Cystic Fibrosis Gene Therapy Well-Tolerated, Yields Transgene Expression in All 7 Participants

4D-710 adeno-associated virus (AAV) gene therapy was well-tolerated and yielded cystic fibrosis transmembrane conductance regulator (CFTR) transgene expression in all 7 participants with cystic fibrosis (CF) enrolled in the phase 1/2 AEROW clinical trial (NCT05248230).¹

“We are pleased with the safety and tolerability of 4D-710 in participants in the AEROW study to date. Participants with cystic fibrosis in this clinical trial do not have the option of treatment with currently available disease modifying therapies and therefore have high unmet need,” lead Principal Investigator 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.² “By delivering copies of the CFTR∆R transgene to the lung epithelium with a novel aerosolized AAV and achieving high levels of CFTR protein expression in airway cells, 4D-710 has the potential to provide durable benefit in these individuals and potentially all individuals affected by CF.”

The therapy was generally well-tolerated as of October 2023 with no clinically significant adverse events (AEs), no decrease in percent predicted forced expiratory volume in 1 second, or bronchospasms. Investigators observed no inflammation in biopsies to date, and all 34 lung samples were positive for CFTR transgene expression. Expression was found in 98% of airway tissue samples up to 450% of normal, compared with 44% of cells in normal control lung samples.¹

There was 1 serious AE of pneumonia possibly related to 4D-710 confirmed to be Inquilinus limosus infection. The patient was treated with oral steroids and outpatient intravenous antibiotics to resolve the AE.¹

READ MORE: FDA Accepts IND Application for Cystic Fibrosis Gene Therapy KB407

“4D-710, our next generation aerosolized A101 vector, has the potential to address the limitations of prior aerosol gene therapies. Initial results from the AEROW study showed that 4D-710 resulted in CFTR expression in lung airways that significantly exceeded our target profile. Safety and pulmonary function measures reinforce a promising emerging tolerability and clinical activity profile,” David Kirn, MD, cofounder and Chief Executive Officer, 4DMT, added.² “We are also excited to welcome Dr. Alan Cohen as our Pulmonology Therapeutic Area Head. Alan brings more than 30 years of broad pulmonology expertise including in cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, plus biotherapeutics and gene editing development, highlighting our commitment to pulmonology. Under Alan’s leadership, we expect to continue advancing the clinical development of 4D-710 for CF lung disease and 4D-725 for alpha-1 antitrypsin deficiency lung disease and future lung programs.”

4DMT has chosen the 1E15 vg cohort 1 dose level to continue into phase 2, although dose ranging continues, and the first participant has been dosed in the lower dose cohort 3 (5E14 vg). The company has added additional functional measures, including high-resolution computed tomography, lung clearance index, mucociliary clearance index, and number and severity of bacterial pulmonary exacerbations. The company will share more interim data in mid-2024 and FDA feedback is expected to be shared in the first quarter of 2024.¹

“The high CFTR expression levels and durable clinical activity of 4D-710 as demonstrated by improvements in quality of life and stability in ppFEV1 through 12 months in Cohort 1 have never been achieved with any gene delivery in CF, making a dose reduction feasible,” said Alan Cohen, MD, senior vice president, Therapeutic Area Head of Pulmonology, 4DMT, added.² “I’m excited to work closely with the CF Foundation, CF community, and regulatory agencies to advance the development of 4D-710, a potentially transformative medicine for people with CF. Given the efficiency we have observed in CF lungs, one of the most difficult organs for gene delivery vectors, I am also energized by the potential of A101 to deliver genetic payloads to treat multiple large-market pulmonology diseases including alpha-1 antitrypsin deficiency lung disease.”

REFERENCES

1. Aerosolized 4D-710 for the treatment of cystic fibrosis (CF) lung disease. Webcast. 4DMT Therapeutics. November 1, 2023. https://ir.4dmoleculartherapeutics.com/static-files/c2590461-dc15-4253-b3fd-0c138037e157
2. 4DMT presents positive interim data from phase 1/2 AEROW clinical trial of aerosolized 4D-710 for cystic fibrosis at 2023 NACFC. News release. 4D Molecular Therapeutics. November 1, 2023. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-interim-data-phase-12-aerow-clinical