmaceuticals have just completed a phase 2 study of setmelanotide in PWS people aged 16-65 years.  The results have not yet been reported, but the team of unnamed researchers from the University of California Irvine and University of Florida suggests strongly that Virginia Kimonis and Jennifer Miller may be involved – both of whom are well known PWS researchers!  Indeed, the results of setmelanotide in the PWS phase 2 trial are eagerly anticipated!

Search “POMC deficiency setmelanotide NEJM” on google for more details!  

Figure 1: weight loss and hunger scores in two POMC deficient patients (from Kuhnen et al, NEJM 2016; 375: 240-6.

Robin Chung