Krystal Biotech has announced the dosing of the first patient in its Phase 3 clinical trial evaluating KB803, a novel gene therapy eye drop designed to treat and prevent corneal abrasions in patients with dystrophic epidermolysis bullosa (DEB). The IOLITE study represents a significant milestone in addressing a critical unmet medical need for DEB patients who suffer from debilitating ocular complications.
The intra-patient, double-blind, multicenter, placebo-controlled study with crossover design will evaluate KB803's ability to deliver two copies of the COL7A1 transgene to the corneal epithelium, enabling local type VII collagen production in the front of the eye. This approach targets the fundamental disease-causing mechanism at the molecular level.
Addressing a Significant Unmet Medical Need
Over 25% of DEB patients are thought to suffer from ocular complications of the disease, including over 50% of patients with the recessive form of DEB (RDEB). The estimated number of DEB patients affected exceeds 750 in the United States and 2,000 worldwide. Currently, there are no corrective therapies available for the treatment or prevention of ocular complications associated with DEB, with disease management limited to supportive wound care and in some cases surgical interventions to remove scar tissue.
"The initiation of IOLITE is another important step for Krystal as we work tirelessly to treat DEB as comprehensively as possible," said Suma Krishnan, President, Research & Development, Krystal Biotech. "With dramatic and durable improvements already reported for the patient treated under compassionate use, we are excited by the potential of KB803 to restore full eye function and reduce or eliminate the otherwise persistent threat of vision loss imposed by these recurring corneal abrasions."
IOLITE Phase 3 Study Design
The IOLITE study will enroll approximately 16 subjects aged 6 months or older with DEB. The sample size was calculated based on average symptomatic days per month and standard deviation data from subjects enrolled in the natural history study, providing 90% power to detect an effect size of at least 25% while allowing for a dropout rate up to 20%.
Patients must first enroll in an ongoing natural history study and complete a 12-week run-in period, during which they report the number of days experiencing corneal abrasion symptoms. Enrolled patients will initially receive either placebo or KB803 at a concentration of 10^9 PFU/mL as a single eye drop to each eye once weekly for 12 weeks. At the conclusion of the first 12 weeks, patients will be switched from placebo to KB803, or vice versa, and continue with once weekly administration for a second 12-week period.
The primary study endpoint will be the change in the average number of days per month with corneal abrasion symptoms while receiving KB803 versus placebo. Statistical significance will be analyzed via intra-patient paired measurements to account for potentially expected high inter-patient variability. Safety and secondary efficacy data, including weekly assessments of eye pain and monthly Epidermolysis Bullosa Eye Disease Index (EB-EDI) questionnaires, will be collected throughout the 24-week study period.
Natural History Study Provides Foundation
The ongoing natural history study has enrolled 48 DEB patients, with 39 of the 48 subjects (81%) having RDEB and the remaining having the dominant form of DEB (DDEB). The average number of days per month with corneal abrasion symptoms reported by RDEB and DDEB subjects were 5.9 and 2.2 days, respectively, highlighting the significant burden of ocular complications in this patient population.
Promising Compassionate Use Results
Previous compassionate use data provides encouraging evidence for KB803's potential efficacy. Beremagene geperpavec-svdt (B-VEC) was previously applied to the eye of one DEB patient under a compassionate use protocol, with clinical observations published in the New England Journal of Medicine in February 2024. The patient presented with severe cicatrizing conjunctivitis secondary to DEB and underwent surgical symblepharon lysis with pannus removal, followed by regular B-VEC administration as an eye drop at a concentration of approximately 10^9 PFU/mL.
Treatment was well tolerated with no drug-related adverse events noted. Full corneal healing was observed at three months, as well as significant visual acuity improvement from hand motion to 20/25 by eight months, demonstrating the therapy's potential to address both healing and functional outcomes.
Gene Therapy Mechanism
KB803 is a redosable, eye drop gene therapy designed to deliver two copies of the COL7A1 transgene to the epithelial cells in a patient's eye. The goal of therapy is to address the fundamental disease-causing mechanism at the molecular level by providing the patient's epithelial cells of the eye with the template to make normal type VII collagen locally. This approach represents a novel therapeutic strategy for addressing the underlying pathophysiology of DEB-related ocular complications.
The IOLITE study is designed as a decentralized trial, with drug administration occurring at the subject's home by a healthcare provider, potentially improving patient access and convenience while maintaining rigorous clinical trial standards.
