Proqr Therapeutics N.v. · NASDAQ:PRQR
Proqr Therapeutics — ProQR Analyst & Investor Event, NACFC 2016
48 slides from Proqr Therapeutics's conference presentation, Oct 28, 2016
Slide 1: ProQR Analyst & Investor Event NACFC 2016
ProQR® ANALYST & INVESTOR EVENT NACFC 2016, Orlando, Florida Date: Presenters: October 27th, 2016 Daniel de Boer, Noreen Henig and JP Clancy
Slide 2: Agenda
Agenda Overview and introduction by Daniel de Boer The relevance of the Nasal Potential Difference test in CF by JP Clancy, M.D. Results of the QR-010 NPD study by Noreen Henig, M.D. Pipeline and path ahead by Daniel de Boer Q&A session with JP Clancy, M.D., Noreen Henig, M.D., Smital Shah and Danie
Slide 3: Forward looking statements
Forward looking statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including but not limited to, statements regarding our strategy, future operat
Slide 4: ProQR's CF journey
ProQR’s CF journey From an idea to clinical proof of concept in 4 years Leiden, The Netherlands & Palo Alto, CA 2012 2013 2014 2015 2016 Founding of ProQR around an idea to impact CF using RNA repair Saliva secretion assay in homozygous D F508 mouse model showed near wild type functional restoration
Slide 5: CFTR is hydrating mucus in normal lung cell
CFTR is hydrating mucus in normal lung cell CFTR Chloride RNA DNA CFTR in normal lung cell: • In healthy people CFTR protein is formed • CFTR protein acts as a chloride channel • Due to chloride transport the extracellular mucus is hydrated ProQR Therapeutics 5
Slide 6: Absence of CFTR is leading to dehydration of mucus
Absence of CFTR is leading to dehydration of mucus CFTR Chloride RNA DNA CFTR in CF lung cell: • In CF patients no functional CFTR protein is formed • In absence of CFTR chloride can not flow out of the cell • Due to the lack of chloride transport the extracellular mucus dehydrates ProQR Therapeutic
Slide 7: CFTR and ENaC channels in normal lung cell
CFTR and ENaC channels in normal lung cell ENaC CFTR Down regulator Sodium Chloride In healthy people: • CFTR and ENaC cooperate to regulate Chloride and Sodium balance • CFTR is a down regulator of ENaC channel activity ProQR Therapeutics 7
Slide 8: CFTR and ENaC channels in CF lung cell
CFTR and ENaC channels in CF lung cell ENaC CFTR Down regulator Sodium Chloride In CF patients: • In absence of CFTR protein ENaC is unregulated and thus hyperactive • This contributes to the CF phenotype ProQR Therapeutics 8
Slide 9: Confirmation: Downregulation of ENaC
ENaC CFTR Down regulator Confirmation: Downregulation of ENaC (Max Basal PD) CFTR mediated total chloride transport (mv) normalized at 0 Cl timepoint 20 10 0 -10 -20 -30 -40 ringer’s amiloride zero chloride isoproterenol units = time in minutes CF patient WT NPD is the only direct in vivo measuremen
Slide 10: CFTR restoration confirmed by ENaC normalization
CFTR restoration confirmed by ENaC normalization Basal PD (ENaC) Change from baseline 9.2mV P=0.0371 CFTR activity is confirmed by normalization of ENaC activity Total Chloride Transport (CFTR) change from baseline -4.1mV P=0.0389 CFTR mediated total chloride transport (mv) normalized at 0 Cl timepo
Slide 11: Putting QR-010 NPD results in perspective
Putting QR-010 NPD results in perspective Total Chloride Transport Non-Cystic -6.6 mV Fibrosis NPD TDN Center of CFTR detection -4.1 mV Homozygous 50% F508 + QR-010 Sermet-Gaudelus et al, of CF patients NACFC, 2016 -3.5 mV G551 D 5% + Kalydeco (150 mg) Accurso et al NEJM, 2010 of CF patients CF pati
Slide 12: The relevance of the Nasal Potential Difference test in CF
The relevance of the Nasal Potential Difference test in CF By JP Clancy, MD Professor of Pediatrics, Research Director Pulmonary Medicine Cincinnati Children’s Hospital ProQR Therapeutics 12
Slide 13: NPD is the only direct measurement of CFTR function
NPD is the only direct measurement of CFTR function NPD is only direct measurement of both sodium and chloride channel function CFTR downregulation of ENaC is well understood A response on both chloride transport and change in basal PD provides validation of a functioning CFTR Nasal epithelium well
Slide 14: NPD methods and interpretation is standardized
NPD methods and interpretation is standardized NIH-PA Author Manuscript NIH- NATIONAL INSTITUTES OF HEALTH NIH Public Access Author Manuscript Methods Mol Biol. Author manuscript; available in PMC 2013 September 03. Published in final edited form as: Methods Mol Biol. 2011 ; 741: 69-86. doi:10.1007/
Slide 15: Relevance of NPD for the lower airway
Relevance of NPD for the lower airway Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials Steven M. Rowe1,2,3,4, Frank Accurso5, and John P. Clancy3,4 1Department of Medicine, 2Department of Physiology and Biophysics, 3Department of Pediatrics, an
Slide 16: Good correlation between bronchial and nasal current
CFTR-dependent ISC Bronchial Current (A/cm2 ) 4 0 3 0 2 0 1 0 0 -1 0 p < 0 .0 0 5 R2: 0 . 6 4 2 5 1 0 1 5 2 0 Nasal Current (A/cm2 ) Good correlation between bronchial current and Nasal current 155 CHARACTERIZATION OF BRUSHED HUMAN UPPER AND LOWER AECS TO DETECT AND QUANTIFY CFTR FUNCTION Filbrandt,
Slide 17: Results QR-010 Nasal Potential Difference study
Results QR-010 Nasal Potential Difference study By Noreen R. Henig, MD ProQR Therapeutics 17
Slide 18: QR-010 for F508 cystic fibrosis
QR-010 for F508 cystic fibrosis CFTR QR-010 Single stranded 33-mer RNA oligonucleotide P=S and 2’Ome chemically modified for stability and uptake Designed to target F508 mutation Formulated in saline solution Inhaled delivery for efficient lung delivery and systemic uptake Delivered by PARI eflow Ne
Slide 19: Pre-clinical data supports QR-010 can restore CFTR function
Pre-clinical data supports QR-010 can restore CFTR function GLP Tox 28 days in mice No DLT up to high dose (30mg/kg) for 28 days in monkeys Inhaled Administration to the Lung In vitro CF mucus penetration Similar biodistribution between wild-type and mice with CF lung phenotype Functional Restoratio
Slide 20: QR-010 PQ-010-002 Proof of Concept study
QR-010 PQ-010-002 Proof of Concept study 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 Design 8 F508 homozygous and 8 compound heterozygous patients F508 CF patients
Slide 21: NPD centers of excellence
NPD centers of excellence Steve Rowe, MD – Central, blinded reader Stuart Elborn, MD – Chairman, Adaptive Design Review Committee Marcus Mall, MD – ADRC member Marty Solomon, MD – University of Alabama David Nichols, MD and Jerry Nick, MD – National Jewish Medical & Research Center JP Clancy, MD – U
Slide 22: NPD: Maximize potential as a useful endpoint
NPD: Maximize potential as a useful endpoint Design Controls Inclusion criteria Well-defined analysis and methods Endpoints (chloride response and confirmatory basal PD) Execution Centers of excellence Standardized methods (SOP) Central supplies Minimizing operator variability Independent analysis B
Slide 23: Demographics
Demographics Homozygous Heterozygous Cohort Cohort (Cohort 1) (Cohort 2) Characteristic Safety Population Safety Population (N=10) (N=8) Age (years) Mean (SD) 25.80(6.7) 36.0(15.8) Min, Max 19, 36 18, 63 Sex, n (%) Male 6(60%) 4(50.0%) Female 4(40%) 4(50.0%) Race, n (%) Caucasian 10(100%) 8(100.0%)
Slide 24: Preliminary safety & tolerability data
Preliminary safety & tolerability data Pooled Cohorts Treatment-Emergent Adverse Events Occurring in >10% Subjects by Preferred Term Safety Population (Pooled Cohorts); N=18 N (%) Subjects with Serious Adverse Events 0(0) Subjects with at least one TEAE 15(83.3) Gastrointestinal disorders Nausea 3(1
Slide 25: QR-010 meets primary endpoint in homozygous patients
QR-010 meets primary endpoint in homozygous patients Measured by CFTR mediated total chloride transport Change from Baseline CFTR-Mediated Total Chloride Transport (mV) Mean +/- SEM Treatment Follow-up Chloride transport improvement -3.0 mV p=0.0797 -4.1 mV p=0.0389 -3.7 mV p=0.0721 2 0 -2 -4 -6 -8
Slide 26: All methods show CFTR response in homozygous patients
All methods show CFTR response in homozygous patients Different methods to determines CFTR response evaluable population (N=7) Change from Baseline CFTR-Mediated Total Chloride Transport (mV) Mean +/- SEM -10 -8 -6 -4 -2 0 2 Treatment Follow-up A L R MP LP A L R MP LP A L R MP LP Day 15 Day 26(EoT)
Slide 27: Basal PD change confirms CFTR activity
Basal PD change confirms CFTR activity Sodium transport measured by Basal PD Max Basal PD (mv) Change from Baseline Mean +/- SEM 15 10 5 0 -5 Treatment Follow-up Sodium transport improvement = -2.9 mV p=0.8615 = +9.2 mV p=0.0371 = +2.2mv p =0.2214 Baseline Day 15 Day 26 (EoT) Day 47 Average Nostrils
Slide 28: All methods show Basal PD response
All methods show Basal PD response Different methods to determines Basal PD response evaluable population (N=7) Change from Baseline Max Basal PD (mv) Mean +/- SEM Treatment Follow-up A L R MP LP A L R MP LP A L R MP LP 20 15 10 5 0 -5 -10 Day 15 Day 26 (EoT) Day 47 Key takeaways: Irrespective of th
Slide 29: Heterozygous CFTR response
Heterozygous CFTR response Change from Baseline CFTR-Mediated Total Chloride Transport (mv) Mean +/- SEM 8 6 4 0 2 0 -2 Treatment Follow-up Chloride transport improvement =2.4mv p=NS =2.2mV p=NS =3.0mv p=NS Baseline Day 15 Day 26 (EoT) Day 47 Functional Class Subject numbers Mutation Legacy Nomencla
Slide 30: PQ-010-002: NPD proof of concept study Conclusions
PQ-010-002: NPD proof of concept study Conclusions QR-010 improves CFTR function in subjects with CF due to r F508 mutation Timepoint CFTR –mediated Total Chloride Response [Mean ± SEM, mV] p-value Day 15 - 3.0 ± 1.9 0.0797 Day 26 (EOT) - 4.1 ± 1.9 0.0389 Day 47 - 3.7 ± 2.2 0.0721 A trend for durabi
Slide 31: Putting QR-010 NPD results in perspective
Putting QR-010 NPD results in perspective Total Chloride Transport Non-Cystic Fibrosis NPD TDN Center of CFTR detection -6.6 mV -4.1 mV Homozygous r F508 + QR-010 Sermet-Gaudelus et al, NACFC, 2016 50% of CF patients -3.5 mV G551D + Kalydeco (150 mg) Accurso et al NEJM, 2010 5% of CF patients -2 mV
Slide 32: Putting QR-010 NPD results in perspective: key takeaways
Putting QR-010 NPD results in perspective Key takeaways: QR-010 improves CFTR function in r F508 homozygous patients Improved total chloride response which shows direct activity Improved max basal PD which shows down-regulation of sodium channels Single agent, innovative approach for r F508 patients
Slide 33: Translating NPD to the lung
Translating NPD to the lung Stability QR-010 is stable in presence of CF lung bacteria Brinks et al. ECFS, 2016 QR-010 is stable in CF mucus and doesn’t degrade Brinks et al. NACFC, 2015 QR-010 is stable in presence of inhaled CF co-medications Brinks et al. NACFC, 2015 Uptake Beta-ENaC mouse with C
Slide 34: Phase 1b update
Phase 1b update Single Ascending Dose 1 dose Cohort 1 6.25 mg DMC review Cohort 2 12.5 mg DMC review Cohort 3 25 mg DMC review Cohort 4 50 mg DMC review 8 patients per cohort, randomized 3:1, double blinded, placebo controlled Multiple Ascending Dose 3 dosings/week x 4 weeks Cohort 5 6.25 mg DMC rev
Slide 35: Treatment-emergent adverse events - SAD
Treatment-emergent adverse events - SAD 6.25 mg N = 8 12.5 mg N = 8 25 mg N = 12 50 mg N = 8 SAD Total N = 36 Subjects with at least one TEAE 4 (50.0) 3 (37.5) 7 (58.3) 5 (62.5) 19 (52.8) Gastrointestinal disorders 2 (50.0) 0 1 (8.3) 3 (37.5) 6 (16.7) Abdominal Pain 0 0 0 1 (12.5) 1 (2.8) Abdominal
Slide 36: Treatment-emergent adverse events - SAD
Treatment-emergent adverse events - SAD 6.25 mg N = 8 12.5 mg N = 8 25 mg N = 12 50 mg N = 8 SAD Total N = 36 Nervous system disorders 3 (37.5) 1 (12.5) 2 (16.7) 2 (25.0) 8 (22.2) Dizziness 0 0 0 2 (25.0) 2 (5.6) Headache 2 (25.0) 1 (12.5) 1 (8.3) 1 (12.5) 6 (16.7) 1 (8.3) Sinus Headache 1 (12.5) 0
Slide 37: Phase 1b update: QR-010 observed to be safe and well tolerated
Phase 1b update QR-010 in doses tested to date is observed to be safe and well tolerated 4 Single dose cohorts completed 8 patients per cohort, randomized 3:1 6.25, 12.5, 25 and 50 mg by inhalation All cohorts reviewed by independent DSMC No SAEs reported No dose limiting toxicity identified Multipl
Slide 38: QR-010 pre-clinical results translated to patients
QR-010 pre-clinical results translated to patients r F508 homozygous Mouse Nasal Potential difference (mV) 10 0 -10 -20 -30 0 5 10 amiloride zero chloride isoproterenol Time (min) Nasal Potential difference (mV) 20 10 0 -10 -20 -30 -40 units = time in minutes ringer’s amiloride zero chloride isoprot
Slide 39: ProQR Pipeline Update
ProQR Pipeline Update By Daniel de Boer ProQR Therapeutics 39
Slide 40: Innovation: in-house discovery engine
Innovation In-house discovery engine RNA based RNA modulation to restore wild-type functionality Well understood causality Genetic defect leading to disease manifestation well understood Product focused High unmet needs Intellectual property Agressive patenting strategy Broad IP portfolio Feasible d
Slide 41: Research and development pipeline
Research and development pipeline QR-313 Dystrophic EB ~2,000 patients QRX-704 QRX-021 QRX-411 Huntington’s Undisclosed Usher syndrome disease CF target QR-110 QR-010 QRX-504 QRX-604 QRX-323 Fuchs (FECD) Friedreich’s Dystrophic EB LCA10 cystic fibrosis ataxia 2,000 patients >49,000 patients Innovati
Slide 42: QR-110 for LCA10
QR-110 for LCA10 mRNA profile mRNA profile restored to wild-type Restoration CEP290 protein levels Significant increase in CEP290 protein levels Local (intravitreal) Eye well validated target for oligo’s Efficient delivery to outer nuclear layer in the retina Regulatory Regulatory discussions suppor
Slide 43: QR-110 for LCA10 PQ-110-001 Phase 1b clinical study
QR-110 for LCA10 PQ-110-001 Phase 1b clinical study Cohort 1 Low dose Cohort 2 Medium dose Cohort 3 High dose 4 patients per cohort, Open-label Ascending Doses 4 doses (every 3 months) 12 homozygous or compound heterozygous p.Cys998X LCA10 patients Adults and children (>6yrs) intravitreal injections
Slide 44: QR-313 for DEB
QR-313 for DEB mRNA profile restoration mRNA profile restored to produce active protein Restoration C7 protein functionality Functional protein restored forming anchoring fibrils Local delivery to the skin Oligo in hydrogel for application to wounds Delivery to C7 producing fibroblasts and keratinoc
Slide 45: Research and development pipeline
Research and development pipeline QR-313 Dystrophic EB ~2,000 patients QRX-704 QRX-021 QRX-411 Huntington’s Undisclosed Usher syndrome disease CF target QR-110 QR-010 QRX-504 QRX-604 QRX-323 Fuchs (FECD) Friedreich’s Dystrophic EB LCA10 cystic fibrosis ataxia ~2,000 patients >49,000 patients Innovat
Slide 46: ProQR Therapeutics - What's next?
ProQR Therapeutics - What’s next? Data read-out QR-010 Phase 1b Readout clinical study QR-313 Cash runway until mid-2018 clinical study expected mid 2017 Start clinical study QR-313 Readout QR-110 study QR-010 clinical data during NACF conference • NPD proof of concept study data • Preliminary data
Slide 47: Putting QR-010 NPD results in perspective: key takeaways
Putting QR-010 NPD results in perspective Key takeaways: QR-010 improves CFTR function in F508 homozygous patients Improved total chloride response which shows direct activity Improved max basal PD which shows down-regulation of sodium channels Single agent, innovative approach for F508 patients Val
Slide 48: It's in our RNA
\ IT’S IN ProQR ) ouR RNA
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