KB407 gene therapy shows promise for all CFTR mutations in CF
Krystal Biotech to launch pivotal trial for treatment after positive safety data
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An experimental inhaled gene therapy for cystic fibrosis (CF), is headed for advanced clinical testing following Phase 1 data that indicated it’s generally tolerated well and appears to be working as designed.
KB407 developer Krystal Biotech recently announced interim data from the CORAL-1 (NCT05504837), a Phase 1 clinical trial primarily designed to evaluate the therapy’s safety in adults with CF. The data show that treatment led to the expression of healthy CFTR protein in the lung cells of patients who are not eligible for CFTR modulator therapies.
“Today’s update has profound implications for Krystal and for the many CF patients unable to benefit from modulator therapy ,” Suma Krishnan, president of research and development at Krystal, said in a company press release. Krystal plans to launch a clinical trial in the coming months to further test the therapy toward seeking its approval.
CF is caused by mutations in the gene that encodes CFTR, a protein that regulates mucus production. Lacking functional CFTR, people with CF produce unusually thick and sticky mucus that builds up in the lungs and other organs, driving most disease symptoms.
Modulator therapies are a recent class of medicine that can improve the functionality of the defective protein in people with CF who have specific underlying mutations. But not all patients can benefit from modulator therapy; those with class 1 mutations, who produce no CFTR protein at all, don’t respond to it.
What is KB407?
KB407 is made to deliver to cells in the lungs a gene encoding a fully-functional CFTR protein. This should restore the protein’s activity in lung cells, normalizing lung mucus production to ease symptoms. And unlike modulators, this strategy should work equally well regardless of an underlying mutation.
The first five patients in the CORAL-1 trial were given one or two daily doses of KB407. Late last year, Krystal announced that no serious safety issues had been reported.
The company has now shared an update from the final seven patients, all of whom received a high dose of the therapy — four daily administrations of 1 billion plaque-forming units (One plaque-forming unit is basically one particle of the gene therapy). Within a few days after the last dose, the patients underwent a procedure to collect lung biopsies for analysis.
Safety data were positive overall. The only serious safety issue reported was a severe asthma attack triggered by the biopsy procedure, which was judged to be unrelated to treatment. It was resolved in five days.
Biopsies were successfully collected from six of the seven patients, including four whose underlying mutations made them ineligible for modulator therapy. In all the patients, mucus-producing airway cells showed evidence of CFTR protein expression and/or a viral marker used in gene therapy to confirm delivery of the genetic payload. The percentage of positive cells in biopsies ranged from 29.4% to 42.1% across the six participants.
“Molecular confirmation of delivery and expression of unmodified, [healthy] CFTR protein in clinically relevant ciliated and secretory cells of the lungs of patients with CF is a tremendous breakthrough and a first for our field,” said Jorge Lascano, MD, director of the University of Florida’s Adult Cystic Fibrosis Program and Cystic Fibrosis Therapeutics Development Center.
“High rates of KB407 [gene delivery] and broad distribution across patient airways irrespective of underlying lung disease, genetic background, or modulator status – combined with the redosability of KB407 and demonstrated functionality of its full-length CFTR payload – underscore the transformative potential of KB407 as a mutation-agnostic therapy for the many patients either ineligible for or underserved by currently availably modulators,” Lascano said.
Krystal plans to launch a study called CORAL-3 that will further test KB407 in CF patients, the aim being to generate positive data to support its approval. The company has submitted plans to the U.S. Food and Drug Administration, and Krystal hopes to align with the agency in the coming months to begin enrollment by June. The company is also working with the Cystic Fibrosis Foundation to get the trial up and running.
“With clear evidence of CFTR protein expression in patients with class I mutations and reproducible KB407 transduction across a diverse CF population, we are moving forward with conviction into our repeat dosing study with registrational intent, CORAL-3,” Krishnan said. “We are excited to be working with the Cystic Fibrosis Foundation to accelerate clinical development and potential registrational timelines.”
