Ph 3 Efficacy and Safety of B-VEC for the Treatment of DEB

Thirty-one (31) participants with DEB, aged 6 months or older at time of consent were enrolled for this Phase III study. The trial duration for each subject was about 6 months, with administration occurring once weekly. A Safety Follow-up Visit occurring 30 days from the date of final treatment with the Investigational Product also occurred. Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. In addition to the primary target wound pair(s), additional wounds (secondary wounds) were selected to be treated with B-VEC. Throughout the study, participants complete questionnaires, had images captured of their study wounds, underwent physical exams, had vital signs and safety labs monitored.

• Topical Beremagene Geperpavec (Biological): Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein
• Placebo (Other): Matching masked inactive topical gel

Primary outcomes

• Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26 [26 weeks post-baseline]: The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 22 and Week 24, or * Complete wound healing on Week 24 and Week 26. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).

Secondary outcomes

• Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12 [12 weeks post-baseline]: The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 8 and Week 10, or * Complete wound healing on Week 10 and Week 12. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
• Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. [26 weeks post-baseline]: Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.

Sex: All, ages: 6 Months to any

Inclusion Criteria:

1. The subject or legally appointed and authorized representative must have read, understood and signed an Institutional Review Board/Ethics Committee (IRB/EC) approved Informed Consent or Assent Form and must be able to and willing to follow study procedures and instructions.
2. Age ≥ 6 months and older at the time of Informed Consent.
3. Clinical diagnosis of the Dystrophic Epidermolysis Bullosa.
4. Confirmation of DEB diagnosis (either DDEB or RDEB) by genetic testing including COL7A1.
5. Two (2) cutaneous wounds meeting the following criteria:

   1. Location: similar in size, located in similar anatomical regions, and have similar appearance
   2. Appearance: clean with adequate granulation tissue, excellent vascularization, and do not appear infected.
6. Subjects and caregivers who, in the opinion of the Investigator, are able to understand the study, co-operate with the study procedures and are willing to return to the clinic for all the required follow-up visits.
7. Male or Female of childbearing potential must use a reliable birth control method throughout the duration of the study and for three (3) months post last dose of B-VEC.
8. Negative pregnancy test at Visit 1 (Week 1), if applicable.

Exclusion Criteria:

1. Medical instability limiting ability to travel to the Investigative Center.
2. Diseases or conditions that could interfere with the assessment of safety and efficacy of the study treatment and compliance of the subject with study visits/procedures, as determined by the Investigator.
3. Current evidence or a history of squamous cell carcinoma in the area that will undergo treatment.
4. Subjects actively receiving chemotherapy or immunotherapy at Visit 1 (Week 1).
5. Active drug or alcohol addiction as determined by the Investigator.
6. Hypersensitivity to local anesthesia (lidocaine/prilocaine cream).
7. Participation in an interventional clinical trial within the past three (3) months (not including BVEC administration).
8. Receipt of a skin graft in the past three (3) months.
9. Pregnant or nursing women.

Participant flow

Outcome results

• Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26 (Primary), Number, number of wounds with complete healing: B-VEC 20.9; Placebo 6.7 (p 0.00192)
• Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12 (Secondary), Number, number of wounds with complete healing: B-VEC 21.9; Placebo 6.1 (p 0.00047)
• Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. (Secondary), Mean, score on a scale of 0 to 10: B-VEC -0.88 +/- 2.346; Placebo -0.71 +/- 2.476

Adverse events

Time frame: 6 months

Serious adverse events by term

Other adverse events by term

• Results publication: Guide SV, Gonzalez ME, Bagci IS, Agostini B, Chen H, Feeney G, Steimer M, Kapadia B, Sridhar K, Quesada Sanchez L, Gonzalez F, Van Ligten M, Parry TJ, Chitra S, Kammerman LA, Krishnan S, Marinkovich MP. Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. N Engl J Med. 2022 Dec 15;387(24):2211-2219. doi: 10.1056/NEJMoa2206663. PMID 36516090

• Study Protocol (PDF, 2021-04-21)
• Statistical Analysis Plan (PDF, 2021-08-25)