4DMT Aligns on Path Forward for Cystic Fibrosis Gene Therapy

Jennifer L. Taylor-Cousar, MD, MSCS

Credit: Intermountain Health

4D Molecular Therapeutics (4DMT) has aligned on a pivotal phase 3 trial and registration path for developing 4D-710 gene therapy for the treatment of cystic fibrosis (CF) lung disease for patients whose disease is ineligible for or cannot tolerate approved CF modulator therapies.¹

“We are encouraged by our productive interactions with the FDA and EMA on pivotal development plans for 4D-710, which we believe has the potential to be a transformative therapy for people with the highest unmet medical need for CF lung disease,” David Kirn, MD, cofounder and Chief Executive Officer, 4DMT, said in a statement.¹

"We are committed to advancing 4D-710 into pivotal trial development efficiently, while maintaining our current focus on initiation and completion of 2 Phase 3 wet AMD studies with 4D-150. Our goal is to initiate Phase 3 development in thesecond half of 2025 with 4D-710 suspension GMP process clinical trial material. We look forward to sharing interim clinical data from the AEROW Phase 1/2 clinical trial at the ECFS conference in June 2024," Kirn continued.1

4D-710 is an adeno-associated virus vector gene therapy delivered as an aerosol to achieve CFTR expression within lung airway epithelial cells. The therapy is currently being evaluated in the phase 1/2 AEROW clinical trial (NCT05248230), the most recent data from which were presented in November 2023 in a company webcast.²

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As of October 2023, data from 7 participants showed that 4D-710 was generally well tolerated 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

“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 about the new data.³ “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.”

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.1More data from AEROW is expected to be presented at the European Cystic Fibrosis Conference in June and will include safety, lung biomarker and clinical activity data on all 9 patients dosed across 4 dose level cohorts.²

4DMT plans to proceed the AEROW trial to its phase 2 expansion cohort in the second quarter of 2024 and initiate the pivotal trial in the second half of 2025. The company has completed initial GMP-ready suspension manufacturing processes in-house at a 500 liter scale and anticipates initiating the transfer to commercial CDMO in the first half of 2025.¹

REFERENCES

1. 4DMT Announces Update on Regulatory Interactions and Development Path for 4D-710 for Treatment of Cystic Fibrosis. News release. 4DMT. March 28, 2024. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-update-regulatory-interactions-and-development
2. 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
3. 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