VYJUVEK Kit, biological suspension and excipient gel for topical application Ref.[107249] Active ingredients: Beremagene geperpavec

Dystrophic epidermolysis bullosa (DEB) is caused by mutation(s) in the COL7A1 gene, which results in reduced or absent levels of biologically active COL7.

Upon topical application to the wounds, VYJUVEK can transduce both keratinocytes and fibroblasts. Following entry of VYJUVEK 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. Patients with autosomal dominant DEB (DDEB) have lower than normal functional anchoring fibrils, and patients with RDEB have no functional anchoring fibrils.

The pharmacodynamic activity (expression and localization of COL7 transgene) of VYJUVEK gel was demonstrated in an initial clinical study (n=6 subjects). Linear deposition of the non-collagenous domain 1 (NC1) and domain 2 (NC2) of COL7 were observed at the dermal-epidermal junction in skin biopsies harvested after VYJUVEK treatment.

In an initial clinical study, viral vector DNA was detected in skin swab samples in all nine treated subjects, with maximum level ranging from 5.1 × 10⁴ to 4.1 × 10⁸ vector genomes. In 6 out of 9 subjects (67%), negative shedding was confirmed with three measurements below limit of detection within 8 weeks of treatment with VYJUVEK. No viral vector DNA was detected in blood or urine.

In the 31-subject randomized, double-blind, intra-subject placebo-controlled trial, systemic and potential environmental exposure assessments were conducted at weekly clinical site visits via quantification of VYJUVEK genomes in blood, urine, skin swabs, and bandage samples (vector shedding) using a validated qPCR assay, and detection of infectious viral particles in skin swabs (infectivity) using a validated plaque titer assay.

All blood samples and all but one urine sample collected throughout the study were below the limit of detection. Skin swabs from 19 of the 31 subjects (61%) were positive for viral vector following treatment with VYJUVEK. Negative shedding from skin swabs was achieved in 16 of the 19 subjects (84%) within six weeks following treatment with VYJUVEK. Most wound dressings (94%, 29/31) contained a range of detectable vector genomes. However, no extracellular infectious particles were detected on the skin surface of any subject at any timepoint tested, after topical VYJUVEK application.

No animal studies have been conducted to evaluate the effects of VYJUVEK on carcinogenesis, mutagenesis, or impairment of fertility.

The efficacy of VYJUVEK gel in subjects one year of age and older with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the COL7A1 gene was evaluated in one randomized, double-blind, intra-subject 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 VYJUVEK gel or the placebo (excipient gel) weekly for 26 weeks.

The study enrolled 31 subjects (20 males and 11 females), including 30 subjects with autosomal recessive DEB and one subject with autosomal dominant DEB. The size of the VYJUVEK gel-treated wounds ranged from 2 to 57 cm², with 74% of wounds <20 cm² and 19% from 20 to <40 cm². The size of the placebo gel-treated wounds ranged from 2 to 52 cm², with 71% of wounds <20 cm² and 26% from 20 to <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 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 VYJUVEK gel-treated and the placebo gel-treated wounds. Complete (100%) wound closure was defined as durable wound closure evaluated at two consecutive visits two weeks apart. The efficacy results are summarized in Table 4.

Table 4. Summary of the efficacy results for VYJUVEK gel (ITT Population):