4D Molecular Therapeutics (FDMT) Study Result summary

Study background and unmet need

• Cystic fibrosis lung disease remains a high unmet need, with many patients ineligible or suboptimal responders to CFTR modulators.

• Conventional gene therapy trials in CF failed due to ineffective gene delivery and expression.

• 4D-710 is a durable, redosable, variant-agnostic gene therapy using a novel AAV vector (A101) for aerosol delivery to airway cells.

• 4D-710 is the first known genetic medicine to demonstrate successful delivery and expression of the CFTR transgene throughout the airways after aerosol delivery.

• Cystic fibrosis is a progressive, inherited disease affecting over 105,000 people worldwide, with lung disease as the leading cause of morbidity and mortality.

Study design and objectives

• Interim phase I/II data from the AEROW trial focused on dose finding, safety, and CFTR expression in adults with CF not eligible for modulators.

• Four dose cohorts (IE15, 2E15, 5E14, 2.5E14 vg) were evaluated, with primary endpoints including safety, lung tissue CFTR expression, and clinical activity (FEV1, LCI, CFQ-R).

• Protocol amendments added lung function and durability assessments, including optional biopsies at ≥1 year.

• Lower doses (5e14 and 2.5e14 vg) were explored after higher dose safety concerns; 2.5e14 vg was selected for Phase II based on safety and efficacy.

• Enrollment for Phase II is underway, targeting patients with FEV1 between 40% and less than 100%.

Safety and tolerability

• 4D-710 was well tolerated at lower doses (5E14, 2.5E14 vg), with most adverse events mild and transient, typical of nebulized therapies.

• No 4D-710-related adverse events beyond day 14, except one mild, transient liver enzyme elevation; non-pulmonary events resolved without intervention.

• Higher dose (2E15) was discontinued due to off-target expression and a serious adverse event that resolved.

• Lower dose administration completed in under an hour, appreciated by participants.