1. © Copyright 2015 Galapagos NV Safety, tolerability and pharmacokinetics of a novel CFTR potentiator GLPG1837 in healthy volunteers F.P. Vanhoutte 1, M-H. Gouy 2, F. Namour 2, W. Haazen 3, D. Kanters 1, G. De Beckker 1, K. Van de Wal 1, D. E. Geller 4 1 Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium 2 Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France 3 SGS-Clinical Pharmacology Unit, Lange Beeldekensstraat 267, 2060 Antwerp, Belgium 4 AbbVie, North Waukegan Road, North Chicago, IL 60064, US Introduction The restoration of CFTR channel activity with modulators targets the cause of CF disease. Galapagos has previously shown (NACFC 2013, ECFS 2014) the identification and development of a novel potentiator series with superior channel opening activity. The series was shown to have good metabolic stability and tissue permeability, supporting favorable pharmacokinetic characteristics in animals. From this series, GLPG1837 was selected to progress into formal pre-clinical and clinical studies as the first component of a CFTR-modulator combination. GLPG1837 has shown potent activity in cellular assays to improve the function of defective gating channels caused by specific CFTR mutations, with higher efficacy than ivacaftor. GLPG1837 can potentiate corrector-rescued Class II and Class III/IV CFTR defective channels. We speculate that this in vitro property will translate into an improved clinical benefit in CF patients. Following successful completion of formal preclinical safety evaluations, GLPG1837 was progressed to Phase 1 clinical evaluations in healthy volunteers. We here present results from these first clinical data. Methods Randomized, double-blind, placebo-controlled study over a range of single and multiple doses of GLPG1837 in healthy, adult subjects In the single ascending dose (SAD) part of the study, 2 alternating cohorts of subjects were exposed to single oral doses of 30 to 2000 mg in fasted conditions and to a single dose of 500mg after a high-fat high-calorie breakfast In the multiple ascending dose (MAD) part of the study, GLPG1837 was given orally at doses of 125 to 800 mg b.i.d. for a period of 14 days At every dose level 6 subjects were exposed to GLPG1837 and 2 to placebo Objectives Evaluate the safety and tolerability of single ascending doses (SAD), multiple ascending doses (MAD) of GLPG1837 compared to placebo. Determine the PK profile of GLPG1837 after single and twice daily dosing in healthy subjects; evaluate the impact of food on the bioavailability of GLPG1837 Conclusions Potentiator GLPG1837 was generally safe and well tolerated in healthy volunteers, with s ingle doses up to 2000 mg and 14-day dosing up to 800mg b.i.d. Final safety data analysis is pending, however preliminary data shows no SAE reported or concerning AEs GLPG1837 showed the following PK characteristics: Rapid absorption, and mean terminal half-life of 6-15 h after single doses. The exposure of GLPG1837 was approximately dose proportional at steady state Improved bioavailability with food Steady state was attained within 2 days of dosing, with no accumulation The metabolite also had high exposure (data not shown) These results support progression of GLPG1837 into a Phase 2 study in CF patients Poster available online at: www.glpg.com NACFC 2015 Poster #258 Figure 1: Mean (±SE) GLPG1837 plasma concentrations after single oral dose as oral nanosuspension in fasted state; linear (top) and semi-logarithmic (bottom) plots. Single Ascending Dose Multiple Ascending Dose Figure 3: Mean (±SE) GLPG1837 plasma concentrations after multiple doses as oral nanosuspension Figure 4: dose normalised C max and AUC demonstrate steady state pharmacokinetics to be approximately dose proportional Improvement of exposure with food Figure 2: Mean (±SE) plasma concentrations after a 500 mg single dose as oral nanosuspension in fasted and fed state; linear (top) and semi- logarithmic (bottom) plots Preliminary Safety Results: GLPG1837 up to a single dose of 2000 mg and up to 800 mg b.i.d. for 14 days was generally safe and well tolerated. The assessment of blinded, unaudited safety data showed no SAEs or clinically relevant AEs, VS, ECG or lab changes. Number of subjects presenting with the event Dose group mg [Active or Pbo] 3090250500100015002000500 fastedfed Blurred vision1 Tooth ache 1 Headache 1111111 Common cold 1 Sore throat 1 Dizziness (orthostatic) 1 Vomiting 11 Diarrhea 1 Events with 2 or more occurrences of the event (# subjects) Dose group mg (b.i.d.) [Active or Pbo] 125250500800 Tiredness3 6 Headache4253 Nose congestion111 Nausea22 1 Dizziness1 3 Back pain1 11 Pharmacokinetic results Table 1: TEAE after single dose administrations Table 2: TEAE after multiple dose administrations for 14 days *AE results not yet MedDRA coded