Beremagene geperpavec-svdt

Recommended Dose

Per the FDA-Label, beremagene geperpavec-svdt should be applied once weekly by a healthcare professional. It may not be possible to apply beremagene geperpavec-svdt to all the wounds at each treatment visit. Beremagene geperpavec-svdt should be applied to wounds until they are closed before selecting new wounds, and previously treated wounds that re-open should be prioritized over new wounds.

PG1. Dosing Recommendations

* Maximum weekly volume is the volume after mixing beremagene geperpavec-svdt biological suspension with excipient gel.
** For wound area of 60 cm², recommend calculating the total dose based on the recommended dosing until the maximum weekly dose is reached.

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 classification^1, 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 US from 1986 to 2002^6,, the prevalence of recessive dystrophic epidermolysis bullosa in the US was estimated to be 1.35 persons per million inhabitants and dominant dystrophic epidermolysis bullosa was estimated to be 1.49 persons per million inhabitants.

Prior to the FDA approval of beremagene geperpavec-svdt, there were no FDA-approved treatments for dystrophic epidermolysis bullosa. Disease management is supportive and includes 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)].

Regulatory Status

In May 2023, beremagene geperpavec-svdt (Vyjuvek; Krystal Biotech) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

Rationale

This evidence review was created in July 2023 with a search of the PubMed database. The most recent literature update was performed through October 6, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Gene Therapy for Treatment of Wounds in Dystrophic Epidermolysis Bullosa

Clinical Context and Therapy Purpose

The purpose of beremagene geperpavec-svdt in individuals who are 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals who are 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the COL7A1 gene.

Interventions

The therapy being considered is beremagene geperpavec-svdt. It is a live, replication defective herpes-simplex virus type 1 (HSV-1) based vector that has been genetically modified to express the human type VII collagen (COL7) protein. Upon topical application to the wounds, beremagene geperpavec-svdt can transduce both keratinocytes and fibroblasts. Following entry of beremagene geperpavec-svdt into the cells, the vector genome is deposited in the nucleus. Once in the nucleus, transcription of the encoded human COL7A1 is initiated. The resulting transcripts allow for production and secretion of COL7 by the cell in its mature form. These COL7 molecules arrange themselves into long, thin bundles that form anchoring fibrils. The anchoring fibrils hold the epidermis and dermis together and are essential for maintaining the integrity of the skin. As beremagene geperpavec-svdt is nonintegrating (i.e., its genetic material remains physically separate from the host cell chromosome), it is not anticipated to carry the potential risk of insertional mutagenesis to trigger oncogenesis.

Comparators

The following therapies are currently being used to make decisions about dystrophic epidermolysis bullosa: disease management is supportive and includes wound care, pain management, control of infection, nutritional support, and prevention and treatment of complications.

Outcomes

The general outcomes of interest are symptoms, change in disease status, quality of life, treatment-related mortality and treatment-related morbidity. The primary endpoints of interest for trials of wound healing consistent with guidance from the Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds are as follows:^7,

• Incidence of complete wound closure.

• Time to complete wound closure (reflecting accelerated wound closure).

• Incidence of complete wound closure following surgical wound closure.

• Pain control.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program for beremagene geperpavec-svdt is summarized in Table 1. The pivotal phase 3 randomized, double-blinded clinical trial (GEM-3) was the basis for FDA approval of beremagene geperpavec-svdt and is reviewed in detail.

Table 1. Summary of the Clinical Development Program for Beremagene Geperpavec-svdt

DMD: Duchenne muscular dystrophy; DBRCT: double-blind randomized controlled study.
^a Each participant serves as his/her own control by contributing a primary size-matched wound pair to be randomized to receive weekly topical application of either gene therapy or the placebo (excipient gel).

Pivotal Randomized Trial

Study characteristics, baseline patient characteristics and results are summarized in Table 2 to 4, respectively. The pivotal GEM-3 study was a 26-week, randomized, double-blind, intra-subject placebo-controlled trial in which 2 comparable wounds in each participant were selected and randomized to receive either topical application of beremagene geperpavec-svdt gel or the placebo (excipient gel) weekly for 26 weeks. The placebo gel and the beremagene geperpavec-svdt gel had the same viscosity and were similar in appearance. The principal investigator at each site was the sole individual who assessed each subject’s primary wound pair at all timepoints for primary and secondary endpoints assessment. The principal investigators were blinded for the entire duration of the study. The primary end point was complete wound healing of treated as compared to untreated wounds at 6 months. Efficacy was established on the basis of improved wound healing defined as the difference in the proportion of complete (100%) wound closure at 24 weeks confirmed at 2 consecutive study visits 2 weeks apart, assessed at weeks 22 and 24 or at weeks 24 and 26, between the beremagene geperpavec-svdt gel-treated and the placebo gel-treated wounds. At 24 weeks, complete wound healing occurred in 65% of the wounds exposed to beremagene geperpavec-svdt gel as compared with 26% of those exposed to placebo (difference, 39 points; 95% confidence interval [CI], 14 to 63; p =.012). The most common adverse drug reactions (incidence >5%) were itching, chills, redness, rash, cough, and runny nose. The intra-subject randomization and comparison of dystrophic epidermolysis bullosa wounds confounds the systemic safety evaluation.

Table 2. Summary of Pivotal Randomized Trial

COL7A1: collagen type VII alpha 1 chain; DBRCT: double-blind randomized controlled trial; PFU: plaque forming units
^a Responder was defined as having wounds that were closed for at least 2 consecutive weeks at defined timepoints. Complete wound closure was defined as 100% wound closure from the exact wound area selected at baseline, specified as skin re-epithelialization without drainage.

Table 3. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Trial

Table 4. Summary of Key Results in Pivotal Trial

CI: confidence interval

The purpose of the study limitations tables (see Tables 5 and 6) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of evidence supporting the position statement. No major study design or conduct limitations were noted. The size of the safety database and the median duration of exposure for beremagene geperpavec-svdt is inadequate to sufficiently assess harms.

Table 5. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 6. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Gene Therapy for Treatment of Wounds in Dystrophic Epidermolysis Bullosa

Evidence for the use of beremagene geperpavec-svdt for the treatment of wounds in individuals with dystrophic epidermolysis bullosa with mutation(s) in the COL7A1 gene includes a single RCT. In the pivotal GEM-3 trial (n=31), 2 comparable wounds in each participant were selected and randomized to receive either topical application of beremagene geperpavec-svdt gel or the placebo (excipient gel) weekly for 26 weeks. The primary endpoint was the difference in the proportion of complete (100%) wound closure at 24 weeks confirmed at 2 consecutive study visits 2 weeks apart, assessed at weeks 22 and 24 or at weeks 24 and 26, between the beremagene geperpavec-svdt gel-treated and the placebo gel-treated wounds. At 24 weeks, complete wound healing occurred in 65% of the wounds exposed to beremagene geperpavec-svdt gel as compared with 26% of those exposed to placebo (difference, 39 points; 95% CI, 14 to 63; p =.012). The most common adverse drug reactions (incidence >5%) were itching, neoplasms, chills, redness, rash, cough, and runny nose.