Epidermolysis bullosa (EB) is an ultra-rare genetic disorder that causes abnormalities in the cohesion of layers of the skin, resulting in blisters, erosions, nonhealing ulceration, and scars in response to even mild skin trauma. Complications of EB can include infection, squamous cell carcinoma, constipation, hair loss, and anemia among others.
DEB is one of four types of EB and is caused by mutations in the COL7A1 gene, which codes for Type VII collagen
that helps bind the dermis to the epidermis. The extent of skin fragility in DEB varies depending on whether the
causative mutation predisposes the individual to mild or severe disease and whether the Type VII collagen is completely
absent or reduced. The prevalence of DEB is about 3.26 per million population with an incidence of 6.65 per million live births.
DEB is categorized as recessive (R) or dominant (D), with recessive (R) being the more severe form. Symptoms can vary widely among affected people. Individuals with DDEB typically have
mild cases with blistering primarily affecting the hands, feet, knees, and elbows. RDEB
cases can be painful and debilitating, often involving widespread blistering that can lead to
vision loss, disfigurement, and other serious medical complications, which could be fatal. Individuals with DDEB
generally survive to adulthood with few complications; however, those with RDEB may only survive to their third or
fourth decade if managed appropriately, with the major causes of death being metastatic squamous cell carcinoma
and renal failure.
There are no U.S. Food and Drug Administration (FDA)–approved treatments and there is no cure for any type of EB. Disease management is primarily
supportive and multidisciplinary, involving wound care, pain control, infection control, nutritional support, and
treatment of complications.
BEREMAGENE GEPERPAVEC (VYJUVEK)
Beremagene geperpavec (Vyjuvek) is a topical gene therapy that uses a herpes simplex virus (HSV-1) to introduce a normal copy of the COL7A1 gene to skin cells. Once beremagene geperpavec (Vyjuvek) enters the nucleus of transduced cells, the vector genome is deposited episomally, and as a result, COL7A1 transcripts are generated, allowing the cell to produce and secrete functional CO7A1 protein necessary for the formation of anchoring fibrils that bind the dermis and epidermis together, and blistered skin to be replaced with healthy skin. The COL7A1 gene does not incorporate itself into individuals' chromosomes; therefore, individuals must be treated with beremagene geperpavec (Vyjuvek) repeatedly in order to continue producing healthy skin.
PEER-REVIEWED LITERATURE
The efficacy of beremagene geperpavec (Vyjuvek) gel in subjects 1 year of age and older with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the COL7A1 gene was evaluated in one randomized, double-blind, intrasubject placebo-controlled trial. All study subjects had clinical manifestations consistent with DEB and genetically confirmed mutation(s) in the COL7A1 gene. Two comparable wounds in each subject were selected and randomized to receive either topical application of beremagene geperpavec (Vyjuvek) gel or the placebo (excipient gel) weekly for 26 weeks. The study enrolled 31 subjects (20 male and 11 female individuals), including 30 subjects with autosomal recessive DEB and one subject with autosomal dominant DEB. The size of the beremagene geperpavec (Vyjuvek) gel–treated wounds ranged from 2 to 57 cm2, with 74% of wounds smaller than 20 cm2 and 19% from 20 to less than 40 cm2. The size of the placebo gel–treated wounds ranged from 2 to 52 cm2, with 71% of wounds smaller than 20 cm2 and 26% from 20 to smaller than 40 cm2. The mean age of the subjects was 17 years (1 year to 44 years), including 61% pediatric subjects (n = 19, age from 1 year to < 17 years). Sixty-four percent of subjects were White; 19% were Asian, and the remainder were American Indian or Alaska Native. 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 two consecutive study visits 2 weeks apart, assessed at Weeks 22 and 24 or at Weeks 24 and 26, between the beremagene geperpavec (Vyjuvek) gel–treated and the placebo gel–treated wounds. Efficacy was supported by the difference in the proportion of complete wound closure assessed at Weeks 8 and 10 or at Weeks 10 and 12 between the beremagene geperpavec (Vyjuvek) gel–treated and the placebo gel-treated wounds. Complete (100%) wound closure was defined as durable wound closure evaluated at two consecutive visits 2 weeks apart. At 6 months, complete wound healing occurred in 67% of the wounds exposed to beremagene geperpavec (Vyjuvek) as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24–68; P=0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to beremagene geperpavec (Vyjuvek) as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29–73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was −0.88 with beremagene geperpavec (Vyjuvek) and –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were observed at weeks 24 and 26.
Eighteen individuals (58%) had at least one adverse event. The majority of adverse events were mild or moderate in severity, as assessed by the investigators. Five serious adverse events occurred in three individuals: one individual was hospitalized three times, once for diarrhea and twice for severe anemia; one individual was hospitalized for treatment of cellulitis; and one individual was hospitalized for a positive blood culture related to a hemodialysis catheter. None of the serious adverse events were considered to be related to beremagene geperpavec (Vyjuvek) or placebo by the investigators. One adverse event, mild erythema, was considered to be related to beremagene geperpavec (Vyjuvek). No adverse events led to discontinuation of beremagene geperpavec (Vyjuvek) or placebo. The most common adverse events were pruritus, chills, and squamous-cell carcinoma of the skin, each of which occurred in three individuals (10%). All three cases of squamous-cell carcinoma occurred at wound sites that had not been exposed to beremagene geperpavec (Vyjuvek) or placebo.
To determine potential immunogenicity, levels of antibodies against HSV-1 and C7 before and after treatment were assessed. Because of the difficulty of venipuncture in these individuals, 22 of 31 individuals (71%) had baseline serum samples. Among the individuals with baseline samples, 14 of 22 individuals (64%) had antibodies against HSV-1, a finding consistent with the prevalence of seropositivity in the U.S. population, and one of 22 individuals (5%) had antibodies against C7. Among the individuals with baseline samples, 19 had samples at both baseline and week 26, including the individual who had antibodies against C7. By week 26, seroconversion had occurred in six of eight individuals (75%) with no antibodies against HSV-1 at baseline and in 13 of 18 (72%) with no antibodies against C7 at baseline. No clinically significant immunologic reactions were reported. Treatment response to beremagene geperpavec (Vyjuvek) was not associated with baseline HSV-1 serostatus or C7 seroconversion.
SUMMARY
DEB is an ultra-rare genetic connective tissue disorder caused by mutations in the collagen type VII alpha 1 chain (COL7A1) gene. The COL7A1 gene codes for type VII collagen (C7), a major component of structures in the skin called anchoring fibrils found in the epidermal basement membrane located between the epidermis (top layer of skin) and dermis (underlying layer). Mutations in the COL7A1 gene disrupt adhesion of the epidermis to the dermis. Individuals with DEB completely lack or are deficient in COL7A1, resulting in skin fragility and multiple recurring wounds that are difficult to manage. Over time, repeated blistering and fibrosis can lead to squamous-cell carcinoma, life-threating infections, and limb deformities. DEB may be inherited as a dominant or recessive trait; generally, RDEB is more severe than dominant disease (DDEB); however, there is considerable phenotypic overlap between types. DEB affects approximately 9000 people globally, including approximately 3000 people in the United States and approximately 3000 in Europe. The current standard of care is supportive treatment with wound care and prevention of infection.
Diagnosis
confirmation through genetic testing, immunofluorescence mapping (IFM) and/or transmission of electron microscopy
(TEM) can be done to determine a precise subclassification. Currently, there have not been any definitive treatments
and symptomatic care is the mainstay of disease management. The prevention of new blisters along with wound care
have been the primary treatment for this disease.
