Setmelanotide Normalizes Satiety in Obese With Rare Gene Defect

Becky McCall

July 20, 2016

Hunger disappears completely and satiety is normalized in patients with obesity because of an extremely rare genetic mutation for melanocyte-stimulating hormone (MSH) deficiency treated with the investigational drug setmelanotide (RM-493, Rhythm Pharmaceuticals), a melanocortin-4 receptor agonist.

Speaking to Medscape Medical News, first author Peter Kühnen, MD, from the Charité–Universitätsmedizin, Berlin, Germany, said that setmelanotide represents "a new treatment paradigm for obesity that restores lost biological function due to the genetic defect," adding that "supplementation of the MSH signal in this pathway led to the transformational changes in body weight."

Published in the July 21 issue of the New England Journal of Medicine, the open-label study of the two patients (who are two of three adults known to have the disease worldwide) showed a "dramatic alteration in their sensation of hunger, and their hyperphagia disappeared for the first time in their lives, leading to a normalization of their satiety," said Dr Kühnen. He added that these patients had no treatment alternative.

Results showed severe weight loss of 51.0 kg after 42 weeks in the first patient and 20.5 kg after 12 weeks in the second patient.

Proopiomelanocortin Deficiency

More specifically, the patients have defects in the gene encoding proopiomelanocortin (POMC), responsible for POMC-derived peptides, MSH and corticotropin.

The defect causes extreme early onset obesity, hyperphagia, and hypopigmentation. Patients also experience adrenal insufficiency, which if unrecognized and untreated can be fatal.

Obesity in patients with POMC deficiency is attributed to lack of activation of melanocortin-4 receptor (MC4R). Acting as a substitute for the absent MSH, setmelanotide binds to the melanocortin-4 receptor, activating it. Effectively, this results in reduced food intake and increased resting energy expenditure.

Dr Kühnen explained that setmelanotide represents a targeted approach aimed at a specific genetic defect in a crucial biological pathway known to regulate weight. "By restoring the lost function in the pathway, hyperphagia can be reduced, enabling weight loss, which is of tremendous importance for the patient."

In January 2016, the US Food and Drug Administration granted breakthrough-therapy designation to setmelanotide for the treatment of POMC-deficiency obesity, which has been designated an ultra-orphan disease. Setmelanotide has previously been given to around 200 obese patients not known to have any genetic defects, Dr Kühnen and colleagues note, and Rhythm Pharmaceuticals is also conducting phase 2 trials with the agent in the treatment of Prader-Willi syndrome, another rare genetic disorder that causes life-threatening obesity.

In an accompanying editorial, Marc L Reitman, MD, from the National Institutes of Health, Bethesda, MD, said that the results reported by Dr Kühnen and colleagues were "exciting for these rare patients, their families, and treating clinicians," but that "interpretation requires caution, because the study includes only two patients."

He continued by discussing other potential applications of setmelanotide, citing the case of another rare disease involving patients with leptin-receptor mutations, for whom there is currently no satisfactory treatment.

Hunger Disappears, Weight Is Lost, and Side Effects Minimized

Patients in the investigator-initiated, phase 2 pilot study self-administered a subcutaneous injection of setmelanotide once daily at a starting dose of 0.25 mg in the first patient and 0.5 mg in the second patient. Dosing was increased incrementally until a dose of 1.5 mg was reached. Weight loss was minimal below 1.0 mg, the researchers note.

The patients visited their clinician every 2 to 4 weeks for the first 3 months, and then every 3 months thereafter. If, after 3 months, the patient was found to be losing weight and showed a drop in hyperphagia, the patients entered an extension phase.

Hunger was measured using a Likert hunger scale ranging from 0 (no hunger) to 10 (extreme hunger). "After dose escalation, patients noticed a distinctive lowering in their hunger levels to normalization. This effect was seen at 1.5 mg/day in both patients," reported Dr Kühnen.

Regarding metabolic markers of disease, prior to treatment insulin levels were markedly elevated during the oral glucose tolerance test, reflecting severe insulin resistance, and these levels normalized completely during treatment, he added.

The loss of body weight, which was the primary end point, was mainly because of loss of body fat, which was accompanied by a substantial decrease in serum leptin levels, write the authors.

Because setmelanotide activates the melanocortin-4 receptor pathway, the researchers expected to see side effects related to this, and they did. The findings included intermittent nausea for a few days, increased tanning of the skin, as well as a darkening of hair from red to brown. However, patients experienced no serious adverse events and did not discontinue treatment because of adverse events.

Blood pressure was carefully monitored because an increase in blood pressure has been observed with other melanocortin-4 receptor agonists, but no signs of increase were observed in these patients.

The researchers write that in the first patient, systolic and diastolic blood pressure as well as heart rate were reduced during the extension phase after weight loss, a finding of clinical significance. Pubertal development did not change.

A dose–response relationship was observed. "In the first patient we noticed a correlation between dose and hunger score, and a mild reduction in dose led to a slight increase in hunger," Dr Kühnen pointed out, adding that this patient also experienced an off-drug period, "and within only a few days we saw an increase in hunger and weight gain."

Other Obesity-Related Rare Diseases And More . . .

Regarding the wider relevance of the findings from this limited study to a broader population of obese patients, Dr Reitman noted in his editorial that leptin-replacement therapy was informative.

"Leptin replacement in patients with a deficiency due to leptin mutations or lipodystrophy produces dramatic clinical benefits. However, leptin treatment of patients with common obesity, who have high leptin levels, was unsuccessful," he explained. The heterozygous loss of function with MC4R causes an unusual phenotype, and this might make "MC4R agonism a 'sweet spot' for drug therapy, if a modest increase in signaling provides more clinical benefit than risk."

Asked a similar question, Dr Kühnen emphasized that their study provides insight into how the genetics of obesity work.

"We are focused on upstream defects in the POMC signaling pathway, where the treatment led to this transformational change in hyperphagia in the POMC-deficient patient, and we are now focusing on other patients who have genetic defects within the hypothalamic leptin–melanocortin pathway."

Rhythm Pharmaceuticals says it expects to soon expand setmelanotide development to include two other MC4 pathway disorders, LepR deficiency obesity, where patients have two defective leptin-receptor genes, and POMC heterozygous deficiency obesity, where patients have only one normal copy of the POMC or proprotein convertase subtilisin/kexin type 1 (PCSK-1) gene. Both disorders represent areas of high unmet need with no approved or effective therapies available to patients.

Dr Kühnen added that it was too early to say whether there is a much wider application of this finding. "Right now we are focusing on the rare diseases."

Dr Kühnen has no relevant financial relationships. Disclosures for the coauthors are listed on the journal website.

N Engl J Med. 2016;375:240-246, 275-278. Abstract, Editorial

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