A Phase 2b, Double-blind, Randomized, Placebo-controlled, Multi center, 16-week Dose finding, Safety and Efficacy Study with Open-label Extension Period of Tesomet in Adult and Adolescent Subjects with Prader-Willi Syndrome

INTERVENTION: Product Name: Tesomet Pharmaceutical Form: Capsule INN or Proposed INN: Tesofensine CAS Number: 195875‐84‐4 Current Sponsor code: NS2330 Other descriptive name: TESOFENSINE CITRATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.125‐ INN or Proposed INN: Metoprolol Other descriptive name: METOPROLOL SUCCINATE (PH. EUR.) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 15‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Tesomet Pharmaceutical Form: Capsule INN or Proposed INN: Tesofensine CAS Number: 195875‐84‐4 Current Sponsor code: NS2330 Other descriptive name: TESOFENSINE CITRATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.25‐ INN or Proposed INN: Metoprolol Other descriptive name: METOPROLOL SUCCINATE (PH. EUR.) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 30‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Product Name: Tesomet Pharmaceutical Form: Capsule INN or Proposed INN: Tesofensine CAS Number: 195875‐84‐4 Current Sponsor code: NS2330 Other descriptive name: TESOFENSINE CITRATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.375‐ INN or Proposed INN: Metoprolol Other descriptive name: METOPROLOL SUCCINATE (PH. EUR.) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 45‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Prader‐Willi Syndrome ; MedDRA version: 20.0 Level: PT Classification code 10036476 Term: Prader‐Willi syndrome System Organ Class: 10010331 ‐ Congenital, familial and genetic disorders Therapeutic area: Diseases [C] ‐ Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] SECONDARY OUTCOME: Secondary end point(s): • The change in body weight (%) from Baseline to Week 16;; • The change in the Caregiver Global Impression of Hyperphagia Severity scale (CaGI‐H‐S) from Baseline to Week 16; ; • The proportion of responses to the Caregiver Global Impression of Hyperphagia Change scale (CaGI‐H‐C) at Week 16;; • The change in the Clinical Global Impression of PWS Severity scale (CGIS) from Baseline to Week 16; and; • The proportion of responses to the Clinician Global Impression of PWS Change scale (CGIC) at Week 16.; Timepoint(s) of evaluation of this end point: Baseline to Week 16 PRIMARY OUTCOME: Main Objective: The primary objectives of the study are:; • To examine the efficacy of Tesomet over 16 weeks on hyperphagia in adult and adolescent subjects with PWS and to inform the dose selections for the Phase 3 study; and; • To assess the safety and tolerability of Tesomet over 16 weeks in adult and adolescent subjects with PWS.; Primary end point(s): Efficacy endpoint : The primary efficacy endpoint is the change in total HQ‐CT score from Baseline to Week 16.; Safety endpoints:; • The incidence of treatment‐emergent adverse events (TEAEs) of special interest (secondary endpoint);; • The incidence of TEAEs and treatment‐emergent serious adverse events (TESAEs);; • The incidence of MACE;; • Laboratory evaluation (chemistry and hematology) results at Baseline and at all site visits;; • Vital sign measurements at Baseline and at Week 8 and Week 16;; • ECG assessments at Baseline and at Week 8 and Week 16;; •Physical examination findings at Baseline and at Week 8 and Week 16;; • C‐SSRS administered by a trained rater at Baseline and at all visits; and; • The Aberrant Behavior Checklist (ABC) completed by the caregiver at Baseline and at all visits to assess the change in behavior. Secondary Objective: The secondary objectives of the study are:; • To examine the efficacy of Tesomet on body weight in adult and adolescent subjects with PWS;; • To examine the efficacy of Tesomet on hyperphagia based on Caregivers’ Global Impressions of Hyperphagia Severity and Change in adult and adolescent subjects with PWS;; • To examine the efficacy of Tesomet on overall health based on Clinicians’ Global Impressions of PWS Severity and Change in adult and adolescent subjects with PWS;; • To examine the effects of Tesomet on heart rate (HR) and blood pressure (BP) in adult and adolescent subjects with PWS; and ; • To examine the pharmacokinetic (PK) profile of tesofensine and metoprolol in adult and adolescent subjects with PWS. Timepoint(s) of evaluation of this end point: from Baseline to Week 16 INCLUSION CRITERIA: 1. The subject and their legally authorized representative (ie, parent, legal guardian) and the caregiver must be willing to sign and receive a copy of their respective informed consent form(s) (ICF) after the nature and risk of study participation have been fully explained; a. Informed consent(s) [and assent(s) for subjects below the legal age of consent when applicable] signed by the subject, parent, or legal guardian, as appropriate, prior to the initiation of any study procedures; and b. informed consent(s) from the caregiver, signed prior to the initiation of any study procedures; 2. Confirmed genetic diagnosis of PWS via the central laboratory (Note: past genetic documentation is acceptable for enrollment with confirmatory methylation test done in parallel); 3. Female and male subjects aged 13 to 65 years at the time of informed consent; 4. Female subjects of non‐childbearing potential (WONCBP); defined as follows: surgically sterile (ie,