CF gene therapy 4D-710 shows signs of improving lung function in early trial
Phase 1 data suggest treatment could help patients regardless of their mutation
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The experimental inhaled gene therapy 4D-710 showed acceptable safety and signs of improving lung function in adults with cystic fibrosis (CF), according to new Phase 1 clinical trial data.
Developer 4D Molecular Therapeutics (4DMT) has now selected the study’s lowest dose for further evaluation in a Phase 2 trial, after participants treated at that level showed “clinically meaningful” improvements in their ability to clear air and tracer gases from their lungs.
These findings from the Phase 1 portion of the AEROW trial (NCT05248230) specifically targeted 16 adults who are ineligible for or cannot tolerate standard CFTR modulators. Participants were given one-time treatment with 4D-710 at one of four doses, with follow-up times ranging from four months to more than three years.
“Based on the data shared today, we continue to believe in 4D-710’s potential as a durable, redosable and variant-agnostic genetic medicine that could become a foundational therapy for many people living with CF,” David Kirn, MD, co-founder and CEO of 4DMT, said in a press release.
Dose selection and Phase 2 plans
Based on the Phase 1 findings, the lowest tested dose (2.5 × 10^14 vector genomes) has been selected for further evaluation in the Phase 2 portion of the trial, which will treat six patients. The trial is enrolling patients at more than a dozen U.S. centers, with expected completion of the Phase 2 enrollment in the first half of 2026.
4DMT reported that, in the Phase 1 part of the study, side effects associated with low doses were generally mild, temporary, and resolved within two months of receiving a single dose of 4D-710. Patients given the lowest dose showed “evidence of clinically meaningful activity” in multiple measures of lung function, including lung clearance index (LCI2.5), which measures how long it takes a person to “clear” an inhaled tracer gas from their lungs, and percent predicted forced expiratory volume in one second (ppFEV1), which measures how much air someone can blow out in a forceful breath.
“Lung clearance index, or LCI2.5, was developed to measure lung disease progression earlier and with lower variability than ppFEV1, making it a complementary measure to ppFEV1 for assessing clinical activity in trials like AEROW,” said Felix Ratjen, MD, PhD, co-head of the Cystic Fibrosis Center at SickKids Research Institute, in Toronto. “While, historically, ppFEV1 has been used in most CF trials, it measures large- and mid-airway disease and is effort-dependent and variable. LCI2.5 can detect changes in the small airways, where CF lung disease initially progresses, even before FEV1 declines, providing a more complete view of lung health. I am encouraged by the data from the AEROW trial and look forward to the continued advancement of 4D-710 for the CF community.”
CF is caused by mutations in the CFTR gene, which provides instructions to make a protein with the same name. The CFTR protein is essential for regulating mucus production. Lack of functional CFTR protein in CF leads to the production of thick, sticky mucus that builds up in organs to drive most disease symptoms. CFTR modulators are medicines that can boost protein functionality in people with CF caused by specific mutations, but they don’t work for everyone, and some patients experience intolerable side effects.
4D-710 is designed to deliver a healthy version of the CFTR gene to cells in the lungs, allowing lung cells to produce a functional version of the protein. This mechanism of action is expected to work equally well in CF patients with all types of mutations, according to 4DMT. Data from AEROW indicate that the gene therapy is restoring CFTR protein expression as intended.
“The emerging data from the AEROW trial are highly encouraging, demonstrating the selected Phase 2 dose of 4D-710 was well tolerated and achieved physiologically relevant levels of CFTR expression, with evidence of clinical benefit across multiple lung function and pulmonary symptom measures,” said Jennifer L. Taylor-Cousar, MD, principal investigator in the AEROW trial at National Jewish Health. “I look forward to continuing to enroll participants in the Phase 2 trial.”
