FDA OKs First-Ever Topical Gene Therapy, for Rare Skin Disease

Alicia Ault

May 19, 2023

The US Food and Drug Administration (FDA) has approved the first-ever topical gene therapy, which will be used to treat wounds in patients 6 months of age and older who have either recessive or dominant dystrophic epidermolysis bullosa (DEB), a rare skin disease.

The therapy, Vyjuvek (beremagene geperpavec, formerly known as B-VEC), uses a nonreplicating herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells, restoring the COL7 protein fibrils that stabilize skin structure.

Vyjuvek, developed by Krystal Biotech, is designed to be used repetitively, to heal a single wound, or on more than one wound. In the pivotal study, the gene therapy, delivered in a topical gel, was administered once a week for 6 months.

The FDA gave Vyjuvek priority review, approving the therapy just 9 months after Krystal filed its application for approval. Vyjuvek is also an orphan drug, giving it potentially 7 years of marketing exclusivity.

"Vyjuvek is the first FDA-approved gene therapy treatment for DEB, a rare and serious genetic skin disorder," said Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, in the FDA's statement today announcing the approval.

"With the FDA approval of Vyjuvek, the DEB population has reached a monumental milestone in the treatment of this horrible disorder," said Brett Kopelan, executive director of debra of America, a national advocacy group for people with DEB, in a statement issued by Krystal Biotech. "Our hopes have now been realized for a safe and effective treatment for one of the most devastating symptoms of the disorder," said Kopelan.

"This is a devastating disease," said M. Peter Marinkovich, MD, primary investigator of Krystal's pivotal GEM-3 trial, and director of the Blistering Disease Clinic at Stanford Health Care, in the statement issued by Krystal. "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 Marinkovich, who is also associate professor of dermatology at Stanford University School of Medicine.

"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," he said.

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, said that Vyjuvek is an important advance for DEB. "This to me would be a treatment that I would consider for almost all patients," Vakharia told Medscape Medical News.

Vakharia, who was not involved with trials of Vyjuvek, said he had concerns about whether patients might develop antibodies to either HSV or C7, but that the greater initial worry is if Vyjuvek will be affordable and accessible. "I envision that it will be a costly medication," he said.

Kopelan, the patient advocate, said that his organization "will continue to work closely with Krystal to assure patients have ready access to Vyjuvek."

Krystal did not respond before press time to a request for comment on pricing.

Dystrophic epidermolysis bullosa affects 1 to 3 people per million in the United States. It is caused by mutations in the COL7A1 gene, which encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue. COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile that it tears with the slightest touch.

DEB usually presents at birth and is divided into two major types depending on the inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB).

People with the dominant form typically have mild cases with blistering primarily on the hands, feet, knees, and elbows. The recessive form can be painful and debilitating, causing widespread blistering. Depending on the severity, it can lead to nonhealing wounds, fusing of fingers and toes, anemia, weak bones, and esophageal and genitourinary strictures. Squamous cell cancers are a frequent cause of death.

Vyjuvek is mixed into an inactive gel and is evenly applied to a wound once a week by a healthcare professional, according to the FDA.  

The agency recommends the following precautions for patients and caregivers:

  • Avoid direct contact with treated wounds and dressings of treated wounds for 24 hours following application. Clean any area that is accidentally exposed.

  • Wash hands and wear protective gloves when changing wound dressings.

  • Disinfect the bandages used for the first dressing with a viricidal agent, such as 70% isopropyl alcohol, 6% hydrogen peroxide, or <0.4% ammonium chloride, and dispose of them in a separate, sealed plastic bag in household waste. Subsequent used dressings and cleaning materials should be disposed of in sealed plastic bags in household waste.

FDA approval of Vyjuvek was based on a randomized, double-blinded, placebo-controlled, 31-patient, phase 3 trial published in the New England Journal of Medicine, which showed that 71% of wounds treated with the gene therapy had complete healing at 3 months compared with 20% of those treated with placebo (95% CI, 29 - 73; P < .001). At 6 months, 67% of wounds treated with the gene therapy had complete healing compared with 22% of wounds treated with placebo (95% CI, 24 - 68; P = .002).

Almost two thirds of the patients had at least one adverse event. Most were mild or moderate. The most common events were pruritus, chills, and squamous cell carcinoma (SCC), reported in three patients each. SCC cases occurred at wound sites that had not been exposed to Vyjuvek or placebo. Serious adverse events, which were unrelated to the treatment, occurred in three patients and included diarrhea, anemia, and cellulitis.

Krystal will also be seeking marketing approval for Vyjuvek in the European Union, likely in 2024, said the company. In September, the European Medicines Agency's (EMA) Pediatric Committee issued a positive opinion on the gene therapy and Krystal’s plan to test B-VEC in children.

Marinkovich and Vakharia have disclosed no relevant financial relationships.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on Twitter @aliciaault.

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