Restoret is a tetravalent, tri-specific antibody that acts as an agonist of the Wnt signaling pathway. Restoret is delivered by intravitreal injection to treat retinal diseases characterized by leakage, including Neovascular Age Related Macular Degeneration (NVAMD), Diabetic Macular Edema (DME), and Familial Exudative Vitreal Retinopathy (FEVR). The IND filing for first in human studies will be submitted in 2023.
Despite treatment with anti-VEGF monotherapy, most patients with NVAMD and DME have suboptimal visual gain (>60% of patients) and subsequent loss of vision over time. Many patients have persistent leakage despite frequent delivery with the standard of care. Continued leakage is a modifiable feature of these diseases that is tied to the unmet needs of limited visual gain and visual loss over time that exist despite anti-VEGF therapy.
Restoret (EYE103) seeks to eliminate leakage in retinal vascular diseases by agonizing the Wnt pathway to both restore and maintain the blood retinal barrier (BRB). By actuating this mechanism, the drug may reduce leakage associated with the unmet medical needs in DME and NVAMD.
Restoret mimics the natural ligand Norrin, which agonizes the Wnt pathway. Norrin has been demonstrated to be necessary and sufficient to effectively restore and maintain the BRB (1,2). Preclinical data demonstrate that Restoret effectively mimics this function and resolves leakage with durable effects. The following images illustrate the proposed mechanism of action.
Summary of unmet need and mechanism
- Díaz-Coránguez M, Lin CM, Liebner S, Antonetti DA. Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability. J Biol Chem. 2020 Apr 3;295(14):4647-4660. doi: 10.1074/jbc.RA119.011273. Epub 2020 Feb 21. PMID: 32086377; PMCID: PMC7135996.
- Wang Y, Rattner A, Zhou Y, Williams J, Smallwood PM, Nathans J. Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell. 2012 Dec 7;151(6):1332-44. doi: 10.1016/j.cell.2012.10.042. PMID: 23217714; PMCID: PMC3535266.
- Yemanyi F, Bora K, Blomfield AK, Wang Z, Chen J. Wnt Signaling in Inner Blood-Retinal Barrier Maintenance. Int J Mol Sci. 2021 Nov 2;22(21):11877. doi: 10.3390/ijms222111877. PMID: 34769308; PMCID: PMC8584977.
- Chidiac R, Abedin M, Macleod G, Yang A, Thibeault PE, Blazer LL, Adams JJ, Zhang L, Roehrich H, Jo HN, Seshagiri S, Sidhu SS, Junge HJ, Angers S. A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy. EMBO Mol Med. 2021 Jul 7;13(7):e13977. doi: 10.15252/emmm.202113977. Epub 2021 Jun 9. PMID: 34105895; PMCID: PMC8261507.