Slide 1: Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: A Phase 3 Trial
Efficacy and Safety of the MC4R Agonist Setmelanotide in POMC Deficiency Obesity: A Phase 3 Trial Karine Clément,1,2 Jesús Argente,3 Allison Bahm,4 Hillori Connors,5 Kathleen De Waele,6 Sadaf Farooqi,7 Greg Gordon,5 James Swain,8 Guojun Yuan,5 Peter Kühnen9 1 Sorbonne Université, INSERM, Nutrition a
Slide 2: Melanocortin Signaling Is Crucial for Regulation of Body Weight
Melanocortin Signaling Is Crucial for Regulation of Body Weight1,2 • Body weight is regulated by the hypothalamic central melanocortin pathway • In response to leptin signaling, POMC is produced in POMC neurons and is cleaved by protein convertase subtilisin/kexin type 1 into α-MSH and β-MSH • α-MSH
Slide 3: Rare Genetic Variants in POMC and PCSK1 Are Associated With Early-Onset Severe Obesity and Hyperphagia
Rare Genetic Variants in POMC and PCSK1 Are Associated With Early-Onset Severe Obesity and Hyperphagia • Obesity is a disease caused by environmental and genetic factors, including common or rare genetic variants that can impair gene expression or function1,2 • Rare genetic variants in the central m
Slide 4: Setmelanotide Is an MC4R Agonist That Targets the Impaired Central Melanocortin Pathway
Setmelanotide Is an MC4R Agonist That Targets the Impaired Central Melanocortin Pathway Results from a phase 2 study showed that setmelanotide, an MC4R agonist, reduced weight in 2 patients with POMC deficiency obesity1 This multicenter, placebo-controlled, phase 3 trial investigated the efficacy an
Slide 5: Phase 3 Study Design
Phase 3 Study Design Dose Titration Open-Label Treatment and Withdrawal Establish therapeutic Early Screening dose of daily self- Open-label Open-label termination Withdrawal administered treatment at treatment at or Days sequencea subcutaneous therapeutic dose therapeutic dose follow-up -28 to -1 s
Slide 6: Endpoints and Inclusion Criteria
Endpoints and Inclusion Criteria Primary endpoint: • Proportion of participants who achieved ≥10% weight loss Key secondary endpoints: • Mean percent change in body weight • Mean percent change in “most hunger” scorea • Proportion of participants who achieved ≥25% reduction in “most hunger” score Po
Slide 7: Ten Participants With POMC or PCSK1 Deficiency Obesity Were Enrolled
Ten Participants With POMC or PCSK1 Deficiency Obesity Were Enrolled Baseline Characteristics Genotype, n (%) POMC 9 (90) PCSK1 1 (10) Age, mean (range), years 18.4 (11-30) Male, n (%) 5 (50) Ethnicity, n (%) Hispanic and Latino 1 (10) Not Hispanic and Latino 8 (80) Unknown 1 (10) Weight, mean (rang
Slide 8: Body Weight and Hunger Reduction in Patients With POMC Deficiency Obesity Treated for ~1 Year
Body Weight and Hunger Reduction in Patients With POMC Deficiency Obesity Treated With Setmelanotide for ~1 Year Setmelanotide 0 dose, mg 1.0 1.5 (placebo) 1.5 0 10 -4.6 9 Weight change from baseline (kg) -8.6 Weekly average of daily “most -10 -11.5 8 -11.6 -15.1 -15.3 -17.6 7 -14.7 -19.2 hunger” sc
Slide 9: Setmelanotide Was Associated With Significant Weight Reductions Over ~1 Year at Therapeutic Dose
Setmelanotide Was Associated With Significant Weight Reductions Over ~1 Year at Therapeutic Dose 40 30 Percent change in body weight at ~1 year 20 8 of 10 participants (80% [90% CI, 49.31%– at therapeutic dose 10 96.32%]; P<0.0001) achieved the primary 0 endpoint threshold of ≥10% Mean percent chang
Slide 10: Setmelanotide Was Associated With Significant Reductions in Most Hunger Score Over ~1 Year
Setmelanotide Was Associated With Significant Reductions in “Most Hunger” Score Over ~1 Year at Therapeutic Dose “Most Hunger” score parameter (n=7)a Mean (SD) Range Baseline 8.1 (0.78) 7.0 to 9.0 ~1 year at therapeutic dose 5.8 (2.02) 3.0 to 8.0 Percent change at ~1 year at therapeutic dose, % -27.
Slide 11: Withdrawal Was Associated With Increases in Weight and Hunger Score During Placebo Withdrawal
Setmelanotide Withdrawal Was Associated With Increases in Weight and Hunger Score During the 4-Week Placebo Withdrawal Period +5.5 kg +2.2 n=8 n=6 Range, 1.53–10.5 kg Range, 2.0–9.86 Mean weight change Change in mean “most hunger” 11
Slide 12: Setmelanotide Was Associated With Reductions in BMI and BMI Z-Score Over ~1 Year
Setmelanotide Was Associated With Reductions in BMI and BMI Z-Score Over ~1 Year at Therapeutic Dose Participants aged ≥19 years (n=4) Participants aged <19 years (n=6) Mean change from baseline: -9.3 kg/m2 Mean change from baseline: -1.6 Mean % change from baseline: -22.3% (P=0.056) Mean % change f
Slide 13: Effect of Setmelanotide on BMI and BMI Z-Score
Effect of Setmelanotide on BMI and BMI Z-Score Baseline ~1 year at therapeutic dose Percent change from baseline Participants aged ≥19 years, 43.90 (8.91) 34.58 (12.42) -22.33 (14.75) mean (SD) BMI, kg/m2 (n=4) P=0.056 Participants aged <19 years, 3.35 (0.61) 1.73 (1.04) -49.18 (27.20) mean (SD) BMI
Slide 14: Effect of Setmelanotide on Vital Signs
Effect of Setmelanotide on Vital Signs Percent change from Parameter (N=10) Baseline ~1 year at therapeutic dose baseline Mean (SD) diastolic blood 73.13 (10.75) 71.50 (9.17) -1.81 (6.27) pressure, mm Hg P=0.384 Mean (SD) systolic blood 111.57 (7.78) 109.83 (6.12) -1.355 (5.11) pressure, mm Hg P=0.4
Slide 15: Setmelanotide Was Well Tolerated in Individuals With POMC or PCSK1 Deficiency Obesity
Setmelanotide Was Well Tolerated in Individuals With POMC or PCSK1 Deficiency Obesity Parameter n (%) • There were no reported cardiovascular AEs Treatment-related AEs 10 (100) related to setmelanotide Injection-site reaction 10 (100) Diffuse hyperpigmentation of the skin 10 (100) • There were no AE
Slide 16: Conclusion
• In this phase 3 study, 80% of participants achieved the primary endpoint of ≥10% weight loss from baseline at ~1 Conclusion year from therapeutic dose Setmelanotide reduced • Setmelanotide was associated with clinically meaningful hunger and body weight weight loss and reduction in “most hunger” s
Slide 17: Future Directions
Future Directions • This study is one of two phase 3 trials supporting the potential use of setmelanotide for the treatment of early-onset severe obesity and hyperphagia • The second phase 3 trial supports the potential use of setmelanotide in individuals with LEPR deficiency obesity • The results f