Effect of semaglutide 2.4 mg - PowerPoint Presentation

1. Effect of semaglutide 2.4 mgon alanine aminotransferase in adolescents with obesity: a post-hoc analysis of the STEP TEENS trialDaniel Weghuber,1 Burak Demirel,2 Igne Gies,3 Lise Lotte Gluud,4 Aske Thorn Iversen,5 Signe Schmidt,6 Rasmus Sørrig,2 Martin Wabitsch,7 Mazen Noureddin,8,9**Presenting author11Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria; 2Global Medical Affairs, Novo Nordisk A/S, Søborg, Denmark; 3Department of Pediatrics, Division of Pediatric Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium; 4Gastro Unit, Copenhagen University Hospital Hvidovre and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 5Biostatistics, Novo Nordisk A/S, Søborg, Denmark; 6Medical and Science, Novo Nordisk A/S, Søborg, Denmark; 7Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, University of Ulm, Ulm, Germany; 8Sherrie & Alan Conover Center for Liver Disease & Transplantation, Houston Methodist Hospital, Houston, TX, USA; 9Houston Research Institute, Houston, TX, USA. Signe Schmidt was employed by Novo Nordisk at the time of the study.This trial was sponsored by Novo Nordisk and is registered with ClinicalTrials.gov (NCT04102189). The authors acknowledge the medical writing assistance of Anusha Bolonna, a contract writer working on behalf of OPEN Health Communications and Claudia Venables-Stack of OPEN Health Communications, and funded by Novo Nordisk, in accordance with Good Publication Practice (GPP) guidelines.

2. Presenter disclosureMazen Noureddin has served on advisory boards for 89BIO, Altimmune, Boehringer Ingelheim, Bristol Myers Squibb, EchoSens, Gilead, GSK, Merck, Novo Nordisk, OWL, Pfizer, Roche Diagnostic, Siemens, Takeda and Terns; was a drug study Principal Investigator for Akero, Allergan, Bristol Myers Squibb, Conatus, Corcept, Enanta, Galectin, Genfit, Gilead, Madrigal, Novartis, Novo Nordisk, Shire, Terns, Viking and Zydus; and is a stockholder in Anaetos, ChronWell, CIMA, Rivus Pharma and Viking.

3. IntroductionWeight loss can improve hepatic parameters such as ALT in participants with obesity‑related NAFLD/steatohepatitis1The phase 3, double-blind, placebo-controlled STEP TEENS trial (NCT04102189) reported the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg for weight management among adolescents with overweight or obesity2This post-hoc analysis of the STEP TEENS trial aimed to examine the change in ALT levels and presumed NAFLD in adolescents treated with semaglutide 2.4 mg vs placebo, including in subgroups with elevated ALT or presumed NAFLD at baselineALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease.1. Brunner KT, et al. Curr Obes Rep 2019;8:220–8; 2. Weghuber D, et al. N Engl J Med 2022;387:2245–57.

4. STEP TEENS trial background and rationale GLP-1, glucagon-like peptide-1.1.Apperley LJ, et al. Clinical Endocrinology 2022; 96:288–301; 2. Simmonds M, et al. Obesity reviews 2016;17:95–107 ; 3. Kolsgaard MLP, et al. BMC Pediatr 2011;11:47; 4. Woodard K, et al. Ther Adv Endocrinol Metab 2020;11:2042018820918789; 5. Bensignor MO, et al. Front Endocrinol (Lausanne) 2022;13:1043650; 6. Wilding JPH, et al. Diabetes Obes Metab 2022;24:1553-1564; 7. Wilding JPH, et al. N Engl J Med 2021;384;989; 8. Davies M, et al. Lancet 2021;397;971–84; 9. Wadden TA, et al. JAMA 2021;325:1403–13; 10. Rubino D, et al. JAMA 2021 325;1414–25.Background Paediatric obesity can lead to a range of complications and increased risk for obesity in adulthood;this can predispose adolescents to reduced quality of life and life expectancy1,2Weight loss in these participants is associated with improvement in cardiometabolic risk factors3There are few approved pharmacotherapies for weight management in this population, meaning thereis a need for effective and well tolerated therapeutic options4,5Semaglutide, a long-acting GLP-1 analogue, has been approved for weight management at a dose of2.4 mg. Phase 3a trials have demonstrated benefits in glucose metabolism and cardiovascular disease risk factors6–10RationaleThe STEP TEENS trial was conducted to address the unmet need for treatment of obesity in adolescents by assessing the efficacy and safety of semaglutide in this population

5. STEP TEENS: trial designRandomised, double-blind, multinational, placebo-controlled trial*Lifestyle intervention: individualised counselling in healthy nutrition with the goal of obtaining weight loss and encouraging 60 minutes of moderate- to high-intensity physical activity per day. †Run-in period: 12 weeks off-drug lifestyle intervention before randomisation (baseline). ‡On sex-specific BMI-for-age growth charts (cdc.gov).ALT, alanine aminotransferase; BMI, body mass index; PHQ-9, Patient Health Questionnaire 9; T2D, type 2 diabetes.Weghuber D, et al. N Engl J Med 2022;387:2245–57.Lifestyle intervention*Dose escalationMaintenanceFollow-up75End oftrial68End oftreatment1612RandomisationScreening840–12–14Week:Run-in†0.25 mg0.5 mg1.0 mg1.7 mgPlacebo once weeklySemaglutide 2.4 mg once weekly(or maximum tolerated dose)2:1Key inclusion criteria12 to <18 years Tanner stage 2‒5BMI ≥95th percentile‡ or BMI ≥85th percentile‡ with ≥1 weight-related comorbidity: hypertension, dyslipidaemia, obstructive sleep apnoea or T2DBMI criteria to be met at randomisation alsoKey exclusion criteriaSecondary causes of obesityPHQ-9 score ≥15 at screening/randomisationT2D: uncontrolled and potentially unstable diabetic retinopathy or maculopathyPrimary endpoint Change in BMI from baseline (week 0) to week 68 (%)The current post-hoc analysis assessed the supportive secondary endpoint of change in ALT levels

6. Primary and secondary endpointsALT, alanine aminotransferase; BMI, body mass index; HbA1c, glycated haemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; SAE, serious adverse event; TEAE, treatment-emergent adverse event; VLDL, very low-density lipoprotein.PrimaryPrimaryChange in BMI from baseline (week 0) to week 68 (%)Confirmatory: Participants achieving ≥5% reduction of body weight from baseline to week 68 (yes/no)Supportive secondaryEffect endpoints from baseline to week 68:Change in:Body weight (kg)Body weight (%)SecondarySupportive secondary Effect endpoints from baseline to week 68: Change in: Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) HbA1c (% point, mmol/mol) Fasting plasma glucose (mmol/L, mg/dL) Fasting insulin (pmol/L, mIU/mL)Total cholesterol (mmol/L, mg/dL) HDL cholesterol (mmol/L, mg/dL) LDL cholesterol (mmol/L, mg/dL)VLDL cholesterol (mmol/L, mg/dL)Triglycerides (mmol/L, mg/dL)ALT (U/L) SecondarySupportive secondary Safety endpoints from baseline to week 75: Number of TEAEs Number of treatment-emergent SAEs Safety endpoints from baseline (week 0) to week 68: Change in: Pulse (bpm) Amylase (U/L) Lipase (U/L) Calcitonin (ng/L)

7. Baseline characteristics and obesity-related complications at screening *Elevated ALT defined as >25.8 U/L in male participants, >22.1 U/L in female participants.1 Percentages are the proportion of participants in the full analysis set. **Black refers to Black or African American; Other refers to American Indian, Alaska Native or Other. †Without the eight participants who had T2D at screening. 1. Schwimmer JB, et al. Gastroenterology 2010;138:1357–64.e13642. ALT, alanine aminotransferase; BMI, body mass index; HbA1c, glycated haemoglobin; NAFLD, non alcoholic fatty liver disease; T2D, type 2 diabetes.Male/female38/62%Mean age15.4 years79/8/2/11%White/Black/Asian/Other**Presumed NAFLD34%Elevated ALT*38%Glycaemic statusNormoglycaemia82.6%Prediabetes13.4%T2D4.0%Obstructive sleep apnoea1.5%Hypertension13.4%Dyslipidaemia18.4%ComplicationsBaseline characteristicsMean HbA1c†5.5%Mean BMIMean waist circumference110.4 cmMean body weight37.0 kg/m2107.5 kg4/7/27/62%Tanner stage 2/3/4/5

8. Statistical analysis The prespecified secondary endpoint of change in ALT at week 68 was assessed in the on-treatment period for the trial product estimand* in the full analysis setA mixed model for repeated measures, adjusted for stratification groups (sex and Tanner stage) and baseline ALT, was usedResults are presented for the overall population and for subgroups with elevated ALT and presumed NAFLD*Assessed treatment effect if all participants remained on treatment without rescue interventions.ALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease.

9. Change in ALT levels over time in all participantsLeft figure: Error bars are ± standard error of the mean. Numbers shown below the graph are participants contributing to the mean. Geometric mean data from the on-treatment period. ALT, alanine aminotransferase; CI, confidence interval; ETD, estimated relative treatment difference. 496867017Semaglutide 2.4 mgPlacebo25232119Semaglutide 2.4 mg:Placebo:Time since randomisation (weeks) Geometric mean ALT (U/L) 1111256528134No. of participants:Observed geometric mean by weekEstimated mean percent changefrom baseline at week 68Change from baseline in ALT (%)Semaglutide 2.4 mgPlaceboETD −17.2%[95% CI −28.8, –3.6]−20−16−12−8−40–18.1–1.1

10. Change in ALTChange from baseline to week 68 in participants with elevated ALT* levels*Elevated ALT defined as >25.8 U/L in male participants, >22.1 U/L in female participants.1 ALT, alanine aminotransferase; CI, confidence interval; CV, coefficient of variation; ETD, estimated treatment difference.1. Schwimmer JB, et al. Gastroenterology 2010;138:1357–64.e13642. Semaglutide 2.4 mgPlacebo ALT change from baseline at week 68 (%) ALT at week 0, geometric mean (CV)n=5642 (51.2)n=2040 (51.1)ETD −20.5 %-points [95% CI −38.5, 2.8]−25−20−15−10−500.5

11. Change in ALTChange from baseline to week 68 in participants with presumed NAFLD**Presumed NAFLD defined as BMI ≥85th percentile, FLI (a surrogate index of fatty liver based on BMI, waist circumference, triglycerides and γ-glutamyl transferase) ≥60 and elevated ALT.1,2 ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; CV, coefficient of variation; ETD, estimated treatment difference; FLI, fatty liver index; NAFLD, non-alcoholic fatty liver disease.1. Schwimmer JB, et al. Gastroenterology 2010;138:1357–64.e13642; 2. Arshad T, et al. Hepatol Commun 2021;5:1676–88.Semaglutide 2.4 mgPlacebo ALT change from baseline at week 68 (%) n=5043 (51.4)n=1839 (48.7)ETD −23.7 %-points [95% CI −41.7, −0.0]−25−20−15−10−50510ALT at week 0, geometric mean (CV)–15.510.6

12. ALT levelsPercentage body weight loss at week 68 Observed data from the on-treatment period.*Includes participants who gained weight.ALT, alanine aminotransferase; CV, coefficient of variation.Geometric mean, U/L (CV)Semaglutide 2.4 mgPlaceboBaselineWeek 68BaselineWeek 68<10% weight loss*n=53n=39n=62n=4424.4 (72.8)27.4 (72.6)19.9 (72.1)21.0 (58.4)≥10% weight lossn=81n=72n=5n=522.6 (68.3)15.9 (49.9)15.0 (49.5)14.8 (27.2)

13. Change from baseline in NAFLD statusParticipants with presumed NAFLD* at baseline *Presumed NAFLD defined as BMI ≥85th percentile, FLI (a surrogate index of fatty liver based on BMI, waist circumference, triglycerides and γ-glutamyl transferase) ≥60 and elevated ALT.1,2 ALT, alanine aminotransferase; BMI, body mass index; FLI, fatty liver index; NAFLD, non-alcoholic fatty liver disease.1. Schwimmer JB, et al. Gastroenterology 2010;138:1357–64.e13642; 2. Arshad T, et al. Hepatol Commun 2021;5:1676–88.Semaglutide 2.4 mgWeek 0(n=111) Week 68(n=46)Presumed NAFLDNo NAFLDPlaceboWeek 0(n=49) Week 68(n=14)

14. SafetyHepatic-related adverse eventsThe proportion of participants reporting hepatic-related adverse events, which were mostly non‑serious, was higher in the semaglutide 2.4 mg group (7.5%) than placebo (1.5%)The imbalance was mainly driven by events reported at the day of randomisation (not exposure to semaglutide) and events in participants with pre‑existing hepatic disordersProportion of participants (%) Semaglutide 2.4 mgPlacebo

15. ConclusionsALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease.Treatment with semaglutide 2.4 mg once weekly for 68 weeks was associated with a significant reduction in ALT levels vs placebo in adolescents with overweight or obesity, including among participants with elevated ALT or presumed NAFLDThese findings from the STEP TEENS trial will inform future studies on the management of paediatric patients at risk of obesity-related conditions such as NAFLD/steatohepatitisImbalances in hepatic-related adverse events were mainly driven by events at randomisation ​(not semaglutide exposure) and pre-existing hepatic disorders