the Effects of QR-010 on Nasal Potential Difference in Subjects With - - PowerPoint PPT Presentation

▶
the effects of qr 010 on nasal potential
SMART_READER_LITE
LIVE PREVIEW

the Effects of QR-010 on Nasal Potential Difference in Subjects With - - PowerPoint PPT Presentation

Nov 06, 2022 392 likes •556 views

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

slide-1
SLIDE 1

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

JP Clancy, MD Professor of Pediatrics Research Director Pulmonary Medicine Cincinnati Children’s Hospital Noreen R Henig, MD Chief Development Officer ProQR Therapeutics

North American Cystic Fibrosis Conference 27 October 2016

slide-2
SLIDE 2

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

slide-3
SLIDE 3

c

QR-010 for F508del cystic fibrosis

ProQR Therapeutics | NACFC 2016 3

RNA DNA

QR-010

  • Single stranded 33-mer RNA
  • ligonucleotide
  • Chemically modified for stability

and uptake

  • Designed to target F508del

mutation

  • 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

CFTR

slide-4
SLIDE 4

Nasal Potential Difference is direct measurement of CFTR function

  • NPD is the only direct in

vivo measurement capable of separating sodium and chloride transport

  • NPD has been used as

an important endpoint in clinical trials evaluating therapeutic agents

Sodium Chloride ENaC Protein CFTR Protein

Down regulator

ProQR Therapeutics | NACFC 2016 4

slide-5
SLIDE 5

Study Design

ProQR Therapeutics | NACFC 2016 5

Open-label NPD study in F508del CF subjects

  • 8 homozygous and 8 compound heterozygous (all-

comers) subjects >18 years old

  • Multiple dose design: 12 doses (3 per week x 4

weeks)

  • Intranasal administration
  • 5 expert participating sites in EU (CTN) and US (TDN)
  • Endpoints:
  • CFTR-mediated total chloride transport (primary)
  • Other NPD parameters
  • Safety, SNOT-22 and NERS assessments
  • Sweat test

14 Day SCREENING 28 Day TREATMENT PERIOD 21 Day FOLLOW-UP Screening NPD Baseline NPD & Nasal Sample Day 15 NPD Day 26 (EOT) NPD & Nasal Sample End of Study NPD

= Dose Administered

slide-6
SLIDE 6

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
  • ppFEV1 ≥40%
  • Body mass index ≥ 18 kg/m2

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

ProQR Therapeutics | NACFC 2016 6

slide-7
SLIDE 7

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

slide-8
SLIDE 8

Subject Demographics

ProQR Therapeutics | NACFC 2016 8

Characteristic F508del / F508del F508del Heterozygous

Mean ± SD (N=10) 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/m2) 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

slide-9
SLIDE 9

Preliminary Safety & Tolerability Data

  • 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

Pooled cohort data (N=18)

slide-10
SLIDE 10

PQ-010-002 Top-Line NPD Results

ProQR Therapeutics | NACFC 2016 10

slide-11
SLIDE 11

CFTR-Mediated Total Chloride Transport

ProQR Therapeutics | NACFC 2016 11

Change from baseline in F508del/F508del Subjects

N = 7 p = one-sided 5% paired t-test NPD = change in ZeroCl+Iso

slide-12
SLIDE 12

CFTR Mediated Sodium Down-Regulation

ProQR Therapeutics | NACFC 2016 12

Change in Max Basal PD Parameter in F508del/F508del Subjects

N = 7 Baseline defined by average of both nostrils

slide-13
SLIDE 13

CFTR-Mediated Total Chloride and Down-Regulated Sodium Transport Comparison of analysis methods in F508del/F508del Subjects

ProQR Therapeutics | NACFC 2016 13

N = 7 Baseline defined by average of both nostrils

slide-14
SLIDE 14

CFTR-Mediated Total Chloride Transport

ProQR Therapeutics | NACFC 2016 14

Change from Baseline in F508del Heterozygous Subjects

N = 7 p = one-sided 5% paired t-test NPD = change in ZeroCl+Iso

Functional Class Mutation I Q493X 621+1 G>A Y1092X 1717-1 G>A II N1303K I336K V 2789+5 G>A

slide-15
SLIDE 15

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

ProQR Therapeutics | NACFC 2016 15

Study results presented in poster #764

slide-16
SLIDE 16

Acknowledgments

Stuart Elborn, Marcus Mall and Jim Bolognese for ADRC guidance Steve Rowe and Bo Liu for NPD central reading

ProQR Therapeutics | NACFC 2016 16 The QR-010 project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633545

Isabelle Sermet-Gaudelus, MD, PhD Christiane de Boeck, MD, PhD JP Clancy, MD David Nichols, MD Jerry Nick, MD George Solomon, MD