Dr Matthew Coghlan Novo Nordisk

Dr Matthew Coghlan Novo Nordisk

Preventing diabetes and its complications Matthew Coghlan PhD Senior Director Search & Evaluation Global Drug Discovery Novo Nordisk A/S

Obesity rates worldwide are increasing Men BMI 30 kg/m 2 Women BMI 30 kg/m 2 350M 350M 300M 250M 200M 150M 100M Number of people 300M 250M 200M 150M 100M Number of people 50M 50M 1975 1980 1985 1990 1995 2000 2005 2010 2015 1975 1980 1985 1990 1995 2000 2005 2010 2015 M, million Sub-Saharan Africa Central Asia, Middle East and North Africa South Asia East and South East Asia High-income Asia Pacific Oceania Latin America and Caribbean High-income English speaking countries and Western Europe Central and Eastern Europe Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet 2017:390;2627 42

Age-adjusted relative risk of developing T2D* Greater risk of developing T2D with higher BMI 100 80 60 40 Relative risk of developing T2D with: BMI 29.0 30.9 kg/m 2 = 28* BMI 31.0 32.9 kg/m 2 = 40* BMI 33.0 34.9 kg/m 2 = 54* BMI 35 kg/m 2 = 93* 20 0 22 22.9 23 23.9 24 24.9 25 26.9 27 28.9 29 30.9 31 32.9 33 34.9 35 BMI (kg/m 2 ) *vs. BMI <22 kg/m 2 ; Data are for women only. n=114,281 female registered nurses aged 30 55 years; T2D, type 2 diabetes Colditz et al. Ann Intern Med 1995;122:481 6

Weight change (kg) Cumulative incidence T2D (%) Weight loss reduces the risk of type 2 diabetes Adults with prediabetes Placebo Metformin Lifestyle changes 2 60 0 50-2 40-4 30 20 34% reduction -6 10-8 0 1 2 3 4 5 6 7 8 9 10 0 Metformin = 18% reduction in risk 0 1 2 3 4 5 6 7 8 9 10 Time (years) Time (years) n=2766 males and females. Knowler et al. Lancet 2009;374:1677 86

Lifestyle intervention

The Global Research Framework of Cities Changing Diabetes Prof. David Napier Global Academic Lead Cities Changing Diabetes

Today, two thirds of people with diabetes live in cities 2017 65% OF PEOPLE WITH DIABETES LIVE IN URBAN AREAS 1 2045 75% OF PEOPLE WITH DIABETES WILL LIVE IN URBAN AREAS 1 References 1. International Diabetes Federation. IDF Diabetes Atlas. 8th edn. Brussels, Belgium: International Diabetes Federation. 2017.

Cities Changing Diabetes partnership working to bend the diabetes curve 1 0 16 partner cities - Representing more than 120 million people Employers Mayor s office Planning and transport department Social service providers Patients groups Backbone Community groups Health department Researchers

Liraglutide is a once-daily, human GLP-1 analogue His Ala Glu Gly Thr Phe Thr Ser Asp Val Human endogenous GLP-1 Lys Glu Ala Ala Gln Gly Glu Leu Tyr Ser Ser Phe Ile Ala Trp Leu Val Lys Gly Arg Gly C-16 fatty acid (palmitoyl) T ½ = ~2 mins His Ala Glu Gly Thr Phe Thr Ser Glu Lys Glu Ala Ala Gln Phe Ile Ala Trp Leu Val Asp Val Ser Gly Glu Leu Tyr Ser Arg Gly Arg Gly Liraglutide 97% amino acid homology to human GLP-1; improved PK: albumin binding through acylation; heptamer formation Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (T ½ =13 h) DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PK, pharmacokinetics; T ½, plasma half-life Knudsen et al. J Med Chem 2000;43:1664 9; Degn et al. Diabetes 2004;53:1187 94

Energy intake (kj) Liraglutide 3.0 mg reduces energy intake Individuals with obesity after 5 weeks of treatment Liraglutide 3.0 mg Placebo Appetite 5000 4000 3000 2000 3024 p=0.003 3592 Satiety POMC/ CART Hunger NPY/ AgRP Arcuate nucleus 1000 0 Liraglutide Data are estimated means. In the post hoc analysis for total energy expenditure, body weight after 5 weeks of treatment was added to the original linear mixed-effect model Adapted from: van Can et al. Int J Obes 2014;38:784 93

Liraglutide 1.8 mg is not approved for weight management SCALE Phase 3a clinical trial programme SCALE Obesity and Prediabetes (1839) 1 SCALE Maintenance (1923) 3 Weight management and delayed onset of diabetes Liraglutide 3.0 mg n=2487 Placebo n=1244 Prevention of weight regain Liraglutide 3.0 mg n=212 Placebo n=210 SCALE Diabetes (1922) 2 SCALE Sleep Apnoea (3970) 4 Weight management in type 2 diabetes Liraglutide 3.0 mg n=423 Liraglutide 1.8 mg n=211 Placebo n=212 Effect of liraglutide in subjects with obesity and moderate to severe OSA Liraglutide 3.0 mg n=180 Placebo n=179 *SCALE, Sleep apnoea 3970 trial BMI 30 kg/m 2 plus co-morbidities; BMI, body mass index; OSA, obstructive sleep apnoea; SCALE, Satiety and Clinical Adiposity Liraglutide Evidence in individuals with and without diabetes 1. Pi-Sunyer et al. N Engl J Med 2015;373:11 22; 2. Davies et al. JAMA 2015;314:687 99; 3. Wadden et al. Int J Obes (Lond) 2013;37:1443 51; 4. Blackman et al. Int J Obes (Lond). 2016;40:1310-9

Trial design: SCALE Obesity and Prediabetes Liraglutide 3.0 mg in weight management (160 weeks) Inclusion criteria: 18 years Stable BW BMI 30 kg/m 2 or 27 kg/m 2 + comorbidities Without prediabetes With prediabetes 1 Liraglutide 3.0 mg Placebo Liraglutide 3.0 mg (n=1505) Placebo (n=749) Trial information June 2011 to March 2015 Randomised controlled double-blind study 191 sites in 27 countries Lifestyle intervention: -500 kcal/day diet + 150 min/week physical activity Dose escalation 0 4 weeks Randomisation (2:1) Treatment duration 156 weeks 12-week off-drug FU 160 weeks End of trial Trial objective Efficacy of liraglutide 3.0 mg in delaying the onset of T2DM in participants with overweight/obese prediabetics Key endpoints Primary: time to onset of T2DM at 160 weeks Secondary: weight measures, glycaemic control variables, cardiometabolic risk factors, HRQoL, safety and tolerability 1. ADA. Diabetes Care 2010;33(Suppl. 1):S62 9 BW, body weight; D&E, diet and exercise; FU, follow-up; HRQoL, health-related quality of life; T2DM, type 2 diabetes mellitus le Roux et al. Lancet 2017;389:1399 409

Summary of baseline characteristics All randomised participants entering the 3-year treatment arms Liraglutide 3.0 mg (n=1505) Placebo (n=749) Sex, female 1141 (76) 573 (77) Sex, male 364 (24) 176 (23) Mean age, years 47.5 ± 11.7 47.3 ± 11.8 White 1256 (83) 628 (84) Mean fasting body weight, kg 107.5 ± 21.6 107.9 ± 21.8 Mean BMI, kg/m 2 38.8 ± 6.4 39.0 ± 6.3 Mean HbA 1c, % 5.8 ± 0.3 5.7 ± 0.3 Mean FPG, mmol/l 5.5 ± 0.6 5.5 ± 0.5 Mean 2-hour PG during OGTT, mmol/l 7.4 ± 1.8 7.4 ± 1.7 History of dyslipidaemia 499 (33) 249 (33) History of hypertension 635 (42) 312 (42) Data are observed means ± SD or number (%) FPG, fasting plasma glucose; OGTT, oral glucose-tolerance test; PG, plasma glucose; SD, standard deviation *The diagnoses of dyslipidaemia and hypertension were based on reported medical history le Roux et al. Lancet 2017;389:1399 409

Change in weight (%) Change in body weight (%) 0 172 weeks 0-2 Liraglutide 3.0 mg Off-drug follow-up Observed mean LOCF Placebo Off-drug follow-up Observed mean LOCF ETD at week 160: 4.3% [ 4.9; 3.7] p<0.0001-1.9% -2.1% -4-6 -3.5% -3.4% -6.1% -2.7% -5.2% -8-10 -9.2% -8.5% -7.1% -12 0 16 28 40 56 68 80 92 104 116 128 140 152 160 172 n= n= Week 1467 1295 1223 1161 1100 1030 971 911 885 849 830 805 780 734 635 576 544 508 465 436 399 375 365 354 336 327 747 322 778 320 Full analysis set, fasting visit data only. Line graphs are observed means (±SE) LOCF, last observation carried forward; SE, standard error le Roux et al. Lancet 2017;389:1399 409

Participants (%) Participants diagnosed with T2DM over time Kaplan Meier plot: 0 172 weeks 12 10 Liraglutide 3.0 mg Off drug follow up Placebo Off drug follow up 46 47 8 6 4 2 26 31 n= n= 0 0 16 32 48 64 80 96 112 128 144 160 Week 1472 1313 1204 1135 1060 977 910 863 830 799 738 636 569 523 468 422 376 350 328 310 776 296 172 504 205 Full analysis set. Numbers in the figure correspond to the accumulated number of diagnosed participants T2DM, type 2 diabetes mellitus le Roux et al. Lancet 2017;389:1399 409

Liraglutide 3.0 mg label updates EU Summary of Product Characteristics SCALE Obesity and Prediabetes 160 week data 1 Published 22 Feb 2017 Liraglutide 3.0 mg (Saxenda ) EU Summary of Product Characteristics 2 Label updated approved 1 Dec 2016 In the 160 weeks part of trial 1 the weight loss occurred mainly in the first year, and was sustained throughout 160 weeks At week 160, while on treatment, 3% treated with Saxenda and 11% treated with placebo were diagnosed with type 2 diabetes mellitus The estimated time to onset of type 2 diabetes mellitus for patients treated with liraglutide 3.0 mg was 2.7 times longer (with a 95% confidence interval of [1.9, 3.9]), and the hazard ratio for risk of developing type 2 diabetes mellitus was 0.2 for liraglutide versus placebo 1. le Roux et al. Lancet 2017;389:1399 409: 2. Novo Nordisk. Saxenda Summary of Product Characteristics 2017. Available at: https://www.medicines.org.uk/emc/medicine/32753 (accessed 10 May 2017);

NASH coincides with obesity, diabetes USA estimate NASH patient with co-morbidity NASH patient without co-morbidity % co-morbidity in NASH patients 20% 30% 10 million pts with NASH 65% 80% 70% 35% Majority of NASH patients have obesity and hypertension 25-50% of NASH patients have diabetes Obesity Hypertension T2DM Williams CD et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology 2011; 140: 124-31. Armstrong MJ et al. Liraglutide safety and effi cacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679-90. Neuschwander-Tetri BA et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385: 956 65. Ratziu V et al. Elafibranor, an Agonist of the Peroxisome Proliferator - Activated Receptor-a and -d, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016;150:1147 1159

Obesity is an independent risk factor for NAFLD 2 1 Meta-analysis including 21 cohort studies including 13 prospective studies and 8 retrospective studies A total of 381,655 participants were included Obesity was associated with an approximately 3.5- fold increased risk of NAFLD after adjusting for Diabetes Dyslipidemia Blood pressure Physical activity Liver enzymes Alcohol intake Li et al., Obes Rev, 2016

Effect of weight loss on NASH/fibrosis Prospective study with bx-proven NASH Lifestyle changes over 52 weeks: 1. 750 kcal/d 2. Walk 200 mins/wk 3. Behavioural (/8wk) Overall (n=293) % weight loss achieved <5 n=205 5-6.99 n=34 7-9.99 n=25 10 n=29 Variables Overall (n=293) WL < 5 (n=205) WL = 5 6.99 (n=34) WL = 7 9.99 (n=25) WL 10 (n=29) Weight loss, % 3.8 ± 2.7 1.78 ± 0.16 5.86 ± 0.09 8.16 ± 0.22 13.04 ± 6.6 Resolution of steatohepatitis 72 (25) 21 (10) 9 (26) 16 (64) 26 (90) NASH, non-alcoholic steatohepatitis; WL, weight loss. Vilar-Gomez et al, Gastro, 2015.

Proportion of patients (%) Weight loss improves NASH liver fibrosis Prospective lifestyle modification* trial p=0.04 100% 80% 60% 10 45 18 44 50 19 Stabilized 40% 20% 0% 45 38 n=73 n=16 n=8 n=16 Weight loss <5% Weight loss 5 7% Weight loss 7 10% Weight loss 10% 50 81 Regressed Worsened Stabilized Regressed In patients with fibrosis at baseline, a 10% WL significantly reduced the fibrosis score by at least 1 point in 13 of 16 (81%). *Lifestyle changes are defined as consumption of 750 fewer calories daily, walking 200 minutes per week, and behavioural individual sessions every 8 weeks to promote adherence to diets. NASH, non-alcoholic steatohepatitis; WL, weight loss. Source: Vilar-Gomez E. et al. Gastroenterol. 2015;149:367 378.

COOH Semaglutide is a once-weekly GLP-1 analogue 94% homology to human GLP-1 t 1/2 of approximately 1 week His 8 Ala Aib Glu Amino acid substitution at position 8 (alanine to alpha-aminoisobutyric acid) protects against DPP-4 degradation Gly Thr Phe Thr Ser Asp Val Spacer and C-18 fatty diacid chain to lysine in position 26 provide strong binding to albumin spacer Amino acid substitution at position 34 (lysine to arginine) prevents C-18 fatty diacid binding at the wrong site Lys Ala Ala Gln Gly Glu Leu Tyr Glu 26 Phe 34 Ile Ala Trp Leu Val Lys Arg Gly Arg Ser Ser Gly DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; t 1/2, half-life Lau J et al. J Med Chem. 2015;58:7370 80; Kapitza C et al. J Clin Pharmacol. 2015;55:497 504; Marbury TC et al. Diabetologia. 2014;57(Suppl. 1):S358.

Change in body weight (%) Semaglutide 0.4 mg OD showed improved weight reduction 11.5% reduction vs placebo 0-2 -4-6 -8-10 -12-14 Semaglutide -13.8 Placebo -2.3 From a mean baseline weight of around 111 kg and a BMI of approximately 39 kg/m 2, a weight loss up to 17.8 kg was observed after 52 weeks of treatment with semaglutide This corresponded to a 13.8% weight loss compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone, with all treatment arms adjusted for people discontinuing treatment in the study Semaglutide OD had a well-tolerated safety profile, with the most common adverse events being gastrointestinal side effects -16 N=957 people with obesity were treated with semaglutide or placebo for 52 weeks, followed by a 7 week follow-up. Mean baseline weight: 111 kg. Mean baseline BMI: 39 mg/m 2 BMI, body mass index; OD, once daily. O Neil et al. ENDO 2018; 17 20 March 2018, Oral OR12-5.

26 Semaglutide for NASH PURPOSE AND MEDICAL RATIONALE NASH is associated with Obesity Diabetes Insulin resistance Inflammation Cardiovascular risk Potential benefits of GLP-1 receptor agonists Weight loss Improved glucose metabolism Improved lipid metabolism Reduced inflammation Resolution of NASH (LEAN study) 1 CVOT data in patients with T2D 2,3 Semaglutide has promising potential for NASH 1 Armstrong et al. Lancet 2016;387(10019), p679 690 2 Marso SP, et al. N Engl J Med 2016;375:1834 44. 3 Marso SP, et al. N Engl J Med. 2016; 375:311-22

Semaglutide NASH phase 2b dose-finding trial TRIAL NN9931-4296 372 patients Biopsy confirmed NASH Fibrosis stage 1-3 NAS 4 With or without T2D HbA1c 9.0% BMI 25-45 kg/m 2 Liver biopsy (recent or new) Semaglutide 0.4 mg s.c. once daily Semaglutide 0.2 mg s.c. once daily Semaglutide 0.1 mg s.c. once daily Placebo 0.1 mg, 0.2 mg or 0.4 mg Duration 72 weeks 7 weeks follow up Liver biopsy Trial information Global trial FPFV: 30 Nov 2016 Randomised and double-blind Primary endpoint NASH resolution without worsening of fibrosis after 72 weeks Secondary endpoint At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks

Semaglutide DEVELOPMENT STATUS Diabetes (s.c., QW) Obesity (s.c., QW) NASH (s.c., OD) Diabetes (oral, OD) OD, once daily; OW, once weekly; s.c., subcutaneous.