Phase 4 Master Protocol for Patients Prescribed Prademagene Zamikeracel for the Treatment of Wounds

The Master Protocol includes 3 studies (Study A, Study B, and Study C) that will evaluate pz-cel (LZRSE-COL7A1 gene-corrected cellular sheets with type VII collagen \[C7\] expression) and related processes in the post-marketing setting.

Pz-cel is a genetically engineered autologous cell therapy indicated for the treatment of wounds associated with RDEB. Pz-cel is composed of autologous keratinocytes from patients with mutations in the collagen type VII alpha 1 chain (COL7A1) gene, which have been transduced ex vivo with the Moloney leukemia virus-derived retroviral vector (LZRSE)-COL7A1. The gene-corrected cellular sheets express functional C7.

The pz-cel sheets are a one-time surgical application to debrided and cauterized wound beds of the corresponding patients with DEB. The COL7A1 transgene integrates into the host cell genome, resulting in durable expression and secretion of collagen protein, which addresses the underlying mechanism of the disease.

Study A is an open-label, non-randomized study in patients who are expected to receive gene-corrected cellular sheets (pz-cel) for the treatment of RDEB wound sites in the post-marketing setting and whose manufactured patient-specific batch of pz-cel intended for commercial treatment did not meet commercial release criteria, but had no safety concerns associated with its use. This study will allow surgical application of such non-conforming pz-cel when the benefit of application outweighs the risks. All patients will be followed through 24 weeks after treatment and may be eligible for further follow-up after Week 24. Patients will be evaluated at their Screening visit (30 days before surgery), at Day 0 (Surgery day), by phone on Week 4 (Month 1) and by Telehealth or Clinic Visit at Week 12 (Month 3) and Week 24 (Month 6).

Study B is a study to collect additional biopsy samples from patients who are expected to receive treatment with pz-cel in the post-marketing setting. The additional biopsy samples are being collected to support pz-cel product optimization. Patients receiving treatment with pz-cel can consent to have 2 additional 8-mm biopsies for use in the pz-cel assay and process development as well as in the optimization of the pz-cel manufacturing processes. The study will consist of Screening (in-person or via phone and eConsent), a pre-surgery biopsy and an End of Study Phone call 10-14 days after biopsy.

Study C is an open-label, non-randomized study in patients who are prescribed gene-corrected cellular sheets (pz-cel) in the post-marketing setting and who are part of a patient population not represented in the VIITAL Clinical Trial (NCT04227106). This study will enable patients with wounds that could benefit from treatment with pz-cel, especially those requiring special access for application of pz-cel, to receive pz-cel. All patients will be followed through 24 weeks after treatment and may be eligible for further follow-up after Week 24. Patients will be evaluated at their Screening visit (25-60 days before surgery), at Day -1 (one day prior to surgery), at Day 0 (Surgery Day), by phone on Week 4 (Month 1) and by Telehealth or Clinic Visit at Week 12 (Month 3) and Week 24 (Month 6).

• Non-conforming pz-cel surgical application to RDEB wounds (Biological): Non-conforming pz-cel is pz-cel intended for commercial treatment that did not meet commercial release criteria, but had no safety concerns associated with its use.
• Additional biopsies (Procedure): Additional biopsy samples from patients who are expected to receive treatment with pz-cel in the post-marketing setting.
• Pz-cel surgical application to DEB wounds (Biological): This intervention is for patients requiring special access for application of pz-cel.

Primary outcomes

• Study A - Wound Healing ≥50% [From Baseline at Week 24 (Month 6)]: Proportion of RDEB wounds with healing ≥50% from Baseline at Week 24 (Month 6) as determined by direct Investigator assessment.
• Study A - Pain Severity Scale (Wong-Baker FACES) [At Week 24 (Month 6)]: Pain reduction assessed by the Wong-Baker FACES Pain Rating Scale (for patients ≥6 years of age) at Week 24 (Month 6). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.
• Study C - Wound Healing ≥50% [From Baseline at Week 24 (Month 6)]: Proportion of wounds with healing ≥50% from Baseline at Week 24 (Month 6) as determined by direct Investigator assessment.
• Study C - Pain Severity Scale (Wong-Baker FACES) [At Week 24 (Month 6)]: Pain reduction assessed by Wong-Baker FACES Pain Rating Scale (for patients ≥6 years old) at Week 24 (Month 6). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.

Secondary outcomes

• Study A - Wound Healing ≥50% [At Week 12 (Month 3)]: Proportion of RDEB wounds with ≥50% healing at Week 12 (Month 3) as determined by direct Investigator assessment.
• Study A - Wound Healing ≥75% [At Weeks 12 (Month 3) and 24 (Month 6)]: Proportion of RDEB wounds with ≥75% healing at Weeks 12 (Month 3) and 24 (Month 6) as determined by direct Investigator assessment.
• Study A - Wound Healing Complete [At Weeks 12 (Month 3) and 24 (Month 6)]: Proportion of RDEB wounds with complete healing (i.e., re-epithelialization with no drainage or erosion and presence of only minor crusting) at Weeks 12 (Month 3) and 24 (Month 6) as determined by direct Investigator assessment.
• Study A - Pain Severity Scale (Wong-Baker FACES) [At Week 12 (Month 3)]: Pain reduction assessed by the Wong-Baker FACES Pain Rating Scale (for patients ≥6 years of age) at Week 12 (Month 3). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.
• Study A - Worst Itch Severity Scale [At Weeks 12 (Month 3) and 24 (Month 6)]: Change in scores of Worst Itch Numeric Rating Scale (WI-NRS; for patients ≥6 years of age) assessed at Weeks 12 (Month 3) and 24 (Month 6). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.
• Study C - Wound Healing ≥50% [At Week 12 (Month 3)]: Proportion of DEB wounds with ≥50% healing at Week 12 (Month 3) as determined by direct Investigator assessment.
• Study C - Wound Healing ≥75% [At Weeks 12 (Month 3) and 24 (Month 6)]: Proportion of DEB wounds with ≥75% healing at Weeks 12 (Month 3) and 24 (Month 6) as determined by direct Investigator assessment.
• Study C - Wound Healing Complete [At Weeks 12 (Month 3) and 24 (Month 6)]: Proportion of DEB wounds with complete healing (i.e., re-epithelialization with no drainage or erosion and presence of only minor crusting) at Weeks 12 (Month 3) and 24 (Month 6) as determined by direct Investigator assessment.
• Study C - Pain Severity Scale (Wong-Baker FACES) [At Week 12 (Month 3)]: Pain reduction assessed by the Wong-Baker FACES Pain Rating Scale (for patients ≥6 years of age) at Week 12 (Month 3). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.
• Study C - Worst Itch Severity Scale [At Weeks 12 (Month 3) and 24 (Month 6)]: Change in scores of WI-NRS (for patients ≥6 years of age) assessed at Weeks 12 (Month 3) and 24 (Month 6). The minimum score value is 0 and the maximum score value is 10, with the higher scores being the worse outcome.

Other outcomes

• Study A - The number of treatment-related cutaneous malignancies. [From enrollment to Week 24]: The number and incidence of treatment-related cutaneous malignancies.
• Study A - The number of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) [From enrollment to Week 24]: The number and incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs) related to pz-cel.
• Study A - The number of positive replication-competent retrovirus (RCR) testing results [From enrollment to Week 24]: The number and incidence of positive replication-competent retrovirus (RCR) testing results required for AEs and SAEs where retroviral infection is a consideration.
• Study A - The number of all treatment-emergent AEs and SAEs. [From enrollment to Week 24]: The number and incidence of all treatment-emergent AEs and SAEs.
• Study C - The number of treatment-related cutaneous malignancies. [From enrollment to Week 24]: The number and incidence of treatment-related cutaneous malignancies.
• Study C - The number of treatment-emergent AEs and SAEs [From enrollment to Week 24]: The number and incidence of treatment-emergent AEs and SAEs related to pz-cel.
• Study C - The number of positive RCR testing results required for AEs and SAEs [From enrollment to Week 24]: The number and incidence of positive RCR testing results required for AEs and SAEs where retroviral infection is a consideration.
• Study C - The number of all treatment-emergent AEs and SAEs. [From enrollment to Week 24]: The number and incidence of all treatment-emergent AEs and SAEs.

Sex: All

Study A

Inclusion Criteria

1. Willing and able to provide informed consent/assent; if under the age of 18, guardian(s) is (are) willing and able to provide consent.
2. Patients who are expected to receive pz-cel manufactured as intended for commercial treatment; however, the final manufactured product was non-conforming and therefore did not meet commercial release criteria.
3. All women of childbearing potential should discuss reproductive and breastfeeding plans and precautions with the treating physician in accordance with the considerations for special populations in the United States Prescribing Information (USPI).

Exclusion Criteria

1. Inability to adequately follow the protocol and ensure the protection of cellular sheet sites, as determined by the Investigator.
2. Hypersensitivity to vancomycin or amikacin.
3. The presence of medical illness expected to complicate participation and/or compromise the safety of this technique, such as, but not limited to, active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
4. Evidence of systemic infection.
5. Current evidence of squamous cell carcinoma (SCC) in the area that will undergo pz-cel application.
6. Grade 3 clinical event or laboratory abnormality prior to pz-cel treatment, with the exception of abnormalities such as esophageal strictures, anemia, low albumin, and pain/itch, which are expected in patients with severe DEB.
7. Any other circumstance where the Investigator believes that it is not appropriate for the patient to participate in the study.

Study B

Inclusion Criteria

1. Willing and able to provide informed consent/assent; if under the age of 18, guardian(s) is (are) willing and able to provide consent.
2. Patients who are expected to receive treatment with pz-cel and are receiving a biopsy prior to pz-cel application in the post-marketing setting.

Exclusion Criteria

1\. Any circumstance where the Investigator believes that the patient may not be appropriate for participation in the study.

Study C

Inclusion Criteria:

1. Willing and able to provide informed consent/assent; if under the age of 18, guardian(s) is (are) willing and able to provide consent.
2. Patients who were prescribed pz-cel for commercial treatment but require special access defined in the protocol for treatment to occur.
3. All women of childbearing potential must have a negative urine pregnancy test and agree to use a reliable birth control method throughout the duration of the study.

Exclusion Criteria:

1. Inability to properly follow protocol assessments and protect cellular sheet sites as determined by the Investigator.
2. Currently enrolled in an interventional clinical trial involving an investigational medicinal product to treat DEB or receipt of the investigational therapy within the 3 months prior to pz-cel application.
3. Breastfeeding.
4. The presence of medical illness expected to complicate participation and/or compromise the safety of this technique, such as, but not limited to, active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
5. Evidence of systemic infection.
6. Current evidence or a history of SCC in the area that will undergo pz-cel application.
7. Active drug or alcohol addiction.
8. Hypersensitivity to vancomycin or amikacin.
9. Grade 3 clinical event or laboratory abnormality prior to pz-cel treatment, with the exception of abnormalities such as esophageal strictures, anemia, low albumin, and pain/itch, which are expected in patients with severe DEB.
10. Any other circumstance where the Investigator believes that it is not appropriate for the patient to participate in the study.