The IND clearance enables the initiation of SPECTRA clinical study sites, and 4DMT expects to begin enrollment in the third quarter of 2023. The doses to be evaluated in DME are anticipated to be between 6E9 to 3E10 vg/eye. The study 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 Phase 2 SPECTRA clinical trial will assess 4D-150 in patients with DME. 02, 2023 (GLOBE NEWSWIRE) - 4D Molecular Therapeutics (Nasdaq: FDMT, “4DMT”), a clinical-stage biotherapeutics company harnessing the power of directed evolution for targeted genetic medicines, announced FDA clearance of the Investigational New Drug Application (IND) for 4D-150, an R100 vector-based intravitreal genetic medicine, for the treatment of patients with Diabetic Macular Edema (DME). Randomized Phase 2 portion of the Phase 1/2 PRISM clinical trial with 4D-150 for wet AMD is currently enrollingĮMERYVILLE, Calif., Feb. Interim PRISM data for dose Cohorts 1, 2, & 3 (n=15) to be presented at the 2023 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting Initial Phase 1 PRISM clinical trial with 4D-150 for wet age-related macular degeneration further validates R100 intravitreal vector potential for other large market eye diseases including geographic atrophy This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.4D-150 Phase 2 SPECTRA clinical trial for diabetic macular edema enrollment is expected to initiate in Q3 2023 Moreover, hPSC-dependent disease models can be used to demonstrate functional rescue, thereby facilitating the path from proof-of-concept to clinical application. These human retinal systems – complemented by in vivo NHP studies – will aid future development of optimized vectors. This study in human retinal cell models clearly illustrates superior gene delivery of our novel retinal AAV variants discovered through Therapeutic Vector Evolution as compared to the clinically relevant AAV2. Robust transduction was also observed in the context of PR-directed gene transfer. PRs generated by a multi-step eye cup formation paradigm expressed recoverin, rhodopsin, and S and M/L opsins after 100 days in culture.Ĭomparative analysis of transduction efficiency and GFP transgene expression by our novel variants in RPEs revealed significantly higher transduction efficiencies versus AAV2 as measured by flow cytometry and western blot. To evaluate the selected variants on human RPEs, cultures were differentiated from hPSCs for 30 days, when 90% of all cells in culture expressed mature RPE markers including RPE65 and BEST1, synthesized VEGF and PEDF, and phagocytosed rod outer segments. We identified novel variants after six rounds of selection. In order to select variants with improved transduction of the NHP retina, 4DMT’s library of approximately 100 million unique AAV capsid variants was delivered via intravitreal administration. The Therapeutic Vector Evolution platform involves applying progressively more stringent selective pressures to a genetically diverse library of AAV capsids to select novel variants with improved gene delivery properties compared to the natural AAV serotypes. However, due to cross-species differences in AAV gene expression profiles and limitations of animal species to recapitulate human disease phenotypes, we have generated retinal pigment epithelium (RPE) and photoreceptors (PRs) from pluripotent stem cells (PSCs) to evaluate transduction and tropism of our novel retinal AAV vectors in human cell models. 4D Molecular Therapeutics (4DMT) has applied its Therapeutic Vector Evolution platform to discover novel adeno-associated virus (AAV) variants with superior gene delivery to the human retina following intravitreal delivery using non-human primates (NHP) as a model system. Gene therapy is a powerful approach for the treatment of inherited and complex retinal disorders.
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