4D Molecular Therapeutics (FDMT) Study Update summary

Key interim results and clinical findings

• Interim Phase 1/2 AEROW trial of aerosolized 4D-710 in cystic fibrosis showed clinically meaningful improvements in lung function (ppFEV1) of 5-6 percentage points at 12 months in two of three participants with mild to moderate impairment at baseline.

• 4D-710 demonstrated robust, widespread, and dose-dependent CFTR protein expression in bronchial epithelial cells, with up to 100% of cells positive and supraphysiological levels compared to non-CF controls.

• Quality of life improvements in the 1 × 10^15 VG cohort exceeded the minimal clinically important difference, with 8-11 point gains over 12 months.

• Pre-existing AAV/A101 immunity did not impact transgene or protein expression, clinical activity, or safety.

• Safety profile was favorable at doses up to 1 × 10^15 VG, with no serious or dose-limiting toxicities; the highest dose (2 × 10^15 VG) was discontinued due to a resolved adverse event.

Study design and patient population

• Phase 1/2 AEROW trial evaluated single-dose aerosolized 4D-710 in 10 CF patients ineligible or intolerant to CFTR modulators, across four dose levels (2.5E14 to 2E15 vg), ages 20–69, with baseline ppFEV1 56%–100%.

• Study endpoints included safety/tolerability, lung biomarkers, clinical activity (ppFEV1, CFQ-R-R), and transgene/protein expression via bronchoscopy.

• The study design included single-dose escalation, bronchoscopy for tissue sampling, and standardized follow-up for lung function and safety.

• High unmet need persists for ~35,000 CF patients globally who are ineligible, intolerant, or suboptimal responders to modulators.

• 4D-710 is positioned as a potential first treatment for CF patients not benefiting from current disease-modifying therapies.

Biomarker and efficacy results

• Dose-dependent CFTR mRNA and protein expression observed in airway epithelial cells at all doses and all participants, confirmed by machine learning-assisted image analysis.

• Protein levels in treated participants were 2–4 fold higher than normal lung samples and 8–12 fold higher than CF lung samples.

• CFTR protein localized to secretory, ciliated, and basal cells, with apical region targeting.

• mRNA expression showed linear dose response, while protein expression reached saturation at higher doses.

• Repeat dosing shown feasible in preclinical and early clinical data.