4D Molecular Therapeutics (FDMT) Study Update summary

Key interim results and study design

• Interim Phase 1/2 AEROW trial data showed single aerosolized doses of 4D-710 tested at four dose levels (2.5E14 to 2E15 vg) in 10 adults with cystic fibrosis ineligible or intolerant to CFTR modulators, using a breath-actuated nebulizer.

• Clinically meaningful improvements in lung function (ppFEV1) of 5-6 percentage points at 12 months were observed in two of three participants with mild to moderate impairment and >6 months follow-up.

• 4D-710 was well tolerated at doses up to 1 × 10^15 vector genomes (VGs), with no dose-limiting toxicities or serious adverse events at or below this dose; at 2 × 10^15 VG, one transient pneumonitis case resolved.

• Dose-dependent, widespread, and robust CFTR protein expression was demonstrated in bronchial epithelial cells across all dose groups, confirmed by machine learning-assisted image analysis.

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

Dose selection and safety profile

• The 2 × 10^15 VG dose was discontinued due to non-target interstitial expression and a resolved case of pneumonitis; 1 × 10^15 VG was selected as the phase II dose.

• Lower dose cohorts (≤1 × 10^15 VG) showed no clinically significant adverse events, with only one mild event at 5 × 10^14 VG.

• No inflammation or toxicity was observed in lung biopsies at any dose.

• The 5 × 10^14 VG dose remains under evaluation as a potential additional phase II dose.

• All participants in 2E15 vg and 1E15 vg cohorts had stable or improved ppFEV1 at 12 months.

Biomarker and efficacy findings

• Linear dose-dependent CFTR mRNA expression was observed, with mean positive cells ranging from 14% at the lowest to 53% at the highest dose.

• CFTR protein expression reached 94%-100% of epithelial cells at all doses, exceeding levels in non-CF controls; protein levels were 2-4 fold higher than normal lung samples and 8-12 fold higher than CF lung samples.

• Widespread and consistent CFTR protein expression confirmed in all major airway epithelial cell types, including secretory, ciliated, and basal cells, with apical region targeting.

• Improvements in quality of life (CFQ-R respiratory domain) exceeded the minimal clinically important difference in the 1 × 10^15 VG cohort, with durable improvement over 12 months.

• No correlation between pre-existing antibodies and efficacy or biomarker expression was observed.