First CF patient dosed in US trial of gene therapy KB407

Phase 1 CORAL-1/US study is recruiting up to 20 adults with 2 copies of CFTR mutation

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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The first patient has been dosed in a Phase 1 clinical trial of KB407, Krystal Biotech’s investigational gene therapy for people with cystic fibrosis (CF) regardless of the type of disease-causing CFTR gene mutation.

The Phase 1 CORAL-1/US study (NCT05504837) is recruiting up to 20 adults with CF with two copies of a disease-causing CFTR mutation. It’s enrolling at the Cystic Fibrosis Institute in Northfield, Illinois, with a site at Yale University School of Medicine expected to open later.

“Dosing our first patient in the KB407 Phase 1 clinical trial is an exciting step forward for the company and for the patients we aim to benefit,” Hubert Chen, MD, senior vice president of clinical development at Krystal Biotech, said in a company press release. “We look forward to continued enrollment into the Phase 1 study with anticipated data in 2024.”

CF is caused by mutations in the CFTR gene, which provides instructions to produce a protein of the same name that regulates the movement of salts and water into and out of cells, which is essential for healthy mucus production.

CFTR mutations cause CFTR to be missing or nonworking, leading to thick and sticky mucus being produced that is a characteristic of the disease, particularly in the lungs and digestive tract.

KB407, administered via a nebulizer, is a repeat-dose therapy that uses a modified and harmless herpes simplex virus 1 to deliver two working copies of the CFTR gene directly to airway cells. Preclinical studies have suggested it can safely and effectively deliver its genetic payload to the lungs as designed.

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“By delivering full-length copies of CFTR directly to the lung via nebulization, KB407 has the potential to address the basic genetic defect present in cystic fibrosis,” said Steven R. Boas, MD, the trial’s principal investigator at the Cystic Fibrosis Institute, where is he acting director. “As this therapy does not depend on the type of CFTR mutation present, KB407 may potentially benefit all individuals affected by cystic fibrosis.”

Boas is also a professor of pediatrics at Northwestern University Feinberg School of Medicine, Chicago.

KB407 was developed using the company’s proprietary STAR-D gene therapy platform, which has been used also to develop treatments for skin conditions, with one of its candidates earning U.S. approval earlier this year.

The CORAL-1/US study is evaluating the safety and tolerability of KB407, administered by nebulization in under 30 minutes, in up to 20 participants who will be divided into three groups. In the first group, five participants will receive a single dose of KB407, while in the second group, five will be given KB407 on two consecutive days. Up to three participants in each of these groups may receive CFTR modulator therapies.

The third group will include 10 participants who are ineligible to receive CFTR modulators and who will be randomly assigned to receive either KB407 or a placebo for four consecutive days.

A data monitoring committee will conduct a safety review to decide whether it’s safe to move to the next group of patients.

The trial will also evaluate KB407’s effects on lung function by measuring the forced expiratory volume in one second, a test of how much air someone can forcibly exhale in a second. The trial is expected to conclude in March 2024.

Another Phase 1 trial (NCT05095246), initiated in March 2022 and conducted at a single site in Australia, also is testing single and multiple doses of KB407 in up to 13 adults with clinically stable CF.

The U.S. Food and Drug Administration and the European Commission have granted orphan drug status to KB407 to treat people with CF. The designation is meant to accelerate the therapy’s clinical development and regulatory review through financial incentives, regulatory support, and marketing exclusivity periods upon approval.