Krystal Biotech (NASDAQ:KRYS) said it has generated positive interim clinical results for its inhaled cystic fibrosis (CF) gene therapy candidate KB407, including molecular confirmation of wild-type CFTR protein expression in patients’ lungs. The company discussed the data on a clinical update call focused on Cohort 3 of its Phase 1 CORAL-1 study and outlined plans to move into repeat dosing with an eye toward a potentially registrational study design.
Management highlights “breakthrough” CFTR delivery milestone
Chief Executive Officer Krish Krishnan said the company has now “confirmed the successful delivery and expression of wild-type CFTR protein in multiple patients with cystic fibrosis,” which he characterized as a breakthrough enabled by the company’s HSV-1-based gene delivery platform. With a wild-type CFTR payload and functionality previously shown in multiple preclinical models, Krishnan said the interim readout gives the company conviction to move “rapidly into repeat dosing.”
Clinician perspective: modulators leave a meaningful subset behind
Dr. Jorge Lascano of the University of Florida emphasized that CFTR modulators have been transformative for many patients, citing sustained improvements in lung function, reduced exacerbations, improved nutritional status, and increased survival in eligible populations. However, he said at least 10% of individuals with CF “either cannot receive or cannot tolerate modulator therapy,” including patients with rare or minimal function mutations such as nonsense mutations that do not produce CFTR protein. He also noted that some patients do not derive meaningful benefit even if their mutations are receptive to modulators.
For those who do not benefit from modulators, Lascano said registry data show ongoing lung function decline, higher rates of pulmonary exacerbations, persistent chronic airway infection, and continued need for hospitalizations and intensive daily therapies. He added that these patients do not share the same survival gains as modulator-treated populations, often leading to early lung transplant considerations and significant uncertainty about long-term outcomes.
KB407 and the HSV-1 platform: mutation-agnostic intent and repeat-dosing focus
President of R&D Suma Krishnan described KB407 as an inhaled genetic medicine designed to deliver “two copies of the full-length CFTR gene” via the lungs to restore CFTR-mediated ion transport, mucus clearance, and lung function. She said the program is supported by preclinical data showing KB407 transduces clinically relevant cell populations and that encoded CFTR is full-length, properly localized, and functional. In GLP enabling toxicology studies in non-human primates, she said KB407 was amenable to nebulization, well tolerated, broadly distributed in airways, and showed payload expression persisting for at least 28 days without notable toxicity.
Krystal positioned the CF lung as a high bar for nebulized gene therapy delivery and said success here, along with prior lung-delivery evidence from its Alpha-1 antitrypsin deficiency program KB408 and lung cancer program KB707, supports broader potential for the platform in lung diseases.
CORAL-1 Cohort 3: CFTR expression and airway transduction across patients
Clinical lead David Sweet said Phase 1 CORAL-1 is evaluating safety and tolerability of ascending doses of nebulized KB407, with Cohort 3 also assessing molecular correction at the highest dose. Cohort 3 enrolled adults with confirmed CF, lung function of 40% to 100% ppFEV1, and limited concurrent modulator use (no more than three patients).
Patients in Cohort 3 received 109 plaque-forming units of KB407 via nebulization once daily for four consecutive days, followed by bronchoscopy one to four days after the last dose. Endobronchial biopsies were evaluated for histology and evidence of transduction and molecular correction using immunofluorescence detection of CFTR protein where feasible, or a viral marker (ICP27) in patients where endogenous CFTR expression could confound CFTR staining. Patients were followed for eight weeks, with sampling for shedding and immunogenicity.
Seven patients were dosed in Cohort 3, and six had successful bronchoscopies yielding biopsy samples suitable for molecular analysis. Lung function among patients ranged from 45% to 82% ppFEV1, and three of the seven were modulator-eligible.
- Class I (“null”) mutation patients: In one Class I patient, all seven usable biopsies were positive for human CFTR protein, with 42.1% of conducting airway surface cells CFTR-positive and an apical distribution pattern. In a second Class I patient, five usable biopsies showed 29.4% of conducting airway surface cells CFTR-positive, with broad distribution across tested lobes.
- Other patients assessed via viral marker: Sweet reported ICP27-based transduction rates of 36.5%, 33.8%, 36.8%, and 31.4% in additional patients, including modulator-ineligible individuals and two patients homozygous for ΔF508 on modulator therapy.
Across all biopsied patients, the company said more than 29% of cells were positive post-dose. Sweet noted this exceeded an “approximately 5%–15%” transduction target that is “currently predicted” to provide meaningful functional correction. The company also said co-staining suggested KB407 delivered CFTR expression across multiple airway cell types, including ciliated, club, and goblet cells.
Safety, immunogenicity, and next steps: repeat dosing and registrational discussions
Sweet said KB407 continued to show a favorable tolerability profile, with stable ppFEV1 levels throughout the eight-week study period. All KB407-related adverse events were transient and mostly mild to moderate. One serious adverse event occurred 24 hours after bronchoscopy; the independent data monitoring committee deemed it related to the bronchoscopy procedure rather than KB407, and it resolved within five days.
On immunogenicity, Sweet said no significant neutralizing antibody response was observed after KB407 administration, which the company said supports the feasibility of long-term repeat dosing. The company also said inhaled KB407 appeared localized to the lungs, citing a lack of systemic vector distribution.
Looking ahead, Suma Krishnan said Krystal has begun working with the CFF Therapeutics Development Network on a repeat dosing CORAL-3 study design that has been submitted to the FDA. She said final details will be disclosed once alignment is reached, but the goal is to assess functional impact by spirometry without bronchoscopy. The company said it is exploring study designs that could support registration if successful and expects to align with the FDA in the months ahead, with the aim to initiate a registrational study in the first half of the year.
During Q&A, management emphasized that it is pursuing an FEV1 endpoint in a registrational repeat dosing study, rather than seeking approval based on CFTR expression as a biomarker alone. Executives also discussed the possibility of accelerated pathways given unmet need, while noting they would not provide specifics until discussions with the FDA are complete.
Krishnan closed by saying the KB407 data put the program on an accelerated path toward a potential registrational readout and filing, and he also pointed to other rare-disease pipeline programs, including ophthalmology candidates KB803 and KB801, which he said could deliver registrational data readouts later in the year.
About Krystal Biotech (NASDAQ:KRYS)
Krystal Biotech, Inc is a clinical-stage biotechnology company focused on developing gene therapies for rare dermatological diseases. Headquartered in Pittsburgh, Pennsylvania, the company applies proprietary viral vector delivery technology to enable topical administration of corrective genes directly to the skin. By targeting the underlying genetic causes of inherited skin disorders, Krystal Biotech seeks to address areas of high unmet medical need with potentially transformative treatments.
The company’s lead product candidate, KB103, is designed to deliver a functional COL7A1 gene to patients with dystrophic epidermolysis bullosa (DEB), a severe and often debilitating blistering condition.
