Aerosol Cystic Fibrosis Gene Therapy Well-Tolerated, Shows Signs of Efficacy


Data on cohort 2 of the AEROW trial are expected in November 2023.

4D-710 (4D Molecular Therapeutics) gene therapy was well-tolerated and showed early signs of clinical activity in 3 patients with cystic fibrosis (CF) treated in the phase 1/2 AEROW clinical trial (NCT05248230).

“This evidence of tolerability, high level CF transmembrane conductance regulator (CFTR) protein expression and early clinical activity in 3 participants is promising for the ongoing development of this aerosolized product candidate for cystic fibrosis lung disease,” Jennifer L. Taylor-Cousar, MD, MSCS, professor, departments of medicine and pediatrics, and codirector, adult cystic fibrosis program, director, Cystic Fibrosis Foundation Therapeutics development center, National Jewish Health, said in a statement. “I’m highly encouraged that the robust and consistent transduction observed is translating into improvements in quality of life and stabilization or improvement in the pulmonary function in these individuals with cystic fibrosis who otherwise do not have disease modifying therapy available to them. Historical data suggests that on average these measures would have declined without treatment in this population.”

The data, from 3 patients who were ineligible (n = 2) for or intolerant of (n = 1) CF modulator treatment, were presented at the European Cystic Fibrosis Society 46th Annual Meeting held in Vienna, Austria on Thursday, June 8. These participants make up the first cohort of the trial and received 1E15 vg of 4D-710 administered via AeroEclipseII breath-actuated nebulizer. The participants had 9 to 12 months of follow-up.

As of April 12, 2023, 4D-710 was well-tolerated, with no therapy-related adverse events (AEs), dose-limiting toxicities, or serious AEs. One patient had mild dry throat and fatigue during the aerosol delivery. Investigators found that quality of life outcomes, as measured by Cystic Fibrosis Questionnaire-Revised respiratory symptom score (CFQ-R-R), meaningfully improved for all 3 participants. In comparison, historical data shows a mean annual decline of 4 points at 48 weeks in patients with CF without modulator treatment.

READ MORE: Carol Miao, PhD, on Bringing Together Novel Gene Editing Tools and Delivery Methods

Percent predicted forced expiratory volume in one second (ppFEV1) meaningfully improved in 1 participant with moderate ppFEV1 impairment at baseline and remained stable in the 2 participants with normal or mild impairment at baseline. In comparison, historical data shows a mean annual decline of 2.3 pp in patients with CF without modulator treatment.

Biomarker analysis, measured by immunohistochemistry in bronchoscopy samples, demonstrated consistent, widespread expression of the FTR transgene protein in 92 to 99% of lung airway cells significantly above normal control lung tissue(n = 10; P = .004) and CF lung control tissue (n = 7; P = .0009) in all 3 participants as well as transgene RNA and DNA.

“The widespread CFTR transgene expression demonstrated in all lung samples from participants in cohort one is a critical first step for the development of 4D-710, especially given the signals of clinical activity in this CF population with the highest unmet medical need,” David Kirn, MD, cofounder and chief executive officer, 4DMT, added. “We believe that 4D-710 represents a potentially transformative new treatment for people with CF. These interim results also demonstrate the potential of our proprietary aerosolized A101 vector for other lung diseases such as alpha-1 antitrypsin deficiency lung disease and other highly prevalent lung diseases.”

4D-710 consists of 4D Molecular Therapeutics’ A101 vector and a codon-optimized recombinant FCTR transgene. The company has plans to assess the therapy in combination with CFTR modulators, more info on its plans is expected in the fourth quarter of 2023.

The AEROW study plans to enroll another cohort of 3 to 6 participants to receive 2E15 vg of 4D-710 in the phase 1 dose exploration stage before selecting a dose and initiating the phase 2 expansion stage enrolling up to 12 participants, which is expected in the second half of 2023. Interim data on cohort 2 is planned to be presented in November 2023.

4DMT presents positive interim data from aerosolized 4D-710 phase 1/2 AEROW clinical trial in patients with cystic fibrosis at the ECFS 46th Annual Meeting. News release. 4D Molecular Therapeutics. June 7, 2023.
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