PITTSBURGH—October saw gene therapy company Krystal Biotech Inc. share positive interim results from an ongoing placebo-controlled Phase 1/2 clinical trial of KB103 in dystrophic epidermolysis bullosa (DEB). DEB is an incurable and often fatal skin blistering condition that results from a lack of collagen in the skin—specifically type VII collagen, or COL7—due to genetic mutations. Given that COL7 is key in anchoring fibrils, which connect the dermis and epidermis, the lack of this protein causes blisters to form in the dermis as it separates from the epidermis.
KB103 is a replication-defective, non-integrating viral vector designed with Krystal’s STAR-D platform. It delivers functional human COL7A1 genes directly to dividing and non-dividing skin cells using HSV-1, a proprietary vector that can penetrate skin cells more effectively while carrying a high payload and presenting with low immunogenicity.
The trial in question consists of two recessive DEB, NC1[+] patients ages 28 and 35, who were treated with topical KB103 and re-dosed. Each patient had two wounds with a surface area of approximately 10 cm2 randomized to be treated with either topical KB103 or placebo), and also received intradermal injections of the compound to intact skin to monitor its mechanism of action. Following administration, the treated wounds and injected intact skin were biopsied to measure COL7 expression and anchoring fibril formation, as well as being evaluated for healing compared to the placebo-treated wounds and baseline.
Both patients met all primary efficacy endpoints in topically treated wounds, which included presence of functional COL7 expression, observation of NC1 and NC2 reactive anchoring fibrils and continued expression after repeat administration. In addition, safety endpoints—no adverse events, inflammation or irritation—were also met.
“With multiple applications of the topical therapy, we saw no inflammation, no systemic symptoms,” Dr. Peter Marinkovich, an associate professor of dermatology at Stanford University and principal investigator in the GEM study, said in a conference call. “We saw no shedding in the blood or urine samples that we collected, and no antibodies to COL7 were detected. Inherent in this therapy is the fact that it does not randomly incorporate into the genome, so unlike other viral therapies, this therapy has no risk of insertional oncogenesis.”
The treated wounds showed robust functional COL7 expression via immunofluorescence in biopsy samples by the second day of treatment, with functional expression measured by staining tissue samples with NP185 and LH24 antibodies, which bind to NC1 and NC2 domains of the COL7 protein, respectively. Both patients were NC1 positive at baseline, and their biopsy samples showed NC1 and NC2 domains, proof of production of functional COL7. Immunoelectron microscopy showed NC1 and NC2 reactive anchoring fibrils in both patients by day 14.
According to Marinkovich in the call, “It’s estimated that collagen 7 half-life is about two months in vivo in human skin, and so the expectation is that when we see linear staining for COL7, this is going to remain durable over a month’s time point.”
The topically treated wounds closed in two weeks, and were still closed by the time of Krystal’s announcement. In the placebo-treated wounds, closure took 10 weeks in Patient 1, while Patient 2’s placebo-treated wounds had not completely closed through the course of the study. Both patients’ KB103-treated wounds remained closed as of mid-October, which comes to 4.5 months of total closure for Patient 1 and 3.5 months for Patient 2.
“Many trials in EB today are looking at wound healing, and there are a number of different types of ways that EB wounds can heal, with either allogeneic treatments, as well as wound care improvements,” Marinkovich explained in the company’s conference call. “However, the real key is to look at durability of wound closure, as epidermolysis bullosa is not a defect of re-epithelialization. The keratinocytes in the epithelium can cover the wound. The problem is adhesion, or maintenance of epithelium on the wound, and the danger of re-blistering after the wound has healed. Many of these patients have repeated healing and wounding occurring continuously, and it’s a cycle that can be broken by adding adhesion to the epidermis. That’s what this therapy seeks to do, is to add adhesion to the epidermis.”
Krystal has submitted the clinical data to the FDA, and the protocol for future patients in this Phase 1/2 trial has been amended to remove the intradermal arm. Additionally, the protocol moving forward will enroll pediatric patients, and will examine the durability of wound closure resulting from KB103 to aid in determining endpoints for a Phase 3 trial. The updated protocol also allows for increased administration to larger wound areas.
“Results on 2 patients demonstrate a meaningful clinical benefit and suggest that KB103 can afford a simple, convenient, painless way to administer treatment for patients suffering with this debilitating disease,” Marinkovich commented in a press release. “These early data are encouraging, and we look forward to continuing the study in pediatric populations.”