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POMC and LEPR deficiency

Positive outcomes for patients with POMC and LEPR deficiency

Data show treatment effect of setmelanotide on additional secondary endpoints, including BMI

Rhythm Pharmaceuticals, a biopharmaceutical company aimed at developing and commercialising therapies for the treatment of rare genetic disorders of obesity, has announced additional data from its two pivotal Phase 3 clinical trials evaluating setmelanotide for the treatment of pro-opiomelanocortin (POMC) deficiency obesity and leptin receptor (LEPR) deficiency obesity showing the effect of setmelanotide on BMI scores and certain cardiovascular parameters. These data are being presented by study investigators at the 37th Annual Meeting of The Obesity Society at ObesityWeek 2019, Las Vegas.

Rhythm previously announced that both Phase 3 clinical trials of setmelanotide met their primary endpoints and all key secondary endpoints, demonstrating a statistically significant and clinically meaningful effect on weight loss and reductions in insatiable hunger (or hyperphagia), in patients with POMC deficiency obesity and LEPR deficiency obesity over the course of one year on setmelanotide treatment.

Setmelanotide is a potent MC4R agonist in development for the treatment of rare genetic disorders of obesity. Setmelanotide activates MC4R, part of the key biological pathway that independently regulates energy expenditure and appetite. Variants in genes within the MC4R pathway are associated with unrelenting hunger and severe, early-onset obesity. Rhythm is currently developing setmelanotide as a replacement therapy for patients with monogenic defects upstream of MC4R, for whom there are no effective or approved therapies.

The FDA has granted Breakthrough Therapy designation to setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway, which includes POMC deficiency obesity, LEPR deficiency obesity, Bardet-Biedl syndrome and Alström syndrome. The European Medicines Agency has also granted PRIority MEdicines (PRIME) designation for setmelanotide for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4R pathway.

Data from both trials also show that when patients withdrew from setmelanotide during a four-week placebo withdrawal period, they experienced rapid increases in weight and hunger. Setmelanotide is a melanocortin-4 receptor (MC4R) agonist designed to target impairments in the central melanocortin pathway, which is known to regulate weight and hunger.

“Setmelanotide has demonstrated a statistically significant and clinically meaningful impact on the severe obesity and unrelenting hunger in patients living with POMC deficiency obesity or LEPR deficiency obesity,” said Dr Murray Stewart, Chief Medical Officer of Rhythm Pharmaceuticals. “With these supporting data, we are also demonstrating that setmelanotide may have additional therapeutic benefits, driving improvements in BMI and other parameters that are critical to overall health.”

The presentations at ObesityWeek include new data showing the effect of setmelanotide on BMI scores for patients older than 19 and BMI z-scores for patients younger than 19 and its effect on vital signs including diastolic blood pressure, systolic blood pressure and heart rate. Additional analyses of safety data from the Phase 3 trials in POMC deficiency obesity and and LEPR deficiency obesity continue to support that setmelanotide is generally well-tolerated.

In the paper, ‘Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: A Phase 3 Trial’, Dr Peter Kühnen, Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Germany, presented data from Rhythm’s Phase 3 POMC deficiency obesity trial.

“Like many people living with rare genetic disorders of obesity, people with POMC deficiency obesity experience early-onset, rapid weight gain and severe, insatiable hunger, which are the two hallmarks of these disorders,” said Kühnen, the lead investigator for this trial. “Despite significant effort to control their weight and appetite, such as supportive care or lifestyle interventions, patients often regain weight after any short-term period of weight loss. By reducing the weight gain and hunger endemic to POMC deficiency obesity, setmelanotide has the potential to shift the treatment paradigm for these patients.”

Setmelanotide was associated with reductions in BMI and BMI z-scores[1] for patients with POMC deficiency obesity who were treated with setmelanotide for over one year at therapeutic dose:

POMC deficiency obesity

 

Baseline

~1 year at therapeutic dose

Percent change from baseline 

Participants aged ≥19 years, mean (SD) BMI, kg/m(n=4)

43.90 (8.91)

34.58 (12.42)

-22.33 (14.75)

P=0.056

Participants aged <19 years, mean (SD) BMI z-score (n=6)

3.35 (0.61)

1.73 (1.04)

-49.18 (27.20)

P=0.007

Consistent with prior clinical experience, setmelanotide was well tolerated in patients with POMC deficiency obesity. There were no reported cardiovascular adverse events (AEs) related to setmelanotide, and no AEs or serious AEs that led to treatment discontinuation or death. Setmelanotide was not associated with significant changes to blood pressure or heart rate:

Mean parameter (SD)[2]

Diastolic blood pressure (mmHg)[3]

Systolic blood pressure (mmHg)

Heart rate (beats/min)

Baseline

73.13 (10.75)

111.57 (7.78)

81.03 (12.08)

~1 year at therapeutic dose

71.50 (9.17)

109.83 (6.12)

75.37 (7.25)

Percent change from baseline, %

P value

-1.81 (6.27)

P=0.38

-1.36 (5.10)

P=0.42

-5.85 (11.44)

P=0.14

In the paper, ‘Efficacy and Safety of the MC4R Agonist Setmelanotide in LEPR Deficiency Obesity: A Phase 3 Trial’, Dr Erica Van Den Akker, Erasmus MC-Sophia Children’s Hospital University in Rotterdam, Netherlands, presented data from Rhythm’s Phase 3 LEPR deficiency obesity trial.

“Broadly, we saw clinically meaningful, significant weight loss in patients with LEPR deficiency obesity in the Phase 3 trial. Notably, after over a year on therapeutic dose of setmelanotide, two patients experienced roughly fifteen percent weight loss, while two other patients showed greater than twenty percent weight loss,” said Van Den Akker, lead investigator in the LEPR deficiency obesity trial. “Weight loss of this magnitude is unprecedented in the natural history of this patient population, and strongly suggests that setmelanotide has the potential to restore MC4R pathway function and serve as a safe, effective therapy for patients with rare genetic disorders of obesity.”

Setmelanotide was associated with reductions in BMI and BMI z-scores[4] for patients with LEPR deficiency obesity who were treated with setmelanotide for over one year at therapeutic dose:

LEPR deficiency obesity

 

Baseline

~1 year at therapeutic dose

Percent change from baseline 

Participants aged ≥19 years, mean (SD) BMI, kg/m2 (n=8)

51.18 (10.67)

45.82 (11.48)[5]

-10.59 (8.11)

P=0.01

Participants aged <19 years, mean (SD) BMI z-score (n=3)

3.52 (0.36)

3.03 (0.08)

-13.35 (8.87)

P=0.12

Consistent with prior clinical experience, setmelanotide was well tolerated in patients with LEPR deficiency obesity. One participant discontinued therapy due to mild, treatment-related hypereosinophilia and one participant died from injuries as a passenger in a car accident, which was unrelated to the study drug. There were no reported cardiovascular AEs related to setmelanotide, and setmelanotide was not associated with significant changes in blood pressure or heart rate:

Mean parameter (SD)[6]

Diastolic blood pressure (mmHg)

Systolic blood pressure (mmHg)

Heart rate (beats/min)

Baseline

67.67 (5.83)

121.697 (8.84)

79.46 (12.60)

~1 year at therapeutic dose

66.48 (8.59)

115.111 (14.57)

77.89 (16.46)

Percent change from baseline, %

P value

-1.58 (13.038)

P=0.73

-3.78 (9.94)

P=0.29

-1.32 (15.46)

P=0. 80

Rhythm is on track to complete submission of a rolling New Drug Application to the FDA for POMC deficiency obesity and LEPR deficiency obesity in the fourth quarter of 2019 or the first quarter of 2020, and the expects to share additional data in forthcoming publications and medical meeting presentations.

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