In the highest-dose cohort of its Phase 1 CORAL-1 study, Krystal’s inhaled gene therapy KB407 achieved confirmed airway transduction in all evaluable patients, with 29.4% to 42.1% of conducting airway cells positive for CFTR or a viral marker on bronchoscopy 24–96 hours post dosing. Among modulator-ineligible patients, two with class I mutations showed wild-type CFTR protein in target cells. Safety remained acceptable at this dose: most adverse events were mild to moderate; one post-bronchoscopy asthma exacerbation was deemed procedure-related and resolved within five days.
The core update centers on molecular proof-of-delivery at the top of the dose-escalation range. Seven patients received four daily inhaled administrations of 10^9 PFU; six had successful bronchoscopies yielding biopsies suitable for analysis, and all showed broad airway distribution. Each patient had at least 28 days of follow-up. On the back of these findings, Krystal has submitted a registrational repeat-dosing protocol, CORAL-3, to FDA, targeting alignment in Q1 2026 and study start in Q2 2026, with spirometry-based assessments planned to support potential registration.
Strategically, Krystal is attempting to convert early molecular validation into a fast pivot toward a registrational path in a segment where small-molecule modulators have left gaps, particularly for nonsense and other non-responsive mutations. The positioning is deliberately mutation-agnostic and leans on the redosability of the HSV-based platform, differentiating from one-time AAV approaches and offering an alternative to inhaled mRNA programs that have struggled with consistency and durability. The choice to emphasize in vivo protein expression in clinically relevant ciliated and secretory cells addresses long-standing skepticism about achieving meaningful transduction in diseased CF airways, but it also sets an evidentiary bar Krystal will now need to translate into functional benefit and durability.
Operationally, the development plan has implications for sites and CROs. CORAL-1 required coordinated bronchoscopy and biopsy within narrow post-dose windows, favoring centers with interventional pulmonology and CF trial infrastructure. If CORAL-3 includes repeat bronchoscopies for biomarker confirmation, site burden and scheduling will be non-trivial, and biosafety protocols for handling a live viral vector in nebulized form will matter. Conversely, if registration pivots to clinical endpoints alone, sponsors and regulators must align on an acceptable surrogate package and the frequency of invasive assessments. For modulator-eligible patients, the add-on versus substitution question will complicate design, standardization of background therapy, and statistical powering, while modulator-ineligible cohorts may offer a clearer regulatory path but a smaller immediate enrollment pool.
For regulators, the unanswered questions are durability, redosing feasibility without loss of effect from anti-vector immunity, and correlation between biopsy-level transduction and clinical outcomes such as ppFEV1, exacerbation rate, and sweat chloride. Sites will look for clarity on procedure intensity and monitoring cadence. Vendors supporting central histology, immunofluorescence quantification, and vector shedding assays should expect specialized workflows and tight turnaround. Patients and advocacy groups will focus on whether molecular success can translate into sustained pulmonary benefit across genotypes that currently lack disease-modifying options.
Next, watch for longitudinal data from CORAL-1 on functional measures and the initial FDA feedback on CORAL-3 endpoints, population selection, and redosing intervals. Manufacturing scale and release testing for a multi-dose, redosable inhaled gene therapy remain a practical risk as the program moves toward larger, longer studies. Competitive readouts from other inhaled genetic approaches could reshape expectations on effect size and dosing cadence. The near-term signal to watch is whether Krystal can demonstrate durable, clinically meaningful improvement beyond early biopsy readouts, which will determine whether the program’s molecular promise can carry into registration-grade evidence.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
