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Energy expenditure

RM-493 peptide increases REE in obese patients

RM-493 increased resting energy expenditure vs. placebo by 6.85%, on average by 111 kcal/24h

RM-493, a small peptide melanocortin 4 receptor (MC4R) agonist, increases resting energy expenditure (REE) in obese patients, according to study presented at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.

“This is the first human study to test the hypothesis that an MC4R agonist increases energy expenditure,” said Dr Monica Skarulis, investigator at the National Institutes of Health (NIH). “The drug’s effect was significant with short-term treatment and has the potential to be clinically meaningful for treating obesity.”

There is compelling scientific evidence that when dieting causes weight loss, the body tries to regain the weight by decreasing energy expenditure. In effect, changes in metabolic rate can make it difficult to maintain the weight loss. Accordingly, approaches to the management of obesity that target decreasing food intake along with increasing the metabolic rate have the potential to improve treatment.

RM-493 is in Phase 2 clinical development for the treatment of obesity, including for obesity caused by genetic deficiencies in the MC4 pathway. The MC4 receptor mediates a key pathway in humans that regulates energy homeostasis and food intake. The MC4 pathway is well validated in humans; loss-of-function mutations of MC4R are associated with obesity and have a reported prevalence of 4%-6% in severe obesity. In the population with a genetic deficiency in the MC4 pathway, RM-493 may restore MC4 function by increasing activity in the one healthy copy of MC4R.

A total of 12 obese, but otherwise healthy individuals, were randomised and completed both RM-493 and placebo periods in this double-blind, placebo-controlled, two-period crossover study to evaluate the effects of RM-493 on resting energy expenditure. The primary outcome measure was resting energy expenditure measured in a room calorimeter on the third day of treatment with either RM-493 or placebo.

RM-493 increased resting energy expenditure vs. placebo by 6.85% (95% CI: 0.68, 13.02%), on average by 111 kcal/24h (95% CI: 15, 207 kcal, p=0.03).  Resting energy expenditure measured by hood method also tended to increase with RM-493 treatment (4.72 ± 8.14%, p=0.06). Twenty-four hour energy expenditure tended to be higher while the thermic effect of a test meal and exercise energy expenditure did not differ significantly. 

The Twenty-four hour respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs. 0.848 ± 0.022, p=0.02) and RM-493 treatment was also associated with slightly higher fasting plasma free fatty acid (0.445 ± 0.089 vs. 0.327 ± 0.071mEq/L, p=0.01),  glucose (94.9 ± 5.8 vs. 91.1 ± 3.6mg/dl, p=0.002), and insulin (26 ± 16 vs. 19 ± 12mcU/mL, p=0.007). 

“These changes were small, and their clinical relevance needs to be established in larger trials,” said the researchers. “No adverse effects on heart rate or blood pressure were observed and few side effects occurred; all were mild and resolved completely.”

“These study results are exciting clinical support for the mechanisms underlying RM-493’s efficacy for weight loss that we have seen in preclinical studies,” said Dr Keith Gottesdiener, CEO of Rhythm, the developer of RM-493. “It is well known that the MC4 receptor modulates weight through a combination of effects on food intake and energy homeostasis. But this is the first time that administration of an MC4 product candidate has demonstrated a substantive effect on energy expenditure in obese patients.”

The company is developing peptide therapeutics that address unmet needs in metabolic diseases and is developing the ghrelin peptide agonist, relamorelin (RM-131), for the treatment of diabetic gastroparesis and other gastrointestinal functional disorders; and the MC4R peptide agonist, RM-493, for obesity and diabetes.

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