Proof of Concept Study to Demonstrate the Effects of QR-010 on Nasal Potential Difference in Subjects With Cystic Fibrosis with the F508del CFTR Mutation Noreen R Henig, MD Chief Development Officer ProQR Therapeutics JP Clancy, MD Professor of Pediatrics Research Director Pulmonary Medicine Cincinnati Children s Hospital North American Cystic Fibrosis Conference 27 October 2016
JP Clancy Disclosures Clinical trial contracts Vertex Nivalis Bayer Parion Gilead CFFT ProQR Educational presentations Vertex Genentech Nivalis Medscape Consulting Vertex Spyryx Nivalis AIT Insmed ProQR Grant funding, grant reviews NIH CFFT CFF Canadian CFF Gilead ProQR Therapeutics NACFC 2016 2
QR-010 for F508del cystic fibrosis RNA DNA CFTR QR-010 Single stranded 33-mer RNA oligonucleotide Chemically modified for stability and uptake Designed to target F508del mutation c Formulated in saline solution Inhaled delivery for efficient lung delivery and systemic uptake Phase 1b Safety and Tolerability study in homozygous F508del Proof-of-concept NPD study ProQR Therapeutics NACFC 2016 3
Nasal Potential Difference is direct measurement of CFTR function Sodium Chloride ENaC Protein CFTR Protein NPD is the only direct in vivo measurement capable of separating sodium and chloride transport Down regulator NPD has been used as an important endpoint in clinical trials evaluating therapeutic agents ProQR Therapeutics NACFC 2016 4
Study Design Open-label NPD study in F508del CF subjects Screening NPD Baseline NPD & Nasal Sample Day 15 NPD Day 26 (EOT) NPD & Nasal Sample End of Study NPD 14 Day SCREENING 28 Day TREATMENT PERIOD 21 Day FOLLOW-UP = Dose Administered 8 homozygous and 8 compound heterozygous (allcomers) subjects >18 years old Multiple dose design: 12 doses (3 per week x 4 weeks) Intranasal administration Endpoints: CFTR-mediated total chloride transport (primary) Other NPD parameters Safety, SNOT-22 and NERS assessments Sweat test 5 expert participating sites in EU (CTN) and US (TDN) ProQR Therapeutics NACFC 2016 5
Subject Eligibility Inclusion Criteria Nasal potential difference (NPD) measurement at screening consistent with CF (> - 6.6 mv) Confirmed diagnosis of CF (sweat chloride > 60 mmol/l) Confirmation of CFTR gene F508del mutations (homozygous or compound heterozygous) Stable lung function Exclusion Criteria Use of lumacaftor and/or ivacaftor Acute allergy or infection affecting nasal conditions not resolved within 14 days prior screening Use of any investigational drug or device Hemoptysis Breast-feeding or pregnant ppfev 1 40% Body mass index 18 kg/m 2 ProQR Therapeutics NACFC 2016 6
Study Conduct 10 subjects F508del/F508del were enrolled in cohort 1 There were no discontinuations All subjects received all 12 doses 8 subjects were enrolled in the F508del heterozygous cohort 2 There were no discontinuations 7 subjects received all 12 doses; 1 subject missed 1 dose due to AE (malaise) NPD tests Standardized SOP with centralized solutions have been used All tracings have been read and scored by a blinded central reader Data was analysed including subjects meeting NPD parameters at baseline within the range as defined by the TDN-CCD of >-6.6 mv ProQR Therapeutics NACFC 2016 7
Subject Demographics Characteristic F508del / F508del Mean ± SD (N=10) F508del Heterozygous Mean ± SD (N=8) Age, years 25.8 ± 6.7 36.0 ± 15.8 Sex, n (%) Male Female 6 (60%) 4 (40%) 4 (50.0%) 4 (50.0%) Race, n (%) Caucasian 10 (100%) 8 (100.0%) BMI (kg/m 2 ) 22.8 ± 2.8 23.1 ± 3.3 Predicted FEV1 (%) 74.2 ± 17.4 74.9 ± 16.9 Sweat Chloride (mmol/l) 98.7 ± 15.0 103.9 ± 18.0 Baseline Cl-Free+Iso (mv) -1.2 ± 5.8-2.4 ± 5.9 Baseline SNOT-22 Total Score 14.9 ± 5.9 19.1 ± 17.7 ProQR Therapeutics NACFC 2016 8
Preliminary Safety & Tolerability Data Pooled cohort data (N=18) No SAE reported AEs reported included nausea, fatigue, headache and cough No change in SNOT-22 and NERS QR-010 was safe and well tolerated during the study ProQR Therapeutics NACFC 2016 9
PQ-010-002 Top-Line NPD Results ProQR Therapeutics NACFC 2016 10
CFTR-Mediated Total Chloride Transport Change from baseline in F508del/F508del Subjects N = 7 p = one-sided 5% paired t-test NPD = change in ZeroCl+Iso ProQR Therapeutics NACFC 2016 11
CFTR Mediated Sodium Down-Regulation Change in Max Basal PD Parameter in F508del/F508del Subjects N = 7 Baseline defined by average of both nostrils ProQR Therapeutics NACFC 2016 12
CFTR-Mediated Total Chloride and Down-Regulated Sodium Transport Comparison of analysis methods in F508del/F508del Subjects N = 7 Baseline defined by average of both nostrils ProQR Therapeutics NACFC 2016 13
CFTR-Mediated Total Chloride Transport Change from Baseline in F508del Heterozygous Subjects Functional Class I II V Mutation Q493X 621+1 G>A Y1092X 1717-1 G>A N1303K I336K 2789+5 G>A N = 7 p = one-sided 5% paired t-test NPD = change in ZeroCl+Iso ProQR Therapeutics NACFC 2016 14
QR-010 Improves CFTR Function Proof-of-concept has been established for QR-010 QR-010 significantly improved CFTR function in F508del/F508del subjects Supported by NPD sensitivity analyses Positive change in sodium transport (maximum basal PD) QR-010 did not improve CFTR function in F508del heterozygous subjects Further data analysis ongoing Preclinical work being considered to better understand the impact of the second allele NPD effect size comparable to other CF approved therapies Study results presented in poster #764 ProQR Therapeutics NACFC 2016 15
Acknowledgments Isabelle Sermet-Gaudelus, MD, PhD JP Clancy, MD Christiane de Boeck, MD, PhD The QR-010 project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement No 633545 David Nichols, MD Jerry Nick, MD Stuart Elborn, Marcus Mall and Jim Bolognese for ADRC guidance George Solomon, MD Steve Rowe and Bo Liu for NPD central reading ProQR Therapeutics NACFC 2016 16