Slide 1: Efficacy and Safety of the MC4R Agonist Setmelanotide in LEPR Deficiency Obesity: A Phase 3 Trial
Efficacy and Safety of the MC4R Agonist Setmelanotide in LEPR Deficiency Obesity: A Phase 3 Trial Erica van den Akker, 1 Karine Clément,2,3 Wendy K. Chung, 4,5 Sadaf Farooqi, 6 Julie Gonneau-Lejeune,7 Greg Gordon, 8 Jim Murray,8 Guojun Yuan,8 Martin Wabitsch 9 1 Division of Pediatric Endocrinology,
Slide 2: The Regulation of Body Weight Is Complex
The Regulation of Body Weight Is Complex Body weight is determined by the balance between food intake and energy Satiety expenditure1 Feeding The hypothalamus regulates both aspects in response to cues from peripheral hormones that reflect nutritional state1,2 Energy output Circulating hormones BMI,
Slide 3: Leptin-Melanocortin Signaling Is Crucial for Regulation of Body Weight
Leptin-Melanocortin Signaling Is Crucial for Regulation of Body Weight • The melanocortin 4 receptor (MC4R) is a component of the central melanocortin pathway in the hypothalamus and is a key regulator of energy intake, expenditure, and body weight1,2 • Leptin is a satiety hormone that binds to lept
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 trial showed that setmelanotide, an MC4R peptide agonist, reduced weight in 3 patients with LEPR deficiency obesity1 This multicenter, placebo-controlled, phase 3 trial investigated the eff
Slide 5: Phase 3 Study Design
Phase 3 Study Design Primary endpoint: Dose Titration Open-label Treatment and Withdrawal • Proportion of participants who achieved ≥10% weight loss Screening Establish therapeutic Early Key secondary endpoints: Open-label Open-label termination dose of daily self- Withdrawal • Mean percent change i
Slide 6: Enrollment Criteria
Enrollment Criteria Key Inclusion Criteria Key Exclusion Criteria • Biallelic for loss-of-function LEPR variants • Recent diet and/or exercise regimen (homozygote or compound heterozygote) resulting in weight loss or stabilization • Adults (aged ≥18 years) with BMI of • Prior gastric bypass surgery
Slide 7: Eleven Participants With LEPR Deficiency Obesity Were Enrolled
Eleven Participants With LEPR Deficiency Obesity Were Enrolled Baseline characteristics (n=11) Age, mean (range), years 23.4 (12-37) Male, n (%) 3 (27) Genotype, n (%) 6 (55) Compound heterozygous 5 (45) Homozygous Ethnicity, n (%) White 10 (91) South Asian 1 (9) Weight, mean (range), kg 133.3 (89.4
Slide 8: 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 25% % Change in body weight at ~1 year from therapeutic dose 20% 15% 5 of 11 participants (45%; 90% CI: 19.96% to 10% 72.88%); P=0.0001) 5% achieved the primary endpoint threshold of 0% ≥10% weight loss
Slide 9: 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 7.0 (0.77) 6.0 to 8.0 ~1 year at therapeutic dose 4.1 (2.09) 2.0 to 8.0 Percent change from baseline, % -43.7 (23.7) -67.0 to
Slide 10: Example of Single Patient Body Weight and Hunger Curve Over 1 Year
Example 1 of 2 of Single Patient Body Weight and Hunger Curve Over 1 Year Setmelanotide 0 dose, mg 0.5 1.0 1.5 2.0 (placebo) 2.0 2.5 0 -1.6 10 -1.3 -4.4 9 -5.9 -7.9 Weekly average of daily hunger score Weight change from baseline (kg) 8 -10 -13.6 7 when most hungry -12.3 6 -16.5 -20 5 -18.1 -21.9 -2
Slide 11: Example of Single Patient Body Weight and Hunger Curve Over 1 Year
Example 2 of 2 of Single Patient Body Weight and Hunger Curve Over 1 Year Setmelanotide 0 Dose, mg 1.0 1.5 2.0 2.5 3.0 (placebo) 3.0 0 -2.4 10 -0.2 -3.9 -4.4 -3.7 -4.3 -3.6 -3.5 9 -5.8 Weekly average of daily hunger score -6.5 -6.6 -7.1 -6.7 Weight change from baseline (kg) -10 -7.5 8 -8.7 7 when mo
Slide 12: Withdrawal During the Placebo Sequence Was Associated With Increases in Weight and Hunger Score
Setmelanotide Withdrawal During the Placebo Sequence Was Associated With Increases in Weight and Hunger Score +4.97 kg +3.1 n=7 n=6 Range: +2.85 kg Range: 4.0 to 10.0 to +9.03 kg Absolute Absolute mean mean weight “most hunger” score increase 12
Slide 13: 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=8)* Participants aged <19 years (n=3) Mean change from baseline: -5.2 kg/m2 Mean change from baseline: -0.49 Mean % change from baseline: -10.6% (P=0.01) Mean % change
Slide 14: Effect of Setmelanotide on BMI and BMI Z-score
Effect of Setmelanotide on BMI and BMI Z-score Percent change from ~1 year at therapeutic dose baseline, % (SD); Baseline (SD) (SD) P value BMI (kg/m2) of participants aged 51.18 (10.67) 45.82 (11.48)a -10.59 (8.11) ≥19 years (n=8) P=0.01 BMI Z-score of participants aged 3.52 (0.36) 3.03 (0.08) -13.
Slide 15: Setmelanotide Was Well Tolerated in Individuals With LEPR Deficiency Obesity
Setmelanotide Was Well Tolerated in Individuals With LEPR Deficiency Obesity Parameter n (%) • One participant discontinued due to Treatment-related AEs 11 (100) mild hypereosinophilia related to Injection-site reaction 11 (100) setmelanotide treatment Hyperpigmentation 8 (73) Nausea 5 (45) • One pa
Slide 16: Effect of Setmelanotide on Vital Signs
Effect of Setmelanotide on Vital Signs Percent change from baseline, %; Baseline ~1 year at therapeutic dose P value Diastolic blood pressure (mmHg) 67.67 (5.83) 66.48 (8.59) -1.58 (13.04) P=0.73 Systolic blood pressure (mmHg) 121.70 (8.84) 115.11 (14.57) -3.78 (9.94) P=0.29 Heart rate (beats/min) 7
Slide 17: Conclusions: Setmelanotide Reduced Hunger and Body Weight and Was Well Tolerated
• In this phase 3 study, 45% of participants achieved the primary endpoint of ≥10% weight loss from baseline at ~1 year from therapeutic dose Conclusions: • Setmelanotide was associated with clinically meaningful weight Setmelanotide Reduced loss and reduction in “most hunger” score Hunger and Body