A Double-blind, Randomized, Intra-subject Placebo-controlled, Multicenter, Multiple Dose Study, Evaluating Safety, Proof of Mechanism, Preliminary Efficacy and Systemic Exposure in Subjects With Confirmed DDEB or RDEB Diagnosis With One or More Pathogenic Mutations in Exon 73 in the COL7A1 Gene

A First in Human, Double-blind, Randomized, Intra-subject Placebo-controlled, Multiple Dose Study of QR-313 Evaluating Safety, Proof of Mechanism, Preliminary Efficacy and Systemic Exposure in Subjects With DDEB or RDEB Due to Mutation(s) in Exon 73 of the COL7A1 Gene

A double-blind, randomized, intra-subject placebo-controlled, multicenter, multiple dose study, evaluating safety, proof of mechanism, preliminary efficacy and systemic exposure in subjects with confirmed DDEB or RDEB diagnosis with one or more pathogenic mutations in exon 73 in the COL7A1 gene.

Study Overview

• Status: Terminated
• Conditions: Epidermolysis Bullosa Dystrophica, Recessive; Epidermolysis Bullosa Dystrophica, Dominant
• Intervention / Treatment: Drug: QR-313; Drug: Placebo

Detailed Description

This clinical trial will evaluate the safety and tolerability, proof of mechanism, systemic exposure and preliminary efficacy following topical application of QR-313 to subjects with confirmed DDEB or RDEB with one or more pathogenic mutations in exon 73 in the COL7A1 gene.

Up to two Target Wound Areas (TWAs) per subject will be selected and randomized. Each TWA will be treated with IMP for 8 weeks, either QR-313 or matching placebo. All subjects will continue to be followed up for 8 weeks post last dose.

Subjects will be monitored through home visits and site visits. An imaging system will be used to assess the target wound at all home and study site visits.

QR-313 is a 21-nucleotide antisense oligonucleotide (AON) designed to hybridize to a specific sequence in the COL7A1 pre-messengerRNA (pre-mRNA).

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker Enfants Malades
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University School of Medicine, LPCH
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • Journey Clinic, Center for Pediatric Blood and Marrow Transplantation
  • Ohio
    • Cincinnati, Ohio, United States, 15005
      • Cincinnati Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, ≥ 4 years of age at Screening with a clinical diagnosis of DDEB or RDEB and at least one pathogenic mutation in exon 73 of the COL7A1 gene.

2. Have at least one TWA, ie, a skin area of 7 x 7 cm that ishows no signs of local infection, and contains a target wound that is either new or shows dynamic wound healing and complies to the following additional criteria:

   1. surface area of the target wound ranging from 5 to 30 cm2, located centrally in the selected 7 x 7 cm TWA.
   2. exposed sub-epidermal tissue to allow absorption of the IMP.
   3. no suspicion of current squamous cell carcinoma (SCC) upon visual inspection.

Exclusion Criteria:

1. Pregnant or breast-feeding female
2. Hemoglobin level at Screening requiring transfusion. The subject may be rescreened when the condition is considered stable.
3. Use of aminoglycosides, by any route of administration, except eye drops, 7 days or 5 half-lives, whichever is longer, prior to Baseline visit.
4. Untreated carcinoma of the TWA or history of carcinoma within 5 years prior to Screening, except adequately treated cutaneous squamous or basal cell carcinoma.
5. Life expectancy less than 6 months, as assessed by the Investigator
6. Current or known history of clinically significant hepatic or renal disease, that in the opinion of the Investigator, could impact subject safety or study participation.
7. Treatment with any systemic immunomodulators, immunosuppressants or cytotoxic chemotherapy within 2 months prior to the Baseline visit.
8. Use of any investigational drug or device within 28 days or 5 half-lives of the Baseline visit, whichever is longer, or plans to participate in another study of a drug or device during the study period. The washout of 5 half-lives does not apply to gene and cell therapy.
9. Known hypersensitivity to oligonucleotide treatment or excipients of the IMP.
10. Bleeding disorder or condition requiring the use of anticoagulants to be confirmed by aPTT by local lab within 48 hours of first treatment.
11. Use of systemic or topical steroids within 1 month prior to the baseline visit (inhaled and ophthalmic drops of corticosteroids or low dose topical solution of budesonide for esophagial strictures may be allowed).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: First TWA (A); In each subject up to two target wound areas (TWA) are randomized, one each to active treatment or placebo. In the first arm; randomization of the first selected TWA to active treatment or placebo	Drug: QR-313; QR-313 will be applied topically once daily for 8 weeks of treatment.; Drug: Placebo; Placebo will be applied topically once daily for 8 weeks of treatment.
Other: Second TWA (B); In each subject, in the second arm; allocation of the second selected target wound area (TWA) to the alternative treatment. Second arm in the same subject as the first arm.	Drug: QR-313; QR-313 will be applied topically once daily for 8 weeks of treatment.; Drug: Placebo; Placebo will be applied topically once daily for 8 weeks of treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment emergent adverse events/serious adverse events	Assessment of treatment emergent adverse events/serious adverse events	through 8 weeks after last dose of IMP (EOS)
To assess the effect of QR-313 on the exclusion (skipping) of exon 73 from COL7A1 mRNA	Absence of exon 73 in COL7A1 mRNA, detected by droplet digital polymerase chain reaction (ddPCR)	after 4 weeks of treatment with IMP

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of wound healing and skin strength measured in surface area (cm2)	Wound size (surface area in cm2)	through 8 weeks after last dose of IMP (EOS)
Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Severity (PSAS)	Wound severity as assessed by Physician Subjective Assessment of Severity (PSAS), a 3-point Likert static scale that classifies a wound in mild, moderate or severe	through 8 weeks after last dose of IMP (EOS)
Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Change (PSAC)	Wound change in severity as assessed by Physician Subjective Assessment of Change (PSAC), a 3-point Likert static scale that classifies a wound as mild, moderate or severe.	through 8 weeks after last dose of IMP (EOS)
Assessment of wound healing and skin strength measuring onset of (re)blistering of a healed wound	Onset of (re)blistering of a healed wound	through 8 weeks after last dose of IMP (EOS)
Assessment of wound healing and skin strength as assessed by Short Wound Specific Questionnaire (SWSQ)	Wound status as assessed by Short Wound Specific Questionnaire (SWSQ) addressing three domains: pruritus, pain, and inflammation. Pruritus and pain are recorded as a Patient Reported Outcome (PRO) measure. Inflammation is reported as an Observer Reported Outcome (ObsRO) measure.	through 8 weeks after last dose of IMP (EOS)
Assessment of systemic exposure after topical administration of QR-313 to the target wound area (TWA)	Serum levels of QR-313	Day 1 and after 4 and 8 weeks of treatment and EOS
Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils	Presence of collagen type VII protein expression (IIF microscopy)	after 8 weeks of treatment
Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils	Presence of anchoring fibrils (TEM)	after 8 weeks of treatment

Collaborators and Investigators

• Sponsor: Phoenicis Therapeutics
• Investigators: Study Director: Clinical Operations, Phoenicis Therapeutics

Publications and helpful links

General Publications

• Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.

Helpful Links

• company website

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2018
• Primary Completion (Actual): December 17, 2018
• Study Completion (Actual): December 17, 2018

Study Registration Dates

• First Submitted: June 25, 2018
• First Submitted That Met QC Criteria: July 20, 2018
• First Posted (Actual): July 30, 2018

Study Record Updates

• Last Update Posted (Actual): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 19, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Antisense oligonucleotide; Topical treatment; RDEB; EB; COL7A1; Exon skipping; DDEB; Dominant Dystrophic Epidermolysis Bullosa; Recessive Dystrophic Epidermolysis Bullosa; RNA Therapies; WINGS; Exon 73; Mutations in exon 73
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Collagen Diseases; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica
• Other Study ID Numbers: PQ-313-002; 2017-004806-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No