Low-Dose Gene Therapy Well-Tolerated, Shows Some Trends of Improvement for Cystic Fibrosis
1x1015 vg 4D-710 has been identified as the maximum tolerated dose in the AEROW trial.
Jennifer L. Taylor-Cousar, MD, MSCS
Credit: Intermountain Health
4D-710, 4D Molecular Therapeutics’ (4DMT) gene therapy candidate for treating cystic fibrosis (CF), has demonstrated CFTR transgene RNA and protein expression in all 10 participants whose disease is ineligible for or cannot tolerate approved CF modulator therapies treated at the higher and lower dose levels with follow-up of to 12 months in the phase 1/2 AEROW clinical trial (NCT05248230).1
Data from the trial were presented at the 47th European Cystic Fibrosis Conference, held in Glasgow, United Kingdom, in June 2024, by lead Principal Investigator Jennifer L. Taylor-Cousar, MD, MSCS, Professor, Departments of Medicine and Pediatrics, and codirector, Adult Cystic Fibrosis Program, and Director, Cystic Fibrosis Foundation Therapeutics Development Center, National Jewish Health.
“All 3 doses showed good expression in the airway. In those cohorts that were dosed at the lower doses, we also showed that people tolerated the drug, and that we saw at least at the 1x1015 vector genome dose, at least 1 person who had a clinically meaningful improvement in their percent predicted lung function, so we think that's very promising for looking at that dose or other lower doses in further participants,” Cousar told CGTLive.
One participant out of 4 in the AEROW trial received the highest studied dose of 2x1015 vg 4D-710 experienced treatment-related adverse events (AEs) of pneumonitis and forced expiratory volume (FEV1) decline and another had a previously reported serious AE of pneumonitis not otherwise specified, both of which resolved. The second participant had a percent predicted (pp) FEV1 6% higher than baseline at 12 months. Lung biopsies in these participants revealed no evidence of inflammation or toxicity but CFTR protein expression that was 400% higher in epithelium compared to normal, non-CF lung samples and widespread, unexpected expression in interstitium. Based off these data, the lower 1x1015 vg dose has been selected as the maximum tolerated dose going forward for evaluation. At this lower dose as well as the 2.5x1014 vg dose, there were no treatment-related serious AEs or dose-limiting toxicities in 6 treated participants.1
WATCH NOW: Jennifer Taylor-Cousar, MD, MSCS, on Early Signals of Efficacy With Cystic Fibrosis Gene Therapy
Investigators found that 2 of 3 participants with baseline ppFEV1 no greater than 80% of normal with over 6 months of follow-up had small improvements in ppFEV1 at 12 months. One participant that received 3x1015 vg had a 6% improvement and 1 that received 1x1015 had a 5% improvement. Although not statistically significant, 4D called the improvements “clinically meaningful”.1
In all 3 participants receiving 1x1015 vg, Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain scores had a positive trend over 12 months, with the mean score change remaining above the minimally importance clinical difference mark of 4 points. Investigators also found no significant differences in bronchoscopy results between participants with and without preexisting A101 antibodies or a101-specific T cells.1
“The clinical data to date from the AEROW clinical trial continues to strongly support the advancement of 4D-710 to the next stage of development for CF lung disease,” Alan H. Cohen, MD, SVP, Therapeutic Area Head of Pulmonology, 4DMT, said in a statement.2 “Based on the emerging favorable safety and clinical activity profile, we look forward to beginning our Phase 2 Dose Expansion stage in participants with mild to moderate lung function impairment, to confirm the clinical activity of the 1E15 vg dose.”
The AEROW trial is continuing to enroll participants at the 1.5x1014 vg and 5x1014 vg dose levels. Back in April, 4DMT shared that it had aligned on a pivotal phase 3 trial and registration path for the 4D-710 therapy and plans to initiate the pivotal trial in the second half of 2025.3
