GLPG1837 in Subjects with Cystic Fibrosis (CF) and the G551D Mutation: results from a Phase II study (SAPHIRA1) ECFS, Sevilla, Spain 9 June 2017 Jane Davies on behalf of the SAPHIRA1 Study Team Copyright 2017 Galapagos NV
Disclosures Jane Davies: Imperial College London has received fees for the following activities: Galapagos: clinical trial leadership Abbvie: Advisory Boards Vertex, Proteostasis, Bayer: Advisory Boards & clinical trials roles 2
Ieq Introduction & Background GLPG1837 Investigational CFTR potentiator molecule Highly efficacious in opening G551D CFTR in in vitro models Generally well tolerated in Phase I clinical studies Evaluated in S1251N CFTR patients, generally well tolerated (SAPHIRA2, De Boeck et al. NACFC 2016) G551D/ F508del HBE Max level VX-770 3
Electrophysiology (TECC) on primary lung cells Swelling of patient-derived intestinal organoids GLPG1837 Pre-clinical data EC 50 = 376 nm 15 Ieq Organoid swelling Chloride current (µa/cm 2 ) 10 5 EC 50 = 373 nm 4 0-8 -6-4 Log [GLPG1837] (M)
SAPHIRA 1 Study Design & Objectives 7 days 7 days 7 days 14 days 4 days Screen on Kalydeco/ naïve Washout 125 mg b.i.d. 250 mg b.i.d. 500 mg b.i.d. Washout Key Eligibility Criteria Adult patient with G551D CFTR Ivacaftor pre-treatment allowed (7 days-washout prior to dosing) Screening ppfev1 40% Study Objectives Primary: safety and tolerability Secondary: Sweat Chloride, pharmacokinetics (PK), Spirometry 5
SAPHIRA 1 Dose Selection vs Efficacy % efficacy vs. kalydeco 200 dose (mg bid) 100 500 250 125 Drug concentration 6
SAPHIRA 1 Countries & Study Conduct Study Initiation: February 23 rd 2016 Study Completion: October 6 th 2016 26 patients enrolled 7
Patient disposition Screened (N=34) Baseline (N=26) Screening failures (N=8) in/exclusion criteria not met pulmonary adverse events Patients decisions D8 (N=26) D15 (N=26) D29 (N=24) Discontinued (N=2) CPK increase patient s decision FU (N=24) 8
Baseline characteristics Baseline Characteristic ITT Population (N=26) Age, years, mean Range 30.3 19-51 Weight, kg, mean 67.6 Male, n (%) 12 (46.2%) [Sw Cl]@Baseline, mmol/l, mean Range Percent predicted FEV1, mean (range) < 40%, n (%) 40% 60%, n (%) 60% 80%, n (%) > 80%, n (%) 97.7 63-116 69.2 (30 104) 2 (8%) 7 (28%) 8 (32%) 8 (32%) F508del CFTR 2nd Allele (%) 18 (69.2%) Ivacaftor use, n (%) Mean duration, weeks (range) 25 (96.2%) 169.9 (44 337) 9
Safety and Tolerability Adverse Events reported by 5% of patients MedDRA preferred Term N (%) GLPG1837 125 mg b.i.d. (7 days) GLPG1837 250 mg b.i.d. (7 days) GLPG1837 500 mg b.i.d. (14 days) Any Adverse Event 14 (53.8%) 14 (53.8%) 20 (76.9% ) Headache 4 (15.4%) 6 (23.1%) 6 (23.1%) Sputum Increased 6 (23.1%) - - Cough 2 (7.7%) 1 (3.8%) 2 (7.7%) Haemoptysis 2 (7.7%) - - Chest Discomfort 2 (7.7%) 1 (3.8%) 2 (7.7%) Fatigue 4 (15.4%) 5 (19.2%) - Chest Pain - - 2 (7.7%) Nausea 1 (3.8%) 1 (3.8%) 2 (7.7%) Abdominal Pain Upper 2 (7.7%) 1 (3.8%) 2 (7.7%) Abdominal Pain - 1 (3.8%) 2 (7.7%) GGT Increase 1 (3.8%) - 2 (7.7%) Adverse Events: predominantly mild or moderate Two Serious Adverse Events in 2 patients: non-cardiac CPK increase (premature withdrawal) - Pulmonary Exacerbation (D28) resulting in hospitalization 10
Safety and Tolerability Lab results (liver biochemical & function test) Liver Parameter Normal Range Baseline Mean (min, max) D8 Mean (min, max) D15 Mean (min, max) D22 Mean (min, max) D29 Mean (min, max) AST 5-34 IU/L 20.8 (12, 36) 19.3 (9, 33) 21.8 (11, 56) 21.2 (12, 32) 21.8 (14, 38) ALT 0-55 IU/L 22.0 (11, 66) 20.7 (9, 42) 23.5 (11, 54) 23.5 (10, 46) 28.2 (12, 73) Alkaline Phosphatase 40-150 IU/L 98.5 (44, 306) 105.7 (45, 214) 112.7 (52, 215) 115.1 (51, 195) 120.7 (59, 245) Bilirubin 0-21 µmol/l 9.6 (3, 19) 4.8 (3, 7) 5.0 (3, 8) 5.8 (4, 8) 5.7 (3, 8) GGT 12-64 IU/L 21.2 (7, 145) 28.1 (10, 122) 41.7 (15, 152) 49.3 (17, 147) 61.7 (18, 240) Increase in GGT without associated changes other liver biochemical and function tests 11
Pharmacokinetics Predose C trough on days 8, 15, 22, 29 10000 Exposure ng/ml 1000 100 target 10 1 8 15 22 29 12 Time (days)
Mean Absolute Sweat Chloride Change ITT Population (overall) Sweat chloride mmol/l 120 125 mg 250 mg 500 mg 100 80 60 97.7 *** *** 66.2 *** 68.3 *** ***: p-value <0.001 40 1 8 15 22 29 0 1 2 3 4 5 6 Time (days) 13
Sweat Chloride mmol/l Sweat Chloride Change vs Exposure 120 125 mg 250 mg 500 mg Exposure ng/ml 350 300 100 *** *** ***: p-value <0.001 250 200 80 60 target *** *** 150 100 50 40 0 1 2 3 4 5 6 Time (days) 1 8 15 22 29 0 14
Sweat Chloride Change vs Exposure Post-hoc exploratory sub-group Analysis Sweat Chloride mmol/l 120 Washout Kalydeco Exposure above target (N=15) Exposure below target (N=6) 100 94 100 98.6 80 80 60 54 51 40-7 1 15
Mean Absolute Change ppfev1 Sub-group Analysis: Ivacaftor Pre-treated 73.3% 73.1% 69.2% 16
SAPHIRA 1 Summary & Conclusions GLPG1837 appears generally well tolerated over dose range tested Most common adverse events were headache and respiratory related Isolated GGT elevations observed Significant reductions in sweat chloride observed Larger reductions in sub-group exceeding predicted target plasma concentration Effect similar to Kalydeco on G551D Full recovery of ppfev1 decline resulting from Kalydeco washout Predictive value of current in vitro models demonstrated First clinical trial with investigational CFTR potentiator molecule showing promising results in an era of efficacious standard of care 17
Acknowledgements Galapagos team: - Olivier Van de Steen - Katja Conrath - Desirée Kanters - Lisa Allamassey - Charlotte Gesson - Sam Corveleyn - Herman De Kock - Gert De Bekker - Christine Guerin - Florence Namour - Daisy van Veghel - Ellen Voorspoels - Frederic Vanhoutte - Gerben Van t Klooster - Piet Wigerinck Investigators & teams: Davies, Bell, van Koningsbruggen-Rietschel, Drevinek, Greville, Bowler, Mulrennan, Daley, Fischer, Derichs, Schulte-Hubbert, McElvaney, McKone, Greenwood, MacGregor, Horsley Vendors: - Quintiles - SGS - BMS - Icon - BNC group Patients for participating in the trial 18