United States

ENDO 2021

Persistent and stable growth promoting effects of vosoritide in children with achondorplasia for up to 2 years: Results from the ongoing Phase 3 extension study

technical paper

Introduction: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist being investigated for chronic weight management in patients with rare genetic diseases of obesity caused by impairment of the MC4R pathway. The objective of this analysis was to assess the efficacy and safety of setmelanotide in patients with partial insufficiency in the MC4R pathway due to heterozygous mutations in the POMC, PCSK1, or LEPR genes. Methods: This was an open-label, single-arm, Phase 2 study of setmelanotide in rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) heterozygous deficiency obesity (NCT03013543). Patients aged ≥6 years with POMC, PCSK1, or LEPR heterozygous deficiency obesity received once-daily setmelanotide, which was titrated for 4 weeks to establish the therapeutic dose of 3 mg daily. Treatment at the therapeutic dose continued for an additional 12 weeks. The primary endpoint was mean percent change from baseline in body weight at Month 3. Hunger scores and adverse events (AEs) were secondary endpoints. A responder was defined as having ≥5% weight loss from baseline at Month 3. Results: A total of 35 patients were included in this analysis, with mean (standard deviation) age of 39.5 (17.6) years and body mass index of 50.3 (9.4) kg/m2. Across all patients, the mean percent change in body weight from baseline to Month 3 was −3.7% (90% confidence interval [CI], −5.3% to −2.1%; n=35). A total of 34.3% of patients (12/35) achieved the responder threshold of ≥5% weight loss from baseline at Month 3. The mean percent change in body weight from baseline to Month 3 was −10.1% (90% CI, −12.4% to −7.9%; n=12) and −0.4% (90% CI, −1.2% to −0.5%; n=23) for responders and nonresponders, respectively. The mean percent change in most hunger score from baseline to Month 3 was −4.4% (90% CI, −5.7% to −3.2%; n=10) and −2.3% (90% CI, −3.2% to −1.5%; n=23) for responders and nonresponders, respectively. Among responders, 4 (33%) had variants that were considered pathogenic/likely pathogenic per American College of Medical Genetics criteria. All patients experienced at least?1 AE. Overall, the most common treatment-emergent AEs were skin hyperpigmentation (51.4%), nausea (48.6%), and injection site pruritis (37.8%). One patient had serious AEs of acute myocardial infarction and gastrointestinal hemorrhage that were considered unrelated to setmelanotide. No AEs led to death.Conclusions: Setmelanotide was associated with reduced body weight and hunger scores in patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity. While the overall mean percent decrease in body weight may have been less than that previously reported in patients with homozygous or compound heterozygous variants, setmelanotide may be a viable treatment option for some patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity.?? 

Effects of Setmelanotide in Patients with POMC, PCSK1, or LEPR Heterozygous Deficiency Obesity in a Phase 2 Study

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We found 17 rare PCOS-specific functional protein-altering variants (PAVs) or mutations in the gene, AMH, that decrease the biologic activity of the encoded protein, anti-Müllerian hormone (AMH), in the heterozygous state. Approximately 3% of European ancestry PCOS cases in our cohort of ~700 were affected. Our preliminary studies found evidence for a metabolic phenotype in both PCOS as well as their male first-degree relatives who were heterozygous carriers of these AMH PAVs. We performed this study to test the hypothesis that AMH mutations are associated with metabolic abnormalities in the general population. The Mount Sinai BioMe Biobank is an electronic health record (EHR)-linked biobank, containing anonymized whole exome sequences from 30,813 participants of diverse ancestries. We interrogated the sequence data to identify individuals with PCOS-related AMH PAVs. IRB-approval was obtained to review the linked EHR. Outcomes were the presence of obesity (BMI ≥ 30 kg/m2), type 2 diabetes (hemoglobin A1C ≥ 6.5%), prediabetes (hemoglobin A1C 5.7% - 6.4%), elevated cholesterol (total cholesterol ≥ 200 mg/dL), hypertriglyceridemia (TG ≥ 150 mg/dL), and hypertension (≥2 blood pressure values ≥140/90, or administration of antihypertensive medications). Control subjects were obtained from the National Health and Nutrition Examination Survey using propensity score matching (for sex, age, and BMI) with a 1:4 case:control ratio. A total of 292 individuals with AMH PAVs were identified, resulting in a combined 0.95% prevalence of AMH PAVs in an unselected population (1.07% in Europeans, 0.28% in African Americans, 0.54% in Hispanics, and 0.07% in Asians). After adjusting for age, BMI, and race/ethnicity, there was a statistically significant increased prevalence of hypertriglyceridemia in both women (OR 7.29, 95% CI 3.77-14.00) and men (OR 10.15, 95% CI 4.68-22.00) with AMH ?PAVs compared to sex-, age- and BMI-matched controls. There was also a statistically significant increased prevalence of elevated cholesterol in men with AMH PAVs compared to controls (OR 2.48, 95% CI 1.15-5.34). There were no significant differences between individuals with AMH PAVs and matched controls with respect to the other outcomes. These findings suggest that decreased bioactivity of AMH is causally related to dyslipidemia in the general population. TG levels are elevated in both sexes, whereas increases in cholesterol are only seen in men. The mechanisms by which decreases in AMH bioactivity alter circulating lipid levels are of considerable interest since AMH has no known metabolic actions. It is possible that the putative metabolic effects of AMH are mediated by increases in circulating testosterone (T) levels that in turn alter lipid metabolism. Since T levels are not commonly available in EHR, future studies will be needed to investigate this hypothesis as well as to explore metabolic actions of AMH.?? 

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Persistent and stable growth promoting effects of vosoritide in children with achondorplasia for up to 2 years: Results from the ongoing Phase 3 extension study

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