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, beremagene geperpavec can transduce both keratinocytes and fibroblasts. Following entry of beremagene geperpavec 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 beremagene geperpavec 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 beremagene geperpavec 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 beremagene geperpavec. 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 beremagene geperpavec 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 beremagene geperpavec. Negative shedding from skin swabs was achieved in 16 of the 19 subjects (84%) within six weeks following treatment with beremagene geperpavec. 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 beremagene geperpavec application.