Rare Skin Blistering Condition Gets First Drug Approved

The FDA granted the first drug approval for dystrophic epidermolysis bullosa (DEB), a topical gene therapy that treats the blistering wounds it causes, the agency announced Friday.

The herpes-simplex virus type 1 vector-based gene therapy, Vyjuvek, was approved for patients ages 6 months and older with mutation in the COL7A1 (collagen type VII alpha 1 chain) gene.

That gene encodes an essential protein, collagen type VII, that helps strengthen and stabilize the outer and middle layers of the skin. Without enough of that protein produced, the connective tissue in the skin and nails is too weak to hold the skin layers together, leading to painful and debilitating blisters and wounds.

The gene therapy agent is mixed into an excipient gel prior to topical application by a healthcare professional to a patient's wounds once a week, either in an office setting or at the patient's home, according to the label.

The approval also marks the first for a redosable gene therapy, noted developer Krystal Biotech in a press release.

DEB usually presents at birth. The dominant inherited form can be mild with blistering primarily affecting the hands, feet, knees, and elbows. The recessive form, in which patients carry two copies of the mutated gene, often causes widespread blistering that can result in vision loss, disfigurement, and other serious or fatal medical complications. The approval covered both forms.

The faulty gene in DEB is too large for the adeno-associated virus (AAV) vectors that have been approved in conditions like hemophilia B and retinal dystrophy as one-time treatments that deliver corrected versions of mutated genes into the nucleus and use the natural machinery there to synthesize and continue pumping out the needed proteins.

Instead, Vyjuvek is based on a herpes-simplex virus type 1 vector that can carry the hefty genetic payload. That viral vector is modified to be unable to replicate and doesn't insert into the chromosome in the host cell, avoiding risk of mutagenesis that could lead to cancer.

Approval of the gene therapy agent, also known as beremagene geperpavec or B-VEC, centered on the GEM-3 trial, in which weekly topical administration led to complete healing of 67% of treated wounds as compared with 22% of those exposed to placebo at 6 months (P=0.002).

The pivotal phase III trial included 31 patients who were ages 6 months and older (cohort median age 16 years). A second study of two patients ages 6 and 7 months of age, respectively, added to the safety findings for weekly topical administration.

The most common adverse reactions with the gene therapy were itching, chills, redness, rash, cough and runny nose.

"Until now, doctors and nurses had no way to stop blisters and wounds from developing on dystrophic EB patient skin and all we could do was to give them bandages and helplessly watch as new blisters formed," said GEM-3 trial primary investigator M. Peter Marinkovich, MD, of Stanford University in California, in a statement. "Because it's safe and easy to apply directly to wounds, it doesn't require a lot of supporting technology or specialized expertise, making Vyjuvek highly accessible even to patients who live far away from specialized centers."

FDA noted precautions that patients and their families need to take to avoid direct contact with treated wounds and their dressings in the first 24 hours after application. These precautions include washing hands and wearing protective gloves when changing wound dressings and disinfecting bandages from the first dressing change with a virucidal agent before sealing them in a separate plastic bag in household waste.

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