4DMT publishes preclinical data demonstrating the potential of the Therapeutic Vector Evolution (TVE) platform

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4DMT announced the publication of preclinical data demonstrating the potential of the Therapeutic Vector Evolution (TVE) platform, intravitreal R100 vector, and the R100-based genetic medicine 4D-150. The publication is entitled, “Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies” and appears in Investigative Ophthalmology & Visual Science (IOVS); December 2024 issue. IOVS is the journal of the Association for Research in Vision and Ophthalmology (ARVO), a leading basic and translational research association in ophthalmology.

The report details the results of preclinical discovery, engineering and characterization studies evaluating the safety, retinal cell transduction, transgene expression and clinical activity of proprietary evolved intravitreal vector R100 and 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: 1) a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B and PlGF, and 2) a microRNA sequence that inhibits expression of VEGF-C.

The data showed that R100 demonstrated significantly superior human retinal cell transduction compared to AAV2, and intravitreal administration of 4D-150 to nonhuman primates was well tolerated and led to robust panretinal expression of both transgenes, especially within the macula region; AAV2 was unable to transduce deep retinal cell layers in the same model. In a difficult-to-treat primate laser-induced choroidal neovascularization model of wet AMD, 4D-150 completely prevented grade IV angiogenic lesions at all tested doses.

David Kirn, MD, senior author of the paper and Co-founder and Chief Executive Officer of 4DMT is quoted in the press release on this subject saying, “We founded 4DMT with the belief that the Nobel Prize-winning technology of directed evolution could be applied to invent highly optimized and customized AAV vectors for any tissue in the body. This proprietary Therapeutic Vector Evolution approach has been validated through clinical results with three different proprietary vectors for transgene payload delivery to the retina (R100, intravitreal), lung airways (A101, aerosol) and heart (C102, intravenous). R100 was invented to be a potentially best-in-class intravitreal vector to address and overcome the limitations of conventional vectors for the retina, and we are now leveraging R100 in our 4D-150 product candidate to potentially bring to market the first large market genetic medicine to transform vision outcomes for millions of patients with wet AMD and diabetic eye diseases. This innovative disease-modifying genetic medicine is designed to continuously suppress all four major molecular drivers of these diseases for years, directly at the site of the disease within the macula, following a single routine clinic-based intravitreal injection. Standard of care bolus anti-VEGF therapies, which generate billions in annual sales, cannot achieve this transformative mechanism of action. The robust results in our primate models reinforce our confidence in 4D-150's efficacy in patients.”

The publication is available online at the IOVS website and on the Scientific Publications page of the 4DMT website.

Reference:

1. 4DMT Announces Landmark Publication of 4D-150 Preclinical Data for the Treatment of Neovascular Retinopathies in IOVS. 4D Molecular Therapeutics, Inc. December 16, 2024. Accessed December 18, 2024. https://www.globenewswire.com/news-release/2024/12/16/2997468/0/en/4DMT-Announces-Landmark-Publication-of-4D-150-Preclinical-Data-for-the-Treatment-of-Neovascular-Retinopathies-in-IOVS.html