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 JP Clancy, MD Chief Development Officer Professor of Pediatrics ProQR Therapeutics Research Director Pulmonary Medicine Cincinnati Children’s Hospital North American Cystic Fibrosis Conference 27 October 2016
JP Clancy Disclosures Clinical trial contracts Consulting Vertex Vertex • • Nivalis Spyryx • • Bayer Nivalis • • Parion AIT • • Gilead Insmed • • CFFT ProQR • • ProQR • Grant funding, grant reviews Educational presentations NIH • Vertex • CFFT • Genentech • CFF • Nivalis • Canadian CFF • Medscape • Gilead • ProQR Therapeutics | NACFC 2016 2
QR-010 for F508del cystic fibrosis QR-010 CFTR • Single stranded 33-mer RNA oligonucleotide • Chemically modified for stability and uptake • Designed to target F508del mutation c RNA • Formulated in saline solution • Inhaled delivery for efficient lung delivery and systemic uptake • Phase 1b Safety and Tolerability DNA 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 • NPD is the only direct in ENaC CFTR vivo measurement Protein Protein capable of separating sodium and chloride transport • NPD has been used as Down regulator 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 Baseline Day 15 Day 26 (EOT) End of Study NPD NPD & Nasal Sample NPD NPD & Nasal Sample NPD 14 Day SCREENING 28 Day TREATMENT PERIOD 21 Day FOLLOW-UP = Dose Administered 8 homozygous and 8 compound heterozygous (all- Endpoints: • • comers) subjects >18 years old CFTR-mediated total chloride transport (primary) • Multiple dose design: 12 doses (3 per week x 4 Other NPD parameters • • weeks) Safety, SNOT-22 and NERS assessments • Intranasal administration Sweat test • • 5 expert participating sites in EU (CTN) and US (TDN) • ProQR Therapeutics | NACFC 2016 5
Subject Eligibility Inclusion Criteria Exclusion Criteria • Nasal potential difference (NPD) • Use of lumacaftor and/or ivacaftor measurement at screening consistent • Acute allergy or infection affecting with CF (> - 6.6 mv) nasal conditions not resolved within 14 • Confirmed diagnosis of CF (sweat days prior screening chloride > 60 mmol/L) • Use of any investigational drug or • Confirmation of CFTR gene F508del device mutations (homozygous or compound • Hemoptysis heterozygous) • Breast-feeding or pregnant • Stable lung function • 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 F508del / F508del F508del Heterozygous Characteristic Mean ± SD Mean ± SD (N=10) (N=8) Age, years 25.8 ± 6.7 36.0 ± 15.8 Sex, n (%) Male 6 (60%) 4 (50.0%) Female 4 (40%) 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 Mutation Class I Q493X 621+1 G>A Y1092X 1717-1 G>A II N1303K I336K V 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 The QR-010 project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633545 Christiane de Boeck, MD, PhD David Nichols, MD Stuart Elborn, Marcus Mall and Jim Bolognese Jerry Nick, MD for ADRC guidance Steve Rowe and Bo Liu for NPD central reading George Solomon, MD ProQR Therapeutics | NACFC 2016 16
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