Krystal Biotech (KRYS) Study Update summary

Clinical context and unmet need

• Over 10% of cystic fibrosis patients are ineligible for modulator therapies, with thousands more experiencing suboptimal responses, leading to ongoing lung function decline, frequent exacerbations, and higher treatment burden.

• Gene-based, mutation-agnostic therapies are needed to address the broad spectrum of CFTR mutations, especially for those with no functional CFTR protein.

KB407 program, platform, and preclinical validation

• KB407 is an inhaled, redosable gene therapy delivering two copies of full-length CFTR via a proprietary HSV-1 vector, overcoming historical gene therapy challenges such as cargo size and redosing.

• The HSV-1 vector platform is FDA-approved for other indications and has shown safety, repeat dosing capability, and broad epithelial tissue applicability.

• Preclinical studies demonstrated efficient, dose-dependent CFTR expression, proper localization, and sustained in vivo expression in animal models, with no notable toxicity in non-human primates.

• Prior clinical success with related programs (KB408, KB707) supports the platform's potential for lung diseases.

Phase 1 CORAL-1 study design and execution

• The Phase 1 CORAL-1 study evaluated safety, tolerability, and molecular efficacy of ascending doses of inhaled KB407 in adults with CF, including those ineligible for modulators.

• Seven adult CF patients were dosed, with lung function ranging from 45%-82% ppFEV1; three were on modulator therapy.

• Cohort 3 received four high doses, with mandatory bronchoscopies and biopsies for molecular assessment; most patients were modulator ineligible.