D19-10 Interim Results of the Coral-1 Trial of Kb407 for the Treatment of Cystic Fibrosis

Rationale

Cystic fibrosis (CF) is caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene and characterized by progressive pulmonary impairment. There is a current unmet need for gene-corrective therapies, particularly for patients who are ineligible for or unable to benefit from approved modulator therapies. KB407 is a herpes simplex virus type 1 (HSV-1)-based gene therapy vector encoding full-length human CFTR developed for the treatment of CF. The vector backbone underlying KB407 is non-replicating, accommodates the large size of the CFTR gene, and is amenable to administration via nebulization. Here, we report interim results of the highest dose cohort (Cohort 3) in CORAL-1 (NCT05504837), a Phase 1, open-label, dose escalation study in adult patients with CF aimed at assessing the preliminary safety of and molecular correction by nebulized KB407.

Methods

A total of seven patients were enrolled in Cohort 3 and received 109 plaque forming units of KB407 via nebulization once daily for four consecutive days followed by a post-dose bronchoscopy one to four days after the last KB407 exposure. Endobronchial biopsies from the lungs of these patients were assessed for expression of CFTR and/or a viral marker of KB407 via immunofluorescence (IF). Safety was assessed by the severity and relatedness of adverse events (AEs).

Results

IF revealed broad airway dissemination of KB407, with vector transduction ranging from 29.4% to 42.1% of all air-exposed cells averaged across examined biopsies, irrespective of the underlying CFTR variant of the patient. CFTR protein expression was detected in individuals without endogenous CFTR expression up to 96 hours post-dose with a cellular distribution pattern suggestive of appropriate apical localization. All KB407-related AEs were transient, and all but one were mild or moderate. One serious AE of asthma exacerbation was reported 24 hours after bronchoscopy. Upon review by the independent data monitoring committee, the case was deemed related to the bronchoscopy procedure and not KB407. There was no evidence of significant neutralizing antibody response or systemic vector distribution following KB407 administration.

Conclusions

KB407 is the first gene therapy to demonstrate molecular correction of full-length, wild-type CFTR in the lungs of patients with CF. A registrational trial is planned to assess the safety of repeat KB407 dosing and the impact of treatment on lung function by spirometry.

This abstract is funded by: Krystal Biotech, Inc