Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2023047
Category:	Pharmacy
Initiated:	December 2023
Last Review:	December 2024

Beremagene Geperpavec-svdt (e.g., Vyjuvek)

Description:

Beremagene geperpavec-svdt (e.g., Vyjuvek) is a topically applied, redosable, live, replication defective herpes simplex virus-1 (HSV-1) vector -based gene therapy, that delivers functional human collagen type VII alpha 1 chain (COL7A1) genes in individuals with both, dominant and recessive dystrophic epidermolysis bullosa. Beremagene geperpavec (B-VEC) can transduce both keratinocytes and fibroblasts and restore functional COL7 protein. It received its first approval in the United States for the treatment of wounds in individuals with dystrophic epidermolysis bullosa (DEB) with mutation(s) of the COL7A1 gene.

Upon topical application to the wounds, B-VEC can transduce both keratinocytes and fibroblasts. Following the delivery of B-VEC into the cells, the vector genome enters the nucleus. Once in the nucleus, transcription of the encoded human COL7A1 is initiated, without the integration of the vector into the human genome. The resulting transcripts allow production and secretion of mature COL7 protein. These COL7 proteins arrange into bundles of long, thin anchoring fibrils that hold the epidermis and dermis together and are essential for maintaining the integrity of the skin. Individuals with DDEB have fewer normal functional anchoring fibrils, and individuals with RDEB have no functional anchoring fibrils.

Epidermolysis bullosa (EB) is a rare, inherited connective tissue disorder characterized by abnormalities in cohesion of the layers of the skin that can result in blisters, erosions, nonhealing ulceration, and scars in response to trauma or friction. DEB is caused by mutations in the COL7A1 gene that lead to dysfunctional type VII collagen protein, which normally binds the dermal and epidermal layers of the skin.

The U.S. prevalence of DEB is estimated to be about 3.26 per million people (which calculates to approximately 1100 individuals). However, DEB is underdiagnosed, and it is estimated that there are currently 3000 U.S. individuals living with DEB. There are two main types of DEB based on the inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). B-VEC is approved to treat both conditions.

Recessive DEB (RDEB) is generally the more severe form. Infants with RDEB typically have widespread blistering and areas of missing skin. As blisters heal, they result in severe scarring, which can cause additional complications. Scarring and blisters in the mouth and esophagus can make it difficult to chew and swallow food, leading to chronic malnutrition and slow growth. Ongoing scarring and fibrosis can lead to fusion of the skin between the fingers and toes (pseudosyndactyly), loss of fingernails and toenails, joint deformities that restrict movement (contractures), and eye inflammation and ulceration leading to vision loss. Early onset of aggressive squamous cell carcinomas (SCCs) at chronic wound sites is typical of RDEB and represents the major cause of death. A systematic review found that in severe RDEB, the risk of SCC was 76% and mortality from SCC reached 84% by 40 years of age (Orphanet Journal of Rare Diseases, 2021).

Dominant DEB (DDEB) is considered the milder form, although its severity is variable. Blisters may be present at birth, but typically appear during early childhood and tend to occur at vulnerable sites such as knees, ankles, elbows, and knuckles. In adulthood, they usually become less frequent and scars fade. Other signs and symptoms of DDEB may include absent fingernails and toenails, constipation, dental caries, and issues with swallowing.

Mild cases of DEB are often not fatal, and individuals have a normal life expectancy. However, individuals with severe disease have a life expectancy that ranges from infancy to about 30–40 years of age.

Regulatory Status

Beremagene geperpavec-svdt (e.g., Vyjuvek) was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2023, for the treatment of wounds in individuals 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for Beremagene geperpavec-svdt (e.g., Vyjuvek).

The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.

Effective December 13, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months

Beremagene geperpavec-svdt (e.g., Vyjuvek) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

1. Individual is ≥ 6 months of age (FDA, 2023); AND

2. Individual has a diagnosis of dystrophic epidermolysis bullosa* confirmed by (FDA, 2023):

a. Documented mutation(s) in the COL7A1 gene; AND

b. Presence of clinical manifestations of dystrophic epidermolysis bullosa including, but not limited to, chronic and recurring wounds of the skin, blistering of skin, and blistering, ulcerations, and scarring of visceral mucosal tissues; AND

3. Beremagene geperpavec-svdt (e.g., Vyjuvek) is being prescribed by, or in consultation with, a dermatologist or a provider who specializes in dystrophic epidermolysis bullosa; AND

4. Individual is not pregnant or breastfeeding (FDA, 2023); AND

5. Individual has no active infection, active squamous cell carcinoma, or history of squamous cell carcinoma in the targeted wound(s) (Guide, 2022); AND

6. Individual has not received a skin graft in the past 3 months on targeted wound(s) (Guide, 2022); AND

7. Beremagene geperpavec-svdt (e.g., Vyjuvek) application is to open dystrophic epidermolysis bullosa skin wounds only (FDA, 2023); AND

8. Must be dosed in accordance with the FDA label.

*Use of beremagene geperpavec-svdt (e.g., Vyjuvek) for dystrophic epidermolysis bullosa does not have sufficient evidence for the dominant dystrophic epidermolysis bullosa subtype.

CONTINUED APPROVAL for up to 1 year:

Reauthorization for beremagene geperpavec-svdt (e.g., Vyjuvek) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals if they meet the following:

1. Continue to meet initial treatment criteria cited above; AND

2. Documentation of a clinical response to therapy (e.g., complete wound closure).

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Beremagene geperpavec-svdt (e.g., Vyjuvek) is a weight-based weekly application.

Wound Area (squared cm)* Dose (PFU**) Volume (mL)

< 20 4 x 100 million 0.2 mL

20 to <40 8 x 100 million 0.4mL

40 to 60 1.2 x 1 billion 0.6 mL

*For a wound area over 60 squared cm, recommend calculating the total dose based on this table until the maximum weekly dose is reached.

** PFU = Plaque forming units

The maximum weekly dose is based on the individual’s age as follows:

Age Range Maximum Weekly dose (PFU**) Maximum Weekly Volume (mL)*

6 months to < 3 yrs old 1.6 x 1 billion 0.8 mL

> 3 years old 3.2 x 1 billion 1.6 mL

*Maximum weekly volume is the volume after mixing beremagene geperpavec-svdt (e.g., Vyjuvek) biological suspension with excipient gel.

** PFU = Plaque forming units

Beremagene geperpavec-svdt (e.g., Vyjuvek) is available as a carton that contains one single-dose vial of Beremagene geperpavec-svdt (e.g., Vyjuvek) biological suspension and one single-dose vial of excipient gel. The biological suspension is supplied as a 1.0 mL extractable volume containing 5 x 1 billion PFU/mL. The excipient gel is supplied as a 1.5 mL fill volume in a separate vial.

Beremagene geperpavec-svdt (e.g., Vyjuvek) should be administered as a topical gel by a healthcare professional.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Beremagene geperpavec-svdt (e.g., Vyjuvek), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, Beremagene geperpavec-svdt (e.g., Vyjuvek), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

The approval of beremagene geperpavec (B-VEC) was primarily based on the pivotal Phase 3 GEM-3 trial (Shireen V. et.al. 2022), which included 30 patients with RDEB and one patient with DDEB, of which 19 were pediatric patients. The primary efficacy endpoint of complete wound healing at 6 months and the secondary endpoint of complete wound healing at 3 months post baseline were both met. Of wounds treated with B-VEC, 65% healed completely at 6 months compared to 26% of wounds treated with placebo (P = 0.012).

Approval of B-VEC was supported by efficacy and safety data from the intra-patient, placebo-controlled Phase 3 GEM-3 study, which included patients as young as one year of age. Two comparable wounds in each patient were selected and randomized to receive either topical application of B-VEC or placebo gel weekly for 26 weeks. In the study, B-VEC met the primary endpoint of complete wound closure (defined as 100% wound closure as indicated by skin re-epithelialization without drainage) at 6 months compared to placebo. Approval for use in patients as young as 6 months of age was supported by safety data from the GEM-3 open-label extension (OLE) study (NCT04917874) that is still ongoing and included two pediatric patients with RDEB, six and seven months of age.

In the one patient included in the study with DDEB, the primary wound that was exposed to B-VEC healed completely at 6 months, whereas the primary wound exposed to placebo did not.

Durability, defined as complete wound healing at both 3 and 6 months, was seen in 50% of wounds exposed to B-VEC and 7% of those exposed to placebo (difference, 43%; 95% CI: 23 to 63).

Another secondary endpoint was the change in the pain severity from baseline to Weeks 22, 24, and 26 during wound dressing changes for the primary wound pair for patients ≥6 years of age using a visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst possible pain). At Week 22, the mean change in VAS was −0.88 for wounds exposed to B-VEC and −0.71 for those exposed to placebo (adjusted least-squares mean difference, −0.61; 95% CI, −1.10 to −0.13). At Weeks 24 and 26, there was a numerically greater reduction in pain from baseline with B-VEC than with placebo during wound-dressing changes; however, the difference was not statistically significant.

The primary safety population included all 31 patients enrolled in the GEM-3 study. A total of 18 patients (58%) had at least one adverse event (AE) with the majority of AEs being mild or moderate in severity. The most common AEs (incidence >5%) observed in the study were pruritus (10%), chills (10%), erythema (6%), rash (6%), cough (6%), and rhinorrhea (6%). Three patients developed SCC; no SCC developed at wound sites treated with B-VEC or placebo, so the SCC cases were considered unrelated to the treatment. Three patients experienced severe AEs, but none were considered to be related to B-VEC or placebo. No AEs led to discontinuation of B-VEC or placebo.

Whole blood, urine, and skin and bandage swabs were collected, when possible, at specific timepoints throughout the trial to evaluate viral shedding by a validated quantitative polymerase chain reaction (qPCR) assay. All blood samples collected throughout the study were below the limit of detection (LOD) for viral/vector shedding for all patients. A urine sample from one subject was positive for viral vector. Thus, the blood and urine viral kinetic data indicate no significant systemic exposure following topical administration of B-VEC. Skin swabs from 19 out of 31 subjects (61.3%) were positive for viral vector following treatment with B-VEC. Skin swabs from 12 out of 31 subjects (38.7%) did not show detectable viral vector at any timepoint during the 26 weeks of treatment. Negative shedding (confirmed by three subsequent measurements below LOD) was achieved in 16 out of 19 subjects (84.2%) within 6 weeks following treatment with B-VEC. Most wound dressings (93.5%, 29/31) contained detectable vector genomes.

Due to difficulty with venipuncture in patients with DEB, only 19 of 31 patients had both baseline and Week 26 serum samples available to assess antibodies against HSV-1 and type VII collagen. Seroconversion occurred in six of eight patients (75%) who had no antibodies against HSV-1 at baseline. Thirteen of 18 patients (72%) who had no antibodies against type VII collagen at baseline developed these antibodies by the end of the study. No clinically significant immunologic reactions were reported, and treatment response to B-VEC up to Week 26 was not associated with baseline HSV-1 serostatus or type VII collagen seroconversion.

Open-Label Extension Trial

At the end of the GEM-3 trial, patients had the option to roll into the GEM-3 OLE study (NCT04917874). In addition, new participants who were unable to participate in the GEM-3 study but meet all enrollment criteria are allowed to enroll in the OLE study. The OLE study is following patients for up to 112 weeks and the primary endpoint will be to assess long term safety and tolerability of B-VEC. Completion of the trial is anticipated at the end of 2023.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Bruckner, A.L., Losow, M., Wisk, J. et al.(2020) The challenges of living with and managing epidermolysis bullosa: insights from patients and caregivers. Orphanet J Rare Dis 15, 1 (2020). https://doi.org/10.1186/s13023-019-1279-y

Feinstein, J.A., Bruckner, A.L., Chastek, B. et al.(2022) Clinical characteristics, healthcare use, and annual costs among patients with dystrophic epidermolysis bullosa. Orphanet J Rare Dis 17, 367 (2022). https://doi.org/10.1186/s13023-022-02509-0

Fine JD.(2016) 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

Guide SV, Gonzalez ME, Bagci IS, et al.(2022) Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. N Engl J Med. Dec 15 2022; 387(24): 2211-2219. PMID 36516090

Has C, Bauer JW, Bodemer C, et al.(2020) Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Br J Dermatol. Oct 2020; 183(4): 614-627. PMID 32017015

Vyjuvek [package insert]. Pittsburgh, PA: Krystal Biotech, Inc.; 2023

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association.