.
In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.
“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.
Dr. M. Peter Marinkovich
“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
Rare, life-threatening, genetic blistering disease
DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that 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 it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
The first therapy for DEB, under FDA review
B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.
On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.
Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).
For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.
The results of the study included the following:
- Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
- Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
- The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
- Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.
“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.
The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.
“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.
Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.
Dr. Christen Ebens
“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.
Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”
In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”
Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.
Dr. Paras P. Vakharia
In an interview, Dr. Vakharia said that he’d like to know whether patients develop antibodies against HSV and C7 with long-term treatment and whether problems will arise related to drug availability.