4D Molecular Therapeutics, Inc. announced product pipeline portfolio updates and preclinical product candidate additions for its large market ophthalmology and pulmonology programs, as well as clinical data and program updates for its 4D-310 Fabry disease program. Ophthalmology Product Candidate Portfolio: 4D-150 for the Intravitreal Treatment of Patients with Wet Age-Related Macular Degeneration (wet AMD) and Patients with Diabetic Macular Edema (DME). Filed IND Application for Phase 2 SPECTRA Clinical Trial with Intravitreal 4D-150 in Patients with DME: 4DMT filed an Investigational New Drug (IND) Application for 4D-150 in patients with DME in December 2022, following pre-IND correspondence and alignment with the FDA.

The Phase 2 SPECTRA clinical trial design consists of a Dose Confirmation stage followed by a masked Dose Expansion stage in which patients will be randomized to receive a single intravitreal injection at one of two dose levels of 4D-150 or aflibercept in a 1:1:1 ratio (n=54 patients). The doses to be evaluated in DME are expected to be similar to those used in the 4D-150 wet AMD clinical trial. The company expects to initiate enrollment in the third quarter of 2023.

Initiated Randomized Phase 2 of PRISM Clinical Trial of Intravitreal 4D-150 in Patients with Wet AMD: The Phase 2 stage of the Phase 1/2 PRISM clinical trial of 4D-150 in patients with wet AMD consists of three treatment groups. Patients will be randomized in masked fashion to receive a single intravitreal injection at one of two dose levels of 4D-150 (3E10 and 1E10 vg/eye) or aflibercept in a 2:2:1 ratio (n=50 patients). This Phase 2 stage of the trial was initiated in January 2023.

Expanded Portfolio with Preclinical Product Candidate 4D-175 for Geographic Atrophy (GA): Geographic atrophy is a highly prevalent disease with significant unmet medical need. It is estimated that there are over one million individuals with GA in the United States according to published data. There are no disease modifying therapies approved for GA to date.

Preclinical development was initiated for a new product candidate designed for single dose intravitreal treatment of patients with GA; the product candidate will utilize 4DMT's proprietary R100 intravitreal vector currently used in the wet AMD and DME programs, and a transgene payload that addresses a complement pathway target (undisclosed). The company anticipates that development and manufacturing activities will benefit from prior clinical experience and GMP manufacturing of three other R100-based ophthalmology product candidates that have been dosed in ophthalmology patients with wet AMD, X-Linked Retinitis Pigmentosa (XLRP) and choroideremia. Enrollment on the Phase 1/2 clinical trials for 4D-125 and 4D-110 was completed in the fourth quarter of 2022: 14 patients have been treated with 4D-125, and 13 with 4D-110.

The safety and tolerability profiles for both product candidates remain unchanged from prior data releases. The company will continue to follow these patients for 24 months to assess the magnitude and durability of key imaging endpoint changes in evaluable patients. The company anticipates providing program and clinical data updates in 2024.

Pulmonology Product Portfolio: 4D-710 for the Aerosol Treatment of Patients with Cystic Fibrosis (CF) Lung Disease: Treated First Patient in High Dose Cohort on Phase 1/2 Clinical Trial with Aerosol Delivered 4D-710 in Patients with Cystic Fibrosis Lung Disease that is Not Amenable to Treatment with CFTR Modulator Therapy: Following three patients dosed in cohort 1 (1E15 vg), the first patient in the high dose cohort (2E15 vg) was treated in December 2022 and no 4D-710 related adverse events were reported through Day 28. Expanded Portfolio with Initiation of Preclinical Research and Development of 4D-710 in Combination with CFTR Modulators: Preclinical research was initiated with the combination of 4D-710 with CFTR modulator therapy to support development of 4D-710 in the approximately 85% of CF patients amenable to CFTR modulator therapy. Expanded Portfolio with Addition of Preclinical Product Candidate 4D-725 for Alpha-1 Antitrypsin Deficiency: Alpha-1 Antitrypsin Deficiency is a prevalent disease, affecting approximately 200,000 individuals in the United States and Europe according to the NIH.

The significant unmet medical need remains despite approved therapies. Preclinical development was initiated for a new product candidate designed for single dose aerosol treatment of patients with alpha-1 antitrypsin lung disease; this product candidate utilizes 4DMT's proprietary A101 aerosol vector currently used in the CF program and expresses a genetically-validated transgene. The company anticipates that development and manufacturing activities will benefit from prior clinical experience and GMP manufacturing of the A101-based 4D-710 product candidate that has been dosed in CF patients.

4D-310 for Fabry Disease Cardiomyopathy: Interim 4D-310 INGLAXA Phase 1/2 Clinical Trials Data in Patients with Fabry Disease: Two clinical trials, one in the U.S. and one in Taiwan and Australia (Asia-Pacific) are evaluating a single intravenous administration of 4D-310 in patients with classic or late-onset Fabry disease. Six patients have been treated at a dose of 1E13 vg/kg with a corticosteroid immunomodulation regimen. There were 3 instances of atypical hemolytic uremic syndrome (aHUS) across the 2 studies; these were the only treatment-related serious or = Grade 3 adverse events reported.

The aHUS process resolved within approximately 2-4 weeks in all three patients. One episode of aHUS qualified as a grade 4 dose-limiting toxicity and required temporary hemodialysis in a 69-year-old man with underlying kidney dysfunction; the other two patients did not receive dialysis. No other clinically significant toxicities were reported, including no infusion-related reactions, and no clinically significant cardiac or liver toxicities (three patients had transient asymptomatic Grade 1 transaminase increases).

Detailed safety data will be presented at the WORLDSymposium on February 25, 2023.