Pivotal Phase 3 Trial Testing Topical Gene Therapy B-VEC Now Enrolling DEB Patients

Krystal Biotech has launched a pivotal Phase 3 clinical trial to investigate the topical gene therapy B-VEC (beremagene geperpavec) as a treatment for skin wounds in people with dystrophic epidermolysis bullosa (DEB).

The GEM-3 trial (NCT04491604) is already recruiting participants with DEB at four sites in the U.S., including one at Stanford University. More information can be found here.

Pending positive results, Krystal is planning to submit the data to the U.S. Food and Drug Administration (FDA) in 2021 to request approval of B-VEC for DEB patients. A submission to the European Medicines Agency is expected shortly thereafter.

“Despite the logistical challenges associated with COVID-19, Stanford and I are excited to begin this pivotal study,” Peter Marinkovich, MD, primary investigator for the trial, said in a press release.

“We and the other study sites have worked closely with the Krystal team to ensure safe trial practices in the context of the ongoing pandemic, enabled by the out-patient nature of B-VEC dosing,” added Marinkovich, a professor of dermatology and director of Stanford’s Blistering Disease Clinic.

Formerly known as KB103, B-VEC is a gene therapy candidate designed to deliver a normal version of the COL7A1 gene directly to the skin cells via a modified and safe herpes simplex virus. Mutations in this gene are the underlying cause of DEB, and lead to deficient production of collagen type VII (COL7). COL7 is an essential protein that keeps skin layers attached to each other.

Lack of COL7 causes the layers to separate, leading to painful blisters in DEB patients. By delivering a healthy copy of the COL7A1 gene, B-VEC is designed to prevent skin blisters and help close skin wounds in people with the disease.

B-VEC has been named an orphan drug for the treatment of DEB by both the FDA and the EMA — a status which provided Krystal with incentives to proceed with the therapy’s development. It also won fast track and rare pediatric designations from the FDA. With fast-track, the FDA will expedite both the development and review of an application for the treatment’s approval.

The FDA last year also granted B-VEC the status of regenerative medicine advanced therapy (RMAT), shortly after the therapy received PRIME (PRIority MEdicine) designation from the EMA. These designations also can help speed regulatory approvals to get new therapies to patients more quickly.

B-VEC is currently being investigated as a potential wound-healing treatment for generalized recessive DEB in a small Phase 1/2 clinical trial (NCT03536143).

That trial was divided in two parts. The proof-of-concept Phase 1 part, called GEM-1, enrolled two adults, ages 35 and 28. The patients were treated with B-VEC in one of their wounds, and a placebo in a matching wound. The selected wounds were about 10 cm² (square centimeters) in size.

The results showed that B-VEC increased the levels of COL7 in the skin of these patients, and helped close their wounds in just two weeks. When given the placebo, the wounds took 10 weeks to close in one patient and never closed in the other.

GEM-2, the Phase 2 part of the trial, then enrolled four adults — ages 22, 19, 21, and 33 — and two children, ages 14 and 15. In each of the children and in two of the adults, three wounds were treated with either B-VEC (two wounds) or a placebo (one wound). The other two adults had two wounds treated with either B-VEC or a placebo.

The wounds in these patients covered an area of up to 20 cm². The treatment was applied topically during the first five days, and then again at days 30, 60, and 90 if the wound was still visible.

B-VEC was well tolerated by all of the participants in both GEM-1 and GEM-2, with no related adverse events.

The final results showed that the treatment closed nearly all wounds after its initial administration. In fact, of the 10 wounds treated with B-VEC, nine (90%) closed completely after the initial five-day dosing. These wounds closed completely within a median of 14 days, and remained closed for a median of 110 days (about 3.6 months).

Only one chronic wound did not close completely after its initial B-VEC treatment — it was 42% closed at day 90. However, within seven days of re-treatment with B-VEC, this wound closed. It then remained closed for at least 100 days.

In contrast, none of the placebo-treated wounds closed completely over the course of the study.

These findings prompted the launch of the GEM-3 Phase 3 trial, which plans to compare repeat dosing of either B-VEC or a placebo in 30 DEB patients. The study will enroll participants, ages 6 months and older, with either the recessive or dominant form of the disease.

The investigators will select up to three wound pairs on each participant, and each pair will be randomly selected to receive either B-VEC or a placebo. The treatment will be given weekly for up to six months, and doses will depend on wound size, ranging from 400 million to 1200 million plaque forming units (PFU; a measure of viral particles).

The maximum weekly dose also will be determined by a patient’s age, with those younger than 3 years receiving up to 1600 million PFUs. Children ages 3-to-6 will be given up to 2400 million PFUs, with older patients receiving a maximum of 3200 PFUs per week. Weekly dosing will continue until the wound is completely closed and re-dosing will be initiated if a wound re-opens.

Additional wounds also may be selected for treatment with B-VEC, to allow doctors to treat a large number of wounds, the company said.

GEM-3’s main goal is to determine if B-VEC closes more wounds than a placebo at weeks 20, 22, and 24. Secondary goals include the proportion of completely closed wounds at weeks 8, 10, and 12, as well as changes in pain severity associated with wound dressing, and the proportion of wounds with at least 75% healing.

Exploratory measures include time to wound closure, how long the wound remains closed, reduction in wound surface, and changes in quality of life. Top-line results from the study are expected in 2021.

“The initiation of the pivotal study marks an important milestone toward our goal of a potential painless, convenient, and corrective approach to treat patients suffering from this debilitating disease,” said Suma Krishnan, founder and chief operating officer of Krystal Biotech.

“We look forward to having a home dosing protocol in place in the upcoming months that, we believe, would further improve the quality of life of our patients and their caregivers,” Krishnan said.

ANCORIS, Krystal’s manufacturing facility in Pittsburgh, is expected to support the commercial launch of B-VEC in the U.S. The company has plans to open a second facility, ASTRA, in early 2022 to support the treatment’s launch into the European and other markets.