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Pioneering gene therapy approval offers hope for dystrophic epidermolysis bullosa sufferers

Dystrophic epidermolysis bullosa is caused by a gene mutation, and the recent FDA approval of the corrective gene therapy VYJUVEK represents the first specific treatment to become available. Rod Tucker finds out more.

Dystrophic epidermolysis bullosa (DEB) is a rare genetic, blistering skin disorder that is usually present from birth. In addition to blistering, open wounds develop together with extra-cutaneous manifestations, affecting the eyes, oral cavity and many internal organ systems. Moreover, the disease places a huge burden on sufferers, caregivers and their families.

DEB occurs as a result of mutations in COL7A1, a gene encoding the alpha-1 chain of collagen type VII (C7) which form the anchoring fibrils of the skin and mucous membranes. Individuals with the disease have been referred to as ‘butterfly children’ due to the mechanical fragility of their skin which is analogous to that of a butterfly’s wings.

The FDA approval of VYJUVEK – also known as beremagene geperpavec or B-VEC – provides the first novel topical gene therapy. The treatment contains two copies of the COL7A1 coding sequence, encapsulated in a modified herpes simplex virus (HSV) type 1.

The delivery of the functional genes within B-VEC is achieved after outer shell viral proteins interact with proteins on the surface of skin cells to facilitate viral nucleocapsid entry. Once within the cell, the viral DNA is transcribed and translated into C7 and secreted into the extracellular space to assemble into anchoring fibrils.

Although yet to be officially approved by the European Medicines Agency (EMA), in 2018 the organisation granted B-VEC orphan drug designation, which will hopefully simplify the approval process. In addition, the UK’s National Institute for Health and Care Excellence is currently appraising the treatment.

But how effective is this novel topical therapy?

Efficacy of B-VEC in DEB

In an abstract abstract presented at the World Congress on Epidermolysis Bullosa in 2020, researchers described the use of B-VEC applied the wounds of two patients with recessive DEB in a phase 1 trial. It also detailed the findings of a phase 2 trial in which a total of 10 patients received the treatment. Overall, seven out of eight wounds treated with B-VEC closed completely within a median of 20.14 days.

Based on these early and positive findings, a phase 3, randomised, double-blind, placebo-controlled trial was initiated and published in the New England Journal of Medicine. The trial enrolled 31 patients, including children and adults, with DEB.

The trial used an intra-patient control design in which for each patient, the site investigator selected two wounds of similar size, anatomical region, and appearance. The wounds within each pair were then randomly assigned in a 1:1 ratio to receive either a weekly application of B-VEC or placebo for 26 weeks. The primary endpoint was complete wound healing at six months, whereas a secondary endpoint was complete wound healing after three months.

The results were remarkable. After six months, 67% of wounds treated with B-VEC were completely healed, compared to 22% of placebo-treated wounds (p = 0.002). Furthermore, complete healing of wounds after only three months occurred in 71% of those using B-VEC and 20% of placebo-treated wounds (p < 0.001). The researchers also examined the durability of the wound response in terms of sustained complete healing at both three and six months. This was seen in 50% of wounds treated with B-VEC but only 7% of placebo-treated wounds.

These positive findings in the phase 3 trial formed the basis of the FDA approval. But the results were important for a number of other reasons. Firstly, the successful use of a topical gene therapy over time bode well for not just DEB, but potentially for other genetic skin disorders. Secondly, the trial demonstrated the successful use a replication-defective HSV vector.

Thirdly, since B-VEC is formulated as a methylcellulose gel, it enables the patient or carer to apply the product themselves to existing wounds. Finally, because patients with epidermolysis bullosa are at an increased risk of squamous cell carcinoma (SCC), which can develop within chronic wounds, B-VEC may ultimately lower the risk of SCC.

Other potential treatments

But B-VEC is not the only therapeutic modality under investigation and there at least three other approaches being trialled. The first involves tautologous keratinocyte sheets containing full-length C7 using a retroviral vector and transplanted onto wound sites. In a phase 1/2 trial using this technique, researchers observed how wound healing exceeding 50% occurred in 95% of treated wounds compared to 0% in untreated control wounds.

The second approach makes use of recombinant human collagen 7 replacement therapy, which is given intravenously. Results from a phase 2 open-label study showed that after 120 days, 69.2% of treated wounds achieved a pre-specified response of a >2-point improvement on a wound-specific assessment scale.

For the third approach, work with topical or intra-dermal gentamicin was seen to induce type VII collagen and anchoring fibril production at the dermal-epidermal junction of erosion sites in five patients with recessive dystrophic epidermolysis bullosa.

While the findings to date are promising, B-VEC is not a panacea. For instance, because the treatment does not penetrate through the skin, it is only able to treat existing wounds rather than preventing new ones from forming. Furthermore, it is likely to require life-long dosing and has no effect on the systemic disease manifestations.

The EMA estimates that epidermolysis bullosa affects up to 36,000 people across Europe and, despite its limitations, B-VEC has the potential to provide relief for the cutaneous symptoms of this burdensome disease, which will be welcomed by sufferers and carers alike.

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