Progress Seen on Five Fronts for Substantially Improving Treatment of Epidermolysis Bullosa

ASHEVILLE, North Carolina — Epidermolysis bullosa (EB), a heterogeneous congenital condition of skin fragility, received its first FDA-approved gene therapy only a few months ago, but accelerated progress across multiple treatment strategies predicts additional important and perhaps dramatic further progress, according to a prominent EB researcher.

Not only are recent developments in EB "exciting," the progress on multiple fronts for control of disease or its symptoms suggests "we are on the cusp of a new era," Jemima Mellerio, BSc, MD, a consultant dermatologist, St. John's Institute of Dermatology, London, England, said at the annual meeting of the Society for Pediatric Dermatology.

Published clinical studies of cell therapies and gene therapies date back at least 15 years, according to a review by Mellerio on why developments are starting to move so quickly. The difference now is that many obstacles to routine use of these options are being resolved, so that viable strategies have reached or are reaching phase 3 trials.

In addition to cell therapies and gene therapies, Mellerio discussed progress in three additional areas: gene editing, protein therapy, and drug repurposing.

Summarizing progress in each, she described improvement in levels of collagen VII, an important deficit in most types of EB, that were achieved with fibroblast injections that improved levels of collagen VII and anchoring fibrils in a study published in 2008. Injection of mesenchymal stromal cells (MSC) have been associated with reduced pain and itch in a series of studies, one of the earliest of which was published in the New England Journal of Medicine in 2010.

Since that time, there have been several approaches using MSC.

Of these approaches, intravenous injection of ABCB5+ MSCs might be the first to gain regulatory approval. According to Mellerio, there is an ongoing phase 3 crossover trial evaluating this approach, which followed several earlier phase studies that demonstrated adequate safety and tolerability while reducing severity scores, relieving pain and itch, and improving wound closure in patients with EB.

In 2006, correction of junctional EB (JEB) was achieved by transplantation of genetically modified epidermal cells to replace the LAMB3 gene, thereby restoring production of laminin 332, which is an essential component of the dermal-epidermal junction, according to Mellerio, citing a study in Nature Medicine.

The next attempt with this approach did not take place until 2015, resurrected to save the life of a 7-year-old Syrian boy — to generate epidermal sheets that eventually covered 80% of his body. The success is supporting further work on this approach but has also been an inspiration to other gene therapies, including a topical gene therapy recently approved in the United States.

Topically applied beremagene geperpavec (Vyjuvek, formerly known as B-VEC) was approved by the FDA in May for treating wounds in patients 6 months of age and older, with recessive or dominant dystrophic EB, on the basis of a phase 3 trial published in the New England Journal of Medicine, in December 2022, but others are coming. Mellerio also described a recently completed phase 3 trial with introduction of ex vivo gene-corrected keratinocytes, which has been associated with long-term improvements among patients with recessive dystrophic EB (RDEB). The responses in early phase studies included wound healing and reduction in pain and itch.

Perhaps less advanced but still promising, protein therapy, gene editing, and repurposing of existing therapies are all approaches that are moving forward. Many are supported by at least some clinical data, according to Mellerio.

As an example of protein therapy, a completed phase I/II trial associated recombinant human collagen with wound healing and pain reduction in RDEB. This study provided proof of principle for a therapy that could be applied topically or intravenously. Further development is anticipated.

Multiple platforms for gene editing have been described with the goal of simply excising pathogenic mutations or antisense oligonucleotides for sustained or permanent control of EB expression. Clinical evidence is limited, but Mellerio suggested that the theoretical potential for eliminating the source of abnormal transcription is the restoration of functional proteins essential for reversing skin fragility.

In some cases, existing drugs have the same potential. Mellerio described efforts to use an aminoglycoside to circumvent nonsense mutations that produce messenger RNA decay and impaired production of the proteins that prevent EB. In a pilot study evaluating topical gentamicin in RDEB, there were substantial improvements at 1 month and 3 months in several measures of skin fragility and encouraged studies that are now ongoing in both RDEB and JEB.

More than promising, a multinational randomized phase 3 study with birch bark extract recently published in the British Journal of Dermatology, associated treatment with this topical gel, known as Oleogel-S10, with higher rates of complete wound closure at 45 days (41.3% vs 28.9% in the control vehicle arm) and a low risk of adverse events.

"This therapy is now approved in Europe and the UK, although, unfortunately, it is not yet available in the US," Mellerio noted.

Importantly, none of these therapies are necessarily effective across subtypes of EB, which often have different underlying pathogenic mechanisms, she said. However, the growing sophistication with which the pathophysiology of these subtypes is understood makes the numerous treatments in the pipeline "exciting."

"We are at a point where we can really start to think of personalized medicine in EB," Mellerio said. With the clinical advances already available and those expected, she suggested the recently approved treatment options are just the beginning. She expects the treatment landscape to evolve quickly over the next few years.

This does not appear to be a personal opinion. Another prominent researcher in EB, M. Peter Marinkovich, MD, director of the Stanford Bullous Disease and Psoriasis Clinics at Stanford University, Stanford, California, is seeing the same real-world promise of therapies that have been in gestation for a decade or more.

"Dr Mellerio is right. This is an exciting time for EB patients," Marinkovich said in an interview. While the approval of B-VEC, the first gene therapy for EB, is the proof, Marinkovich, the lead author of the NEJM paper on B-VEC, noted that "many other potential EB therapies are being studied right now." Based on promise in earlier clinical studies with many of these agents, he, like Mellerio, expects progress in real-world treatments for EB to accelerate.

Mellerio reported financial relationships with Amryt Pharma and Krystal Biotech. Marinkovich receives research support from Abeona Therapeutics, Castle Creek Pharmaceuticals, Krystal Biotech, Phoenix Tissue Repair, and WINGS Therapeutics.

Society for Pediatric Dermatology (SPD) 2023 Annual Meeting: Hurwitz Lecture, Part 1. Presented on July 14, 2023.

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