Epidermolysis bullosa - Emerging treatments

Beremagene geperpavec

Beremagene geperpavec is a topical gene therapy utilizing a live replication-defective HSV-1 based vector that has been genetically modified to express the human type VII collagen (COL7) protein, resulting in sustained production of COL7 with resultant diminished wound burden. Beremagene geperpavec is approved by the Food and Drug Administration (FDA) for wound management in patients with dystrophic epidermolysis bullosa (DEB) and a mutation in the COL7A1 gene. It is the first topical gene therapy approved by the FDA. Beremagene geperpavec has been granted orphan drug designation in Europe for the treatment of epidermolysis bullosa. Complete wound healing was more likely with topical administration of beremagene geperpavec at 3 and 6 months in patients with DEB, compared with placebo, in a phase 3 trial.[67]

Topical birch triterpene gel

Topical gel formulations containing birch triterpenes have been shown to promote keratinocyte migration and differentiation in vitro as well as modulating inflammation. Accelerated wound closure has been demonstrated in a variety of clinical wound scenarios including burns and post-surgery. Phase 3 trials have been completed in the setting of junctional epidermolysis bullosa (JEB) and DEB, with early promising results for expedited wound healing.[68] An open-label extension is currently underway. The FDA rejected approval of the topical birch triterpene gel (known as Oleogel-S10®), requesting further efficacy data. However, the European Medicines Agency (EMA) has approved a formulation (known as Filsuvez® gel, which contains dry extract from two species of birch bark) for the treatment of partial thickness wounds associated with DEB and JEB in patients 6 months and older.

Ex vivo gene therapy

An early proof-of-principle trial of gene therapy for JEB, intermediate was reported from Italy. One patient transplanted with a small, laminin-332 gene-corrected, culture-generated autologous keratinocyte explant has remained blister-free within the artificial skin graft site for many years.[69] A seven-year-old child with generalized JEB was similarly successfully treated with ex vivo laminin-332 gene corrected autologous keratinocytes over large surface areas.[70] A phase 1 clinical trial employing a similar ex vivo approach is ongoing in a small number of patients with RDEB-gen intermed, using keratinocytes corrected with the normal type VII collagen gene and applied as skin grafts to localized affected skin sites.[71] Other groups are pursuing similar approaches worldwide.

Stem cell transplantation

Data have been reported from seven RDEB children enrolled in an experimental clinical trial of bone marrow-derived stem cells.[72] Data from short-term follow-up are encouraging, with clinical improvement seen in some of those so treated. It is far too early, however, to know whether these benefits will persist for longer periods of time. One patient reportedly died prior to receiving the transplant, likely from complications of chemotherapy, and a second child died following transplantation. On the basis of these early results, other additional clinical trials with stem cells are currently underway elsewhere. Extensive studies, including mouse models, are also in progress to determine whether other sources or types of stem cells (i.e., mesenchymal, inducible pluripotential) might be used for transplantation in these patients.[73][74][75][76]

Recombinant protein and allogeneic cell therapies

Data in several mouse models for RDEB suggest that it might be possible to provide molecularly normal type VII collagen, either intravenously or through normal fibroblasts, such that it becomes incorporated in skin otherwise devoid of this protein. If that could be safely given to humans, without risks of autoimmunity, thrombosis, or stroke, then it is theoretically possible that such a treatment, although not curative, might at least temporarily restore structural integrity to the affected tissues, resulting in cessation of blistering. On the basis of these laboratory data, a clinical trial has been considered in which recombinant type VII collagen would be infused intravenously into a limited number of patients with generalized RDEB. Other patients with generalized RDEB are being treated with intradermal injections of allogeneic human fibroblasts into nonhealing skin wounds, based on preliminary data in a limited number of patients so treated.[77] Of note, similar benefits have been seen in some patients receiving only saline injections into their wounds, suggesting that there may be other mechanisms by which those treated with fibroblasts may have improved.

Antifibrotic therapies

A variety of chemicals have shown promise in reducing fibrosis in tissues including skin. As dermal fibrosis is now considered an essential feature in the early pathophysiology of carcinogenesis in RDEB skin, several clinical trials have been proposed to test this hypothesis. One multicenter trial involving a common cardiac drug, losartan (an angiotensin-II receptor antagonist), is now underway, based on promising findings in a mouse model for this disease.[78]

Systemic anticancer therapies

Several different chemotherapeutic drugs, including intravenous PD-1 checkpoint inhibitors (e.g., cemiplimab), are being explored as potential therapy for metastatic squamous cell carcinoma (SCC) in RDEB.[79][80] Data are currently limited, based on short-term findings in individuals or small numbers of patients. A clinical trial of rigosertib, a polo-like kinase inhibitor, is also underway in the setting of advanced EB-SCC in RDEB patients that have failed conventional standard treatments.[81][82]

Repurposed small molecules and biologics

There is interest in repurposing therapeutics already in use for common inflammatory skin diseases given pre-existing safety data and reduced costs of implementation. A variety of small molecules and monoclonal antibody approaches including apremilast, dupilumab, and interleukin-17 inhibitors are being investigated.[83][84] It is thought that by reducing chronic inflammation within wounds, healing may be expedited. Current data is limited to case reports and small case series.