229 Form

1

Medical Policy Gene Therapy for Treatment of Wounds in Dystrophic Epidermolysis Bullosa - Zevaskyn Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History
• Endnotes Policy Number: 229 BCBSA Reference Number: 5.01.47 NCD/LCD: N/A Related Policies
Gene Therapy for Treatment of Wounds in Dystrophic Epidermolysis Bullosa - Prior Authorization Request Form #230 Medical Utilization Management (MED UM) & Pharmacy Prior Authorization Policy #033 - Vyjuvek Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Initial Approval Criteria

INITIAL APPROVAL: 6 months

Zevaskyn (prademagene zamikeracel) may be considered MEDICALLY NECESSARY if indicated for the treatment of wounds in adult and pediatric patients diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) conditions indicated below are met:

1. Patient has wounds associated with recessive dystrophic epidermolysis bullosa (RDEB), AND
2. Documented biallelic pathogenic mutations in the collagen type VII alpha 1 chain (COL7A1) gene, AND
3. Positive expression of the non-collagenous region 1 of the type 7 collagen protein (NC1+) in the skin, AND
4. Presence of at least one chronic wound (e.g., stage 2 wounds that have an area ≥ 20 cm2 ) and have been present for at least 3 months, AND
5. Presence of clinical manifestations of RDEB, such as extensive skin blistering, skin erosions, or scarring, AND
6. Prescribed by or in consultation with a dermatologist or a wound care specialist, AND
7. Prescriber agrees that the affected wound has not been previously treated with Zevaskyn, AND

2

8. NO active infection, active squamous cell carcinoma, or history of squamous cell carcinoma in the targeted wound(s)

   Prior Approval Limits Quantity 12 sheets

   The use of Zevaskyn (prademagene zamikeracel) may be considered INVESTIGATIONAL for all other indications. Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
   Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

   Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

   Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

   To ensure the request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

   Authorization Manager Resources • Refer to our Authorization Manager page for tips, guides, and video demonstrations.

   Complete Prior Authorization Request Form for Gene Therapy for Inherited Retinal Dystrophy (926) using Authorization Manager. For out of network providers: Requests should still be faxed to 888-973-0726. CPT Codes / HCPCS Codes / ICD Codes
   Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

   Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

   The following codes are included below for informational purposes only; this is not an all-inclusive list.

   The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

3

HCPCS Codes HCPCS codes:

Code Description J3389 Prademagene zamikeracel, per treatment [Zevaskyn] C9399 Unclassified drugs or biologicals J3590 Unclassified biologics

ICD-10 Procedure Codes ICD-10-PCS procedure codes: Code Description Q81.2 Epidermolysis bullosa dystrophica XHR0XGA- XHR7XGA Prademagene Zamikeracel, Genetically Engineered Autologous Cell Therapy

Description Dystrophic Epidermolysis Bullosa Dystrophic epidermolysis bullosa is a rare and clinically and genetically heterogeneous skin fragility disorder characterized by blistering of the skin and mucosal membranes that heal with scarring. The onset of symptoms is usually at birth or in early childhood. There may be associated complications, including malnutrition, anemia, infection, and skin cancer. Death may occur prematurely due to multiple causes, including infection, progression of disease, organ failure, and malignancy.1, Dystrophic epidermolysis bullosa is caused by variant in the COL7A1 gene, encoding the alpha-1 chain of type VII collagen. Collagen VII is the main structural constituent of the anchoring fibrils located below the lamina densa of the epidermal basement membrane zone, which hold the epidermis and dermis together and is essential for maintaining the integrity of the skin. It can be inherited in an autosomal dominant or recessive fashion.2,3,4,. Recessive dystrophic epidermolysis bullosa is more severe than dominant disease variants; however, there is a considerable phenotypic overlap among all types. More than 600 distinct mutations in the COL7A1 gene have been identified in dystrophic epidermolysis bullosa. Although a few mutations are recurrent in some populations due to the founder effect, most families carry unique mutations.5, The 2020 consensus classification1, recognizes four major subtypes and several rare, dominant or recessive subtypes of dystrophic epidermolysis bullosa.

1. Localized dominant dystrophic epidermolysis bullosa
2. Intermediate dominant dystrophic epidermolysis bullosa (previously known as generalized dominant dystrophic epidermolysis bullosa)
3. Intermediate recessive dystrophic epidermolysis bullosa (previously known as recessive dystrophic epidermolysis bullosa generalized intermediate, non-Hallopeau-Siemens recessive dystrophic epidermolysis bullosa)
4. Severe recessive dystrophic epidermolysis bullosa (previously recessive dystrophic epidermolysis bullosa generalized severe, Hallopeau-Siemens recessive dystrophic epidermolysis bullosa) Based on the National Epidermolysis Bullosa Registry in the US, the incidence of epidermolysis bullosa was 19.57 per million live births and prevalence of 11.07 per million population over the period from 1986 to 2002. The numbers for recessive dystrophic epidermolysis bullosa was 3.05 per million live births and 1.35 per million population, respectively.6,

4

Prior to the FDA approval of gene therapies for dystrophic epidermolysis bullosa , there were no FDA- approved treatments for dystrophic epidermolysis bullosa. Disease management was supportive including wound care, pain management, control of infection, nutritional support, and prevention and treatment of complications. FDA previously approved a Humanitarian Devices Exemption for the product, Composite Cultured Skin to be used as a wound dressing in patients with mitten hand deformity due to recessive dystrophic epidermolysis bullosa as an adjunct to standard autograft procedures [i.e., skin grafts and flaps for covering wounds and donor sites created after the surgical release of hand contractions (i.e., “mitten” hand deformities)]. Summary of Evidence
For individuals who are pediatric or adult patients with recessive dystrophic epidermolysis bullosa and who receive prademagene zamikeracel, the evidence includes a single RCT. Relevant outcomes are symptoms, change in disease status, quality of life, treatment-related mortality and treatment-related morbidity. In the pivotal VIITAL trial (n=11), 2 comparable wounds in each participant were selected and randomized to receive either prademagene zamikeracel or standard of care wound dressings. The first co-primary endpoint was the proportion of randomized wound pairs with ≥50% healing from baseline at 6 months. The response rate for the wounds was 81% compared to 16% in the treated versus control arm respectively. The second co-primary efficacy endpoint was pain reduction at 6 month from baseline, assessed by the Wong-Baker FACES Scale. The mean pain reduction from baseline at month 6 was -3.07 points versus - 0.90 points in the treated versus control arm respectively. Treatment with prademagene zamikeracel resulted in greater healing and in greater pain reduction as compared to wounds treated with standard-of- care therapy. These results are both clinically and statistically significant and provide the primary evidence of effectiveness. The most common adverse drug reactions (incidence >5%) were procedural pain and pruritus. No major limitations were noted. The size of the safety database and the median duration of exposure for prademagene zamikeracel is inadequate to sufficiently assess treatment durability and harms. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. Policy History Date Action 1/2026 New medical policy describing medically necessary indications for Zevaskyn, a gene therapy for the treatment of wounds in dystrophic epidermolysis bullosa. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. Has C, Bauer JW, Bodemer C, et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Br J Dermatol. Oct 2020; 183(4): 614-627. PMID 32017015
2. Tidman MJ, Eady RA. Evaluation of anchoring fibrils and other components of the dermal-epidermal junction in dystrophic epidermolysis bullosa by a quantitative ultrastructural technique. J Invest Dermatol. May 1985; 84(5): 374-7. PMID 4039741
3. Burgeson RE. Type VII collagen, anchoring fibrils, and epidermolysis bullosa. J Invest Dermatol. Sep 1993; 101(3): 252-5. PMID 8370960
4. Dunnill MG, McGrath JA, Richards AJ, et al. Clinicopathological correlations of compound heterozygous COL7A1 mutations in recessive dystrophic epidermolysis bullosa. J Invest Dermatol. Aug 1996; 107(2): 171-7. PMID 8757758

5

5. Vahidnezhad H, Youssefian L, Zeinali S, et al. Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous Marriages. J Invest Dermatol. Mar 2017; 137(3): 660-669. PMID 27899325
6. Fine JD. Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry. JAMA Dermatol. Nov 01 2016; 152(11): 1231-1238. PMID 27463098
7. Food and Drug Administration (FDA). Guidance for Industry. Chronic Cutaneous Ulcer and Burn Wounds - Developing Products for Treatment. June 2006. Available at https://www.fda.gov/media/71278/download. Accessed July 25, 2025.
8. Gurevich I, Agarwal P, Zhang P, et al. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat Med. Apr 2022; 28(4): 780-788. PMID 35347281
9. Guide SV, Gonzalez ME, Bağcı IS, et al. Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. N Engl J Med. Dec 15 2022; 387(24): 2211-2219. PMID 36516090
10. Marinkovich MP, Paller AS, Guide SV, et al. Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa. Am J Clin Dermatol. Apr 12 2025. PMID 40220208
11. Prescribing label for Vyjuvek (beremagene geperpavec-svdt) biological suspension mixed with excipient gel for topical application. Available at https://www.krystallabel.com/pdf/vyjuvek-us-pi.pdf. Accessed on June 23, 2025.
12. Siprashvili Z, Nguyen NT, Gorell ES, et al. Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. JAMA. Nov 01 2016; 316(17): 1808-1817. PMID 27802546
13. Eichstadt S, Barriga M, Ponakala A, et al. Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa. JCI Insight. Oct 03 2019; 4(19). PMID 31578311
14. So JY, Nazaroff J, Iwummadu CV, et al. Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa. Orphanet J Rare Dis. Oct 17 2022; 17(1): 377. PMID 36253825
15. Mellerio JE, El Hachem M, Bellon N, et al. Emergency management in epidermolysis bullosa: consensus clinical recommendations from the European reference network for rare skin diseases. Orphanet J Rare Dis. Jun 06 2020; 15(1): 142. PMID 32505191
16. International consensus best practice guidelines skin and wound care in epidermolysis bullosa. Published 2017. Available at https://www.debra-international.org/skin-and-wound-care-in-eb-cpg. Accessed June 24, 2025.
17. National Institute for Health and Care Excellence. Beremagene geperpavec for treating skin wounds associated with dystrophic epidermolysis bullosa [ID3959]. Available at https://www.nice.org.uk/guidance/indevelopment/gid-ta10868/documents. Accessed on June 22,

18. Endnotes