The Krystal Biotech treatment, marketed as Vyjuveck, is now the first topical gene therapy for patients with DEB—marking a milestone in the paradigm of care.
The FDA has approved beremagene geperpavec (B-VEC), a topical and redosable gene therapy from Krystal Biotech, for the treatment of dystrophic epidermolysis bullosa (DEB) in patients 6 months or older.1 The gene therapy, the first for this indication, will be marketed under the name Vyjuvek.
B-VEC’s biologics license application (BLA) was supported by data from 2 intrapatient, placebo-controlled clinical trials: the phase 2 GEM-1/2 (NCT03536143) study and the phase 3 GEM-3 study (NCT04491604).
“For so many years, all we have been able to offer DEB patients was palliative care, but now, based on the strength of the Company’s clinical trial data, there is a safe and effective FDA-approved treatment," said Suma Krishnan, the founder, and president of research and development at Krystal Biotech, in a statement.1
"I think many more local primary care pediatricians and dermatologists will start to treat epidermolysis bullosa patients now that they have an easy corrective therapy they can prescribe. This will be a benefit for epidermolysis bullosa patients as well," M. Peter Marinkovich, MD, primary investigator and associate professor of dermatology, faculty member of the Program in Epithelial Biology and the Stanford Cancer Biology Program, as well as director of the Stanford Bullous Disease and Psoriasis Clinics at Stanford University, told CGTLive™. "It's especially important to start treating at a young age, in order to help prevent chronic wounding and fibrosis issues."
DEB is caused by mutations in COL7A1, a gene involved in assembling type 7 collagen that plays a vital role in skin stabilization. B-VEC is a topical herpes simplex virus type 1-based gene therapy that delivers COL7A1 to restore C7 protein. COL7 molecules arrange in long, thin bundles that form anchoring fibrils that hold the epidermis and dermis together, which helps maintain integrity of the skin. The gene therapy has also been modified so that it does not replicate in normal, unaffected cells. The gene therapy is applied to wounds weekly in a gel droplet form.
B-VEC previously received orphan drug, fast track, and rare pediatric disease designations, as well as a Regenerative Medicine Advanced Therapy designation, from the FDA.
“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 a statement.2 “Today’s action demonstrates the FDA’s ongoing commitment to supporting the development and evaluation of new treatments that address unmet needs for rare diseases or conditions.”
A full data readout from the GEM-3 study was published in the New England Journal of Medicine in December 2022,3,4 with data showing that in 31 patients, 67% of wounds treated with B-VEC had complete healing at 6 months compared with 22% of those not treated with B-VEC (difference, 46%; 95% CI, 24-68; P = .002). The gene therapy was also well-tolerated, with pruritis and chills noted as common adverse events (AEs).
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In the published findings from the GEM-3 trial,3,4 71% of wounds treated with B-VEC were completely healed at 3 months compared with 20% exposed to placebo (difference, 51%; 95% CI, 29-73; P <.001). Pain severity during wound-dressing decreased by 0.88 points from baseline to week 22 in B-VEC-treated wounds and by 0.71 in placebo-treated wounds, (adjusted least-squares mean difference, −0.61; 95% CI, −1.10 to −0.13) with similar changes reported at week 24 and week 26.
GEM-3 was a double-blind, intra-patient randomized, placebo-controlled trial that assessed B-VEC in patients at least 6 months of age with genetically confirmed DEB. Investigators selected a primary wound pair on each patient that was matched in size, region, and appearance. Those included were a mean age of 16 years (range, 1-44) and more than half (61%) were 18 years old or younger. All but a single patient—who had a dominant form of DEB—had recessive DEB. Wounds were of similar size, with a median area of 10.6 cm2 in treated wounds and 10.4 cm2 in placebo wounds.
Wounds within each pair were randomized to receive weekly applications of placebo or B-VEC for 26 weeks, with a primary end point of complete wound healing in treated versus untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and changes from baseline in pain severity during wound dressing at weeks 22, 24, and 26, as assessed by a visual analogue scale with scores ranging from 1 to 10.
Marinkovich said “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. Vyjuvek topical gene therapy changes all of this. Vyjuvek both heals patient wounds and prevents skin from re-blistering because it actually corrects the underlying skin defect of dystrophic EB. 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."1
Data from its compassionate use program were also recently reported at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, in New Orleans, Louisiana.5 Those data, presented by Alfonso L. Sabater, MD, PhD, assistant professor of Clinical Ophthalmology at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine, showed improved vision in a patient with DEB who experienced recurrent cicatrizing conjunctivitis. The patient received surgical symblepharon lysis with pannus removal in the right eye, and in addition to routine post-surgical management, the patient's right eye was treated with B-VEC at regular intervals after surgery. B-VEC use was associated with full corneal healing by 3 months and significant visual acuity improvement from hand motion to 20/40 at 7 months, the latest time point of treatment effect evaluation.
The following precautions should be taken among those receiving treatment with or handling B-VEC:
The BLA for B-VEC was originally accepted by the FDA with priority review in August of 2022, after being submitted in June 2022.6 Its review period was extended by the agency in January 2023,7 based on manufacturing process information, including information about the replacement of a hardware unit in the process’s concentration step and associated comparability data regarding its use.