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

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).

• QR-313 (Drug): QR-313 will be applied topically once daily for 8 weeks of treatment.
• Placebo (Drug): Placebo will be applied topically once daily for 8 weeks of treatment.

Primary outcomes

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

Secondary outcomes

• Assessment of wound healing and skin strength measured in surface area (cm2) [through 8 weeks after last dose of IMP (EOS)]: Wound size (surface area in cm2)
• Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Severity (PSAS) [through 8 weeks after last dose of IMP (EOS)]: 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
• Assessment of wound healing and skin strength as assessed by Physician Subjective Assessment of Change (PSAC) [through 8 weeks after last dose of IMP (EOS)]: 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.
• Assessment of wound healing and skin strength measuring onset of (re)blistering of a healed wound [through 8 weeks after last dose of IMP (EOS)]: Onset of (re)blistering of a healed wound
• Assessment of wound healing and skin strength as assessed by Short Wound Specific Questionnaire (SWSQ) [through 8 weeks after last dose of IMP (EOS)]: 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.
• Assessment of systemic exposure after topical administration of QR-313 to the target wound area (TWA) [Day 1 and after 4 and 8 weeks of treatment and EOS]: Serum levels of QR-313
• Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils [after 8 weeks of treatment]: Presence of collagen type VII protein expression (IIF microscopy)
• Assessment of the effect of QR-313 on the presence of collagen type VII protein and anchoring fibrils [after 8 weeks of treatment]: Presence of anchoring fibrils (TEM)

Sex: All, ages: 4 Years to any

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).

• Results publication: 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. PMID 31215818

• Clinical Operations, Study director, Phoenicis Therapeutics

NIH grants: 2017