Krystal Biotech Announces Initial Clinical Update for Rare Respiratory Disease Programs KB408 and KB407 Including Early Clinical Evidence of Gene Delivery to the Lung of AATD Patients and Increase in Lung AAT to Therapeutic Levels
Clear evidence of SERPINA1 gene delivery and AAT expression following KB408 administration in AATD patients
Both KB408 for AATD patients and KB407 for patients with cystic fibrosis were safe and well tolerated at all dosing regimens evaluated to date
Conditional sanctioning of the KB407 Phase 1 CF Study CORAL-1 protocol by CFF TDN
Investor call and webcast to be held
“To achieve meaningful AAT expression levels and functionality with the first dose of KB408 is a very exciting development for this program and for our alpha-1 antitrypsin deficiency (AATD) patients,” said
The Company will host an investor conference call and webcast today,
KB408 for the treatment of alpha-1 antitrypsin deficiency (AATD) lung disease
KB408 is being evaluated in the Company’s Phase 1 SERPENTINE-1 study. SERPENTINE-1 is an open label, single dose escalation study in adult patients with AATD with a Pi*ZZ or a Pi*ZNull genotype. SERPENTINE-1 is designed to include up to three dose escalation cohorts evaluating single administrations of 109, 1010, and 1011 PFU of KB408 via inhalation. Additional details of the SERPENTINE-1 study can be found at www.clinicaltrials.gov under NCT identifier NCT06049082.
As of the
Two patients in Cohort 2 also received bronchoscopies to assess SERPINA1 delivery and AAT levels in the lung. Both a baseline bronchoscopy and a post-dose bronchoscopy, conducted 24 to 48 hours after KB408 dosing, were completed. One of the two patients who received bronchoscopies was receiving background IV augmentation therapy.
Clear evidence of successful gene delivery was observed in both patients, including high rates of transduction and AAT expression in the conducting airways of both patients as assessed via bronchoscopy. Key molecular findings for each patient are summarized below:
- A clinically meaningful proportion of conducting airway epithelial cells were transduced following administration of a single dose of KB408, with the percentage of cells positive for AAT expression increasing from 0% at baseline to 39% after KB408 dosing.
- Free AAT levels in lung epithelial lining fluid increased over 8-fold, rising from 85 nM at baseline to 729 nM after KB408 dosing.
- AAT functionality was also confirmed by detection of AAT-NE binding, with the percentage of active, unbound neutrophil elastase in epithelial lining fluid dropping from 97.2% at baseline to 40.2% – an over 50% absolute reduction achieved within 48 hours after dosing.
Patient on Background IV Augmentation
- Again, a clinically meaningful proportion of conducting airway epithelial cells were transduced following administration of a single dose of KB408, with the percentage of cells positive for AAT expression increasing from 3% at baseline to 35% after KB408 dosing.
- Lavage samples could not be successfully collected from this patient, preventing accurate quantification of AAT and neutrophil elastase binding in lung epithelial lining fluid. However, both KB408 genomes and SERPINA1 RNA transcripts were detected in multiple bronchial brushing samples, with an average of 4 x 103 genome copies and 4 x 102 transcript copies detected, providing further support of successful gene delivery and expression in the KB408 treated lung.
In addition to evidence of KB408 transduction and AAT expression in the lungs of these two patients, increases in serum AAT levels were also detected in all four Cohort 2 patients after KB408 dosing, suggestive of broad dissemination of KB408-encoded AAT following expression in the lung. Increases in serum AAT relative to baseline ranged from 270 nM to 5.3 µM in the three patients that were not on confounding background IV augmentation, including in one case increases in serum AAT from 4.4 µM at baseline to 9.7 µM after KB408 dosing.
KB408-related adverse events for all seven patients treated in Cohort 1 and Cohort 2 were mild to moderate and transient. No serious adverse events have been reported.
“With clear evidence of gene delivery, including detection of high nanomolar concentrations of AAT in lung epithelial lining fluid, as well as corresponding reductions in the percentage of unbound, active neutrophil elastase by over 50%, today’s initial clinical data is a major step forward towards our goal of developing a safe, effective, and non-invasive therapy for AATD patients to maintain therapeutic AAT levels in the lung,” said
The Company will enroll two additional patients in Cohort 2 of SERPENTINE-1 and expects to provide additional data updates in 2025. In parallel, the Company will open Cohort 3 to explore safety and gene delivery at the highest dose of KB408.
KB407 for the treatment of cystic fibrosis (CF)
Based on preclinical data submitted to date by the Company, the
KB407 is being evaluated in the Phase 1 CORAL-1 study. CORAL-1 is an open label, dose escalation study in adult patients with CF. CORAL-1 is designed to include up to three dose escalation cohorts evaluating either one, two, or four daily administrations of 109 PFU of KB407 via inhalation. Additional details of the CORAL-1 study can be found at www.clinicaltrials.gov under NCT identifier NCT05504837.
As of the
The initial focus of Cohorts 1 and 2 was safety of single and repeat inhaled administration of KB407 in patients with CF. As observed with KB408, KB407 has been well tolerated in all patients dosed to date. KB407-related adverse events for all five patients treated in Cohort 1 and Cohort 2 were mild to moderate and transient. No serious adverse events have been reported. The Company expects to report data from Cohort 3 in 1H 2025, including data on CFTR gene delivery and expression in patients with cystic fibrosis.
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Source: Krystal Biotech, Inc.