Timing of Onset of Adverse Events With , an MC4R Agonist, in Patients With Severe Due to LEPR or POMC Deficiency ## Presenting Author: Karine Clément Karine Clément, MD1,2; Erica van den Akker, MD3; Gregory Gordon, MD4; Guojun Yuan, PhD4; Peter Kühnen, MD5 [email protected] 1Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France; 2Sorbonne Université, INSERM, NutriOmics Research Unit, Paris, France; 3Division of Pediatric Endocrinology, Department of Pediatrics, Sophia Children’s Hospital and Obesity Center CGG, Erasmus University Medical Center, Rotterdam, The Netherlands; 4Rhythm Pharmaceuticals, Inc., Boston, MA, USA; 5Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Summary ¡ The onset of adverse events (AEs) of special interest was generally highest during the first month of treatment ¡ Fewer AEs of special interest occurred during each month following Month 1 with setmelanotide in participants with obesity due to (POMC)/proprotein convertase ¡ Apart from hyperpigmentation disorders, all AEs of special interest resolved quickly after onset subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency receiving ≥1 year of treatment

Introduction Figure 1. Study design of the Phase 2 investigator-initiated trial (A) and Phase 3 trials (B) of setmelanotide in participants with POMC, PCSK1, or LEPR deficiency. Figure 2. Onset of the AEs of special interest hyperpigmentation disorders (A), disturbances in sexual arousal (B), nausea (C), vomiting (D), ¡ Rare genetic diseases of obesity are often driven by pathogenic gene A Phase 2 Study Design B Phase 3 Study Design and ISRs (E) by treatment month. 1 variants in the 4 receptor (MC4R) pathway Open-label treatment Long-term extension study Open-label dose titrationOpen-label treatment and withdrawal A Hyperpigmentation Disorders ¡ Treatment with the MC4R agonist setmelanotide demonstrated Adult Double-blind 35 34 Once-daily setmelanotide starting dose Therapeutic withdrawal Final visit or s clinically significant reductions in body weight and hunger after 1 year Dose titration from 0.25 mg Once-daily setmelanotide 1.0 mg dose 30 established Once-daily sequence Once-daily bridge to Screening in Phase 3 trials of participants with obesity due to POMC, PCSK1, or Screening to therapeutic dose Assessment every (maximum setmelanotide •4 weeks setmelanotide extension 25 Adolescent setmelanotide 2 (maximum dose of 3 months dose of study 20 LEPR deficiency 3.0 mg administered) starting dose 3.0 mg) •4 weeks 0.5 mg placebo 15 — The results of these pivotal trials led to the approval by the US Food and 12-13 weeks Variable duration: 2-12 weeks 10 weeks 8 weeks 32 weeks 10 6 Administration of setmelanotide for chronic weight management in individuals 33 3 Number of event 5 2 3 1 0 1 000 with POMC, PCSK1, or LEPR deficiency 0 123456789101112 ¡ AEs of special interest, defined as those related to treatment-emergent Week 0 Week 12 End of study Week 0 Week 2 Week 12 Week 20 Week 52 End of study (baseline) or extension (baseline) (primary or extension Month AEs (TEAEs) commonly occurring with setmelanotide in clinical trials, study assessment) study potential mechanistic-related events, or other events associated with B Disturbances in Sexual Arousal In the Phase 3 trials, the last 2 weeks of the dose titration phase were considered the first 2 weeks of the open-label treatment phase. LEPR, leptin receptor; PCSK1, proprotein convertase subtilisin/kexin type1; POMC, proopiomelanocortin. 7 background disease, include hyperpigmentation disorders, disturbances 6 6 in sexual arousal, nausea, vomiting, and injection site reactions (ISRs)2,4,5 Table 2. Rates of Commonly Occurring AEs of Special Interest 5 Results 4 3 Participants with POMC, PCSK1, or 2 Objective 2 Participant Disposition and Overall Safety LEPR deficiency, n (%) (N=35) 1 11 Number of events 1 ¡ ¡ As of November 10, 2020, 35 participants were enrolled and included a 00 0 0000 To assess the timing of the onset of AEs of special interest in participants ISRs 31 (88.6) 0 with obesity due to POMC, PCSK1, or LEPR deficiency treated with across the 3 trials (Table 1) 1 23456789101112 setmelanotide — POMC: n=15; PCSK1: n=2; LEPR: n=18 Skin hyperpigmentation 30 (85.7) Month ¡ Daily setmelanotide doses ranged from 0.25 to 3.0 mg Nausea 20 (57.1) C Nausea 14 Vomiting 10 (28.6) 12 Methods Table 1. Participant Disposition 12 Disturbances in sexual arousala 6 (17.1) 10 Participants with POMC, PCSK1, or LEPR deficiency, 8 ¡ The timing of AE onset with setmelanotide was evaluated in a pooled set AE, adverse event; ISR, injection site reaction; LEPR, leptin receptor; PCSK1, proprotein convertase subtilisin/kexin Study status n (%) (N=35) a 6 5 5 of trial participants with POMC, PCSK1, or LEPR deficiency who received type 1; POMC, proopiomelanocortin. Represents system/class grouped term. 4 4 setmelanotide in clinical trials Ongoing 2 (5.7) 2 2 2

Number of events 2 1 1 0 00 ¡ A Phase 2 investigator-initiated (Charité Universitätsmedizin Berlin) Completed 25 (71.4) Timing of Onset of AEs of Special Interest 0 trial evaluated setmelanotide in participants aged ≥18 years with obesity ¡ The majority of hyperpigmentation disorders (34 of 53 events [64.2%]) 12345678910 11 12 2 Discontinued 8 (22.9) Month (body mass index [BMI] >30 kg/m ) and POMC, PCSK1, or LEPR and disturbances in sexual arousal (6 of 11 events [54.6%]) had an onset deficiency (RM-493-011 [ClinicalTrials.gov identifier: NCT02507492]; Protocol deviation 3 (8.6) during Month 1 after starting setmelanotide treatment (Figure 2A and 2B) D Vomiting 4-6 7 Figure 1A) Protocol violation 1 (2.9) 6 — Following onset, skin hyperpigmentation continued for the duration of 6 5 ¡ Two Phase 3 trials evaluated setmelanotide in participants aged ≥6 years AE 1 (2.9) setmelanotide treatment; disturbances in sexual arousal resolved quickly 5 2 with obesity (BMI ≥30 kg/m in adults; weight >97th percentile for age Death 1 (2.9)a ¡ The onsets of nausea and vomiting were most frequent during Month 1 4 3 in children and adolescents) and POMC, PCSK1, or LEPR deficiency of treatment (nausea: 12 of 34 events [35.3%]; vomiting: 6 of 19 events 22 2 Lost to follow-up 1 (2.9) 2 (RM-493-012 [ClinicalTrials.gov identifier: NCT02896192] and RM-493-015 1 1 2,7,8 [31.6%]) (Figure 2C and 2D) Number of events 1 [ClinicalTrials.gov identifier: NCT03287960]; Figure 1B) Other 1 (2.9) 0 00 00 — Events of nausea and vomiting were typically of short duration following onset 0 ¡ AEs were assessed using the National Cancer Institute Common aOne participant with LEPR deficiency participating in one of the Phase 3 trials died as a result of injuries sustained 1 23456789101112 as a passenger in an automobile accident occurring at approximately study week 36; the death was considered to be ¡ ISRs were reported throughout the trial, with 41.6% (91 of 219 events) Terminology Criteria for Adverse Events Month unrelated to the study drug. AE, adverse event; LEPR, leptin receptor; PCSK1, proprotein convertase subtilisin/kexin having an onset within the first month of treatment (Figure 2E) ¡ type 1; POMC, proopiomelanocortin. Select AEs of special interest were evaluated on the basis of preferred — Following onset, ISRs typically resolved quickly E ISRs terms (nausea, vomiting) and grouped terms (hyperpigmentation 100 91 ¡ disorders, disturbances in sexual arousal, ISRs) ¡ Each participant experienced at least 1 TEAE, with the most common A slight increase in onset of nausea and vomiting was observed at 80 Month 7, which may have been associated with participants in the Phase — Hyperpigmentation disorders preferred terms were skin hyperpigmentation, being skin hyperpigmentation (85.7%), injection site erythema (68.6%), 60 melanocytic naevus, skin discoloration, and ephelides nausea (57.1%), and headache (51.4%) 3 trials resuming setmelanotide treatment following placebo withdrawal in Month 5 40 — ¡ 25 22 Disturbances in sexual arousal preferred terms were spontaneous penile During setmelanotide treatment, 18 serious AEs occurred, none of which 17 15 20 11 10 10 9 erection (males), erection increased (males), and disturbance in sexual were interpreted as related to the study drug Acknowledgments: This study was sponsored by Rhythm Pharmaceuticals, Inc. Assistance with preparation of this poster was provided under the Number of events 5 3 1 arousal (females) direction of the authors by Rhyomi Sellnow, PhD, and David Boffa, ELS, of MedThink SciCom and funded by Rhythm Pharmaceuticals, Inc. 0 References: 1. Huvenne et al. Obes Facts. 2016;9:158-173. 2. Clément et al. Lancet Endocrinol. 2020;8:960-970. 3. Imcivree. Prescribing 123456789101112 — ISR preferred terms were injection site erythema, pruritus, induration, pain, Rates of AEs of Special Interest Information. Rhythm Pharmaceuticals, Inc.; 2020. 4. Kühnen et al. N Engl J Med. 2016;375:240-246. 5. Clément et al. Nat Med. 2018;24:551-555. 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02507492. Updated February 22, 2016. Accessed February 19, 2021. 7. ClinicalTrials.gov. Month bruising, edema, reaction, and swelling ¡ https://clinicaltrials.gov/ct2/show/NCT02896192. Updated January 27, 2021. Accessed February 19, 2021. 8. ClinicalTrials.gov. https://clinicaltrials.gov/ The most common AEs of special interest are shown in Table 2 ct2/show/NCT03287960. Updated January 27, 2021. Accessed February 19, 2021. Months are defined as 30-day periods. AE, adverse event; ISR, injection site reaction.

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