Galapagos potentiator and correctors Katja Conrath, PhD Therapeutic Area Head UK CF Conference, September 2016, Nottingham 7 September 2016

CF Program aim Develop a combination therapy CFTR Combination Strategy Potentiator Correctors MSD1 MSD2 R NBD1 NBD2 GLPG1837 Early corrector Or C1 Late corrector Or C2 Two correctors with complementary MoAs

Galapagos potentiator and correctors Pipeline AIM: develop triple combination therapy for treatment of most CF patients Discovery Preclinical Phase 1 Phase 2 Potentiator – GLPG1837 Potentiator – GLPG/ABBV2451 CFTR F508del corrector Early – GLPG/ABBV2222 CFTR F508del corrector Early – GLPG2851 CFTR F508del corrector Late – GLPG2737 CFTR F508del corrector Late – GLPGxxxx

Novel potentiators Activity and Efficacy on F508del and G551D CFTR Identification of GLPG1837 GLPG1837, effects in primary patient cells Series 1 Series 2 GLPG1837 GLPG2451

GLPG1837 Phase 1 results MAD PK Day 14 Ctrough F508del/F508del Ctrough F508del/F508del Time (hours after first dosing) Day 1 Day 7 Day 14 Time after first dosing GLPG1837 was generally safe and well tolerated in healthy volunteers, with single doses up to 2000 mg and 14-day dosing up to 800mg b.i.d.

Organoids - EC50 = 15 nM, similar potency as on F508del CFTR GLPG1837 Phase 2 study Two ongoing studies (Saphira 1 and 2) on G551D and S1251N CF patients, respectively Saphira 1 – G551D Saphira 2 – S1251N Organoids - EC50 = 15 nM, similar potency as on F508del CFTR Efficacy = 100% of VX-770 Primary cells - EC50 = 373 nM Efficacy = 180% of VX-770

Corrector Screening Campaigns Multiple approaches to identify correctors with distinct MoAs Series identified Prioritized based on biological profile Prioritized based on chemical attractiveness 10 HTS 6 series progressed: - Early corrector mechanism series - 5 other corrector mechanism series CSE-HRP EA-MEM

Toolbox of assays CF Primary cells CFTR activity and current complexity Ciliary beating ASL patch clamp Cell lines CFTR activity and current TECC & Ussing chamber Organoids Channel restoration, mutants YHA band B/C NBD AVI-tag Function, trafficking, folding Caveat on G442690 compound evolution Cell Surface expression libraries ---------------------------- individual hits --------------------------------------------- correctors

GLPG2222 – Early corrector Increase F508del Surface expression Diseased cells control Treated with GLPG2222 Translation to primary patient cells (F508del/F508del) GLPG/ABBV2222 GLPG/ABBV2222

GLPG2222 – Early corrector GLPG2222 forms foundation for triple combination DR ‘Late corrector’ on DR GLPG2222 DR GLPG2222 on DR ‘Late corrector’

Late corrector – Series 1 Series progression Cell Surface Expression In combination with Early corrector F508del/ F508del HBE cells TECC data GLPG2737 GLPG2737 700 600 500 400 300 200 100 % of GLPG2222 + GLPG1837 GLPG2222+GLPG1837 % of GLPG2222 correction GLPG2222 + GLPG1837 Normalized AUC to 40 100 400 2000 EC50 (nM)

CFTR modulators Correct as much F508del CFTR as possible Surface expression – AVI-tagged F508del CFTR Getting close to Healthy cell status

CFTR modulators Correct as much F508del CFTR as possible CFTR activity

Organoids Organoids from F508del/F508del patient Untreated Orkambi GLPG Triple combination

Galapagos potentiator and correctors Summary Discovery Preclinical Phase 1 Phase 2 Potentiator – GLPG1837 Potentiator – GLPG/ABBV2451 CFTR F508del corrector Early – GLPG/ABBV2222 CFTR F508del corrector Early – GLPG2851 CFTR F508del corrector Late – GLPG2737 CFTR F508del corrector Late – GLPGxxxx

Acknowledgements AbbVie Galapagos RFUMS Chris Tse Martin Andrews Phil Kym Xueqing Wang Wenqing Gao Gao Yi Yi Yang Yihong Fan Ying Jia Arlene Manelli Ashvani Singh Andy Swensen Tim Vortherms Corina Balut Marlon Cowart Andrew Bogdan Steve Greszler Rob Koenig Bo Liu Eric Voight Clinton Yeung Gary Gintant Patricia Banfor Lee Preusser Rick Nelson Gerry Fox Pedro Quintana Diez David Geller Galapagos Martin Andrews Steven van der Plas Gert De Wilde Mathieu Pizzonero Nicolas Desroy Maarten Gees Anne-Sophie Wesse Ann van de Velde Moussa El-Abdellati Sara Musch Kim Carrein Niels Foolen Gregory Malfait Sebastien Dropsit Sebastien Martina Tom de Munck Caroline Joanesse Christel Menet Oscar Mamolliti Monica Borgonovi Florence Namour Luc Nelles Thierry Christophe Christine Guerin Ellen Voorspoels Herman De Kock Karen van de Wal Florence Namour Frederic Vanhoutte Olivier Van der Steen Didier Schils Emanuelle Wakselman Alain Monjardet Romain Gosmini Xavier Bock Dubravko Jelic Line Oste Pierre Deprez Jan van der Schueren Reginald Brys Piet Wigerinck Jack Chen John Fitzgerald Gayle O’Brien Jason Powell Jun Chen Murali Gopalakrishnan Rita Jain Jim Sullivan RFUMS Bob Bridges KUL Kris De Boeck Anabela Ramalho-Venancio UMC Utrecht Jeffrey Beekman University Utrecht Ineke Braakman Bertrand Kleizen Floor Peters