NBG: Progress Update of Key Business Imperatives in FY2017

NBG: Progress Update of Key Business Imperatives in FY2017

Lorcaserin Improves Renal Outcomes in Obese and Overweight Patients in the C AMELLIA-TIMI 61 Trial E.A. Bohula, S.D. Wiviott, J.P. Dwyer, S.E. Inzucchi, D.K. McGuire, K. Im, S.A. Murphy, W. Miao, C. Perdomo, T. Patel, S.R. Smith, A.C. Keech, M.S. Sabatine, & B.M. Scirica on behalf of the CAMELLIA-TIMI 61 Investigators An Academic Research Organization of Brigham and Womens Hospital and Harvard Medical School Background Obesity is associated with an increased risk of developing kidney disease Unclear if mechanism is causal or via associated comorbidities Lifestyle modification & bariatric surgery improves albuminuria, but has mixed effects on eGFR Renal effects of pharmacologically-mediated weight loss not well described An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Lorcaserin Selective agonist of serotonin (5HT)-2C receptor Hypothalamic activation of the POMC (pro-opiomelanocortin) pathway appetite suppression Based on phase 3 studies testing weight loss efficacy, approved for use in the US for chronic weight management An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Lorcaserin + 5HT R 5HT2C 2CR

Image modified from Marx J. Science. 2003;299:846-849. Trial Schema :Median Follow up yrs 3.3 Obese or Overweight (BMI27kg/m2) Established CV disease* or T2DM & other CV risk factors N = 12,000 Exercise & Reduced-Calorie Diet Lorcaserin 10mg BID RANDOMIZE 1:1 DOUBLE BLIND Stratified by CV disease or CV RF PLACEBO Follow up visits Q 3mo x 2yr then Q 4mo Primary CV Safety EP: MACE (CV death, MI, CVA) Primary Metabolic Efficacy EP: Incident T2DM in pts with pre-DM *CAD, PAD or cerebrovascular disease; T2DM with 1 of following: HTN, HL, hsCRP>3, eGFR 30-60, albuminuria An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Bohula EA et al. Am Heart J 2018;202:39-48 Primary Trial Outcomes CV Death, MI, Stroke (CV Safety) Lorc Pbo n (%/yr) n (%/yr) CV death, MI, or stroke N = 3,991

364 (2.0) MACE HR (95%CI) 369 (2.1) 0.99* (0.85, 1.14) 0.8 1.0 1.4 Hazard Ratio (95% CI) Favors Lorcaserin Favors Placebo *P (non-inferiority) < 0.001 *Non-inferiority boundary: HR 97.5% upper bound of 1.4 An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Cum ulative Incidence of new DM in pts w/ pre-DM N = 12,000 12% 10% Incident Diabetes (Metabolic Efficacy) HR 0.81 (0.66, 0.99) P=0.038 10.3% (204 events) 8% 6% 4% 8.5% (172 events) 2%

0% Time From Randomization (Months) Lorcaserin Bohula EA et al. NEJM. 2018;379:1107-1117; Bohula EA et al. Lancet. 2018;epub Placebo Renal Outcomes Pre-specified Primary Renal Composite Outcome Persistent new or worsening micro- or macro-albuminuria* Micro- (UACR 30mg/g) or macro-albuminuria ( 300mg/g) Persistent new or worsening CKD* Increase in CKD stage by KDIGO staging Persistent doubling of serum creatinine* End-stage renal disease (ESRD) = dialysis or eGFR<15 Renal transplant Renal death Other Pre-specified Renal Endpoints Persistent eGFR decline by 30% or 40%* An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School *On 2 consecutive measurements 30 days apart KDIGO CKD Stage Stage eGFR UACR 0 60

None 1 90 30 2 60-89 30 3 30-59 30 4 15-29 30 5 <15 or dialysis 30 eGFR by CKD-EPI (ml/min/1.73m2); UACR by spot urinary albumin to creatinine ratio(mg/g) Baseline Characteristics Characteristic (N=12,000) Age (median, IQR) Male Value 64 [58, 69]

64 Weight in kg (median, IQR) 102 [90, 116] BMI in kg/m2 (median, IQR) 35 [32, 39] Established CV Disease / Multiple CV RF Hypertension DM / Pre-DM / No DM eGFR in ml/min/1.73m2 (median, IQR) >=90 60-<90 <60 UACR in mg/g (median, IQR) <30 30-<300 (microalbuminuria) >=300 (macroalbuminuria) An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School 75 / 25 90 57 / 33 / 10 76 [63-89] 24 57 19 7.0 [3.9-19.0] 82 15 3.2 % unless otherwise specified. Pooled data; no differences between treatment arms (p0.05) W e ig h t f r o m B a s e lin e Weight, BP & HbA1c eGFR <60 (N=2357)

Lorcaserin Placebo eGFR 60-<90 (N=6783) 0 -2 -2 -2.2kg p<0.001 -2 0 -2.9kgkg p<0.001 -3 -3.2kg p<0.001 0 -1 -1 -1 eGFR 90 (N=2851) -3 -4 -4 -5

-5 -6 -6 -3 -4 -5 -6 0 12 at 1 Yr Weight (kg) HbA1c (%) SBP (mm Hg) 24 Months 36 0 12 24 Months 36 0 12 24 Months eGFR <60 -3.2 -0.2

eGFR 60-<90 -2.9 -0.2 eGFR 90 -2.2 -0.2 -1.1 -1.1 -1.1 An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School p<0.05 36 Primary Renal Composite *2 consecutive assessments 30 days apart Overall Lorcaserin 4.2% per year Placebo 4.9% per year HR 0.87 (0.79, 0.96), P=0.006 HR 0.83 95% CI 0.73, 0.93 P=0.002 14% 12% 10% 8% 6% HR 0.86 95% CI 0.74, 1.01 P=0.061

5.7% HR 0.84 95% CI 0.75, 0.93 P=0.001 13.7% 11.7% 9.4% 7.8% 4.9% 4% 2% 0% An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Lorcaserin 16% Kaplan-Meier Estimates (%) Primary renal composite: New or worsening albuminuria* New or worsening CKD* Doubling of serum Cr* ESRD Renal transplant Renal death Placebo 1 Year 2 Year 3 Year Renal PEP by Subgroups An Academic Research Organization of Brigham & Womens Hospital

An Affiliate of Harvard Medical School Individual Components Lorcaserin N=6000 %/Yr Placebo N=6000 %/Yr HR (95%CI) p-value 4.2 4.9 0.87 (0.79, 0.96) 0.0064 Persistent new or worsening albuminuria* 2.7 3.1 0.86 (0.76, 0.9kg7) 0.017 Persistent new or worsening CKD* 2.4 2.9kg 0.81 (0.72, 0.9kg3) 0.0018 Persistent doubling of creatinine*

0.03 0.04 0.75 (0.26, 2.15) 0.59kg ESRD or dialysis 0.11 0.08 1.40 (0.72, 2.71) 0.32 0 0.01 - - Persistent eGFR decline 30%* 0.33 0.39 0.84 (0.60, 1.19) 0.32 Persistent eGFR decline 40%* 0.12 0.14 0.87 (0.49, 1.55) 0.65

Outcome Primary Renal Composite Renal transplant/death *2 consecutive assessments 30 days apart Albuminuria defined as micro (30mg/g) or macro (300mg/g); CKD, KDIGO CKD stage; eGFR by CKD-EPI equation An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School in e G F R fro m B a s e lin e (m l/m in /1 . Renal Parameters Over Time Lorcaserin Placebo UACR 2.5 1.1 p<0.001 0.9 p<0.001 1.2 p<0.001 1.5 0.8 p<0.001 0.5 in UACR from Baseline (mg/g) eGFR 40 6 12

18 24 30 Months Since Randomization -0.5Research Organization An Academic of Brigham & Womens Hospital An Affiliate of Harvard Medical School 36 -12mg/g p=0.013 30 -9mg/g p=0.042 20 10 0 0 -7mg/g p=0.28 0 6 12 18

24 30 Months Since Randomization 36 Summary On a background of lifestyle interventions in overweight or obese patients at high CV risk, lorcaserin: Resulted in modest, durable improvement in risk factors, including weight, HbA1c and blood pressure incident & progressive of renal disease by eGFR and albuminuria Findings consistent over time and across subgroups An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Conclusion Taken together, the findings of CV safety, glycemic benefit and now improved renal status support the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. An Academic Research Organization of Brigham & Womens Hospital An Affiliate of Harvard Medical School Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial Benjamin M. Scirica, Erin A. Bohula, Jamie P. Dwyer, Arman Qamar, Silvio E. Inzucchi, Darren K. McGuire, Anthony C. Keech MD, Steven R. Smith, Sabina A. Murphy, Kyungah Im, Lawrence A. Leiter, Milan Gupta, Tushar Patel, Wenfeng Miao, Carlos Perdomo, Marc P. Bonaca, Christian T. Ruff, Marc S. Sabatine, and Stephen D. Wiviott for the CAMELLIA-TIMI 61 Steering Committee and Investigators An Academic Research Organization of Brigham and Womens Hospital and Harvard Medical School

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