4D Molecular Therapeutics announced an update on its regulatory interactions and development path for 4D-710, an aerosolized genetic medicine for the treatment of CF lung disease. Given high-level cystic fibrosis transmembrane conductance regulator (CFTR) transgene expression in all lung airway biopsies disclosed to date (significantly above normal lung CFTR levels), dose exploration continues with the evaluation of lower doses in the 4D-710 Phase 1/2 AEROW clinical trial in pwCF dosed at 5E14 vg (Cohort 3; n=1) and 2.5E14 vg (Cohort 4; n=1); nine pwCF total have been dosed to date (dose range 2.5E14 to 2E15 vg). Phase 2 Expansion Cohort dose selection is expected in Second Quarter 2024 based on all clinical and lung biopsy data; the Company anticipates enrolling a total of six to nine pwCF in the Phase 2 Expansion Cohort.

The Company submitted an AEROW trial amendment to the Cystic Fibrosis Therapeutics Development Network (TDN) as follows: 1) to enroll pwCF with lower baseline percent predicted forced expiratory volume in 1 second (ppFEV1) (50-90%) to assess ppFEV1 response to 4D-710, and 2) to add a second lung biopsy procedure at a longer-term timepoint (12 months or later) to study long term durability of 4D-710 CFTR transgene expression and optimal timing for redosing. The Company plans to share the following at the 47thEuropean Cystic Fibrosis Conference (ECFS) held on June 5-8, 2024 in Glasgow, United Kingdom: 1) interim AEROW clinical and lung biomarker data on all nine pwCF dosed to date, 2) update on AEROW trial amendment status, and 3) development plan update for pwCF who are on modulators. In addition, the Company recently had discussions with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), regarding the registrational path for 4D-710 for treatment of CF lung disease in pwCF who are ineligible for or cannot tolerate approved CF modulator therapies.

With regards to a full product approval in this patient population, the Company anticipates a Phase 3 randomized, controlled pivotal study enrolling approximately 60-80 pwCF with low baseline ppFEV1 (planned to be approximately 40-80%). Phase 3 clinical endpoints include changes after 4D-710 treatment in ppFEV1, quality-of-life (Cystic Fibrosis Questionnaire Revised Respiratory Domain, CFQ-R-RD) and frequency of pulmonary exacerbations. 4DMT is preparing for initiation of a Phase 3 clinical trial in H2 2025.

Given the high unmet need in this CF population, an accelerated approval path may be feasible. The Company intends to have discussions with the FDA and EMA on an accelerated approval pathway, in parallel with Phase 3 planning, following additional AEROW clinical and lung biomarker data in pwCF with low baseline ppFEV1. 4D-710 is the first genetic medicine product candidate to demonstrate widespread and high-level CFTR expression (both RNA and protein) in the airways of pwCF; the Company will continue to evaluate the correlation between clinical endpoints and biomarker endpoints in participants with low baseline ppFEV1 in anticipation of further interactions on an accelerated approval pathway.

In addition, the Company has completed in-house process development of a suspension GMP-ready manufacturing process for 4D-710 at 500 liter scale for the pivotal study and potential commercialization. This process, in combination with investigating lower doses, enables potentially lower cost of goods. The Company anticipates initiation of technology transfer to a commercial contract development and manufacturing organization (CDMO) in H1 2025.

Cystic fibrosis (CF) is an inherited, progressive disease caused by mutations in the CFTR gene. It affects the lungs, pancreas, and other organs. According to the Cystic Fibrosis Foundation, close to 40,000 people in the United States and an estimated 105,000 people people have been diagnosed with CF across 94 countries, with approximately 1,000 new cases of CF diagnosed in the United States each year.

Lung disease is the leading cause of morbidity and mortality in people with CF. CF causes impaired lung function, inflammation and bronchiectasis and is commonly associated with persistent lung infections and repeated exacerbations due to the inability to clear thickened mucus from the lungs. People with CF require lifelong treatment with multiple daily medications.

The complications of the disease result in progressive loss of lung function, increasing need for IV antibiotics and hospitalizations, ultimately leading to end-stage respiratory failure.4D-710 is comprised of targeted and evolved next generation vector, A101, and a codon-optimized CFTR?R transgene. 4D-710 has the potential to treat a broad range of people with CF, independent of the specific CFTR mutation, and is designed for aerosol delivery to achieve CFTR expression within lung airway epithelial cells. 4D-710 is being initially developed for the approximately 10-15% of people whose disease is not amenable to existing CFTR modulator medicines (based on variant-eligibility and/or drug intolerance) targeting the CFTR protein.

In people with CFTR mutations whose disease is amenable to modulator medicines, and in some people with CF the improvement in lung function is incomplete and is variable. therefore expect to potentially develop 4D-710 in this broader population, as a single agent and/or in combination with CFTR modulator small molecule medicines. 4D-710 has received the Rare Pediatric Disease Designation and Orphan Drug Designation from the FDA.