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Restoret

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

Breakdown of the blood-retinal barrier (BRB), and subsequent vascular leakage, is both a hallmark and major disease driver of retinal vascular diseases including NVAMD and DME. Leakage from the microvasculature in these conditions leads to edema (fluid accumulation), dysfunction and degeneration of the neurosensory retina, and subsequent loss of visual function. At the molecular level, vascular leakage follows disruption of the vascular barrier, driven in large part by loss of tight junctions between vascular endothelial cells (3).
In normal biology, the Wnt signaling pathway plays a critical role in the development and maintenance of the retinal vasculature and the blood retinal barrier. The pathway includes the endothelial-specific frizzled-4 (FZD4) receptor, low-density lipoprotein receptor related protein 5 (LRP5), and the co-receptor tetraspanin-12 (TSPAN12) (4). When Wnt signaling is disrupted, the integrity of the endothelial cell barrier function is disrupted, resulting in fluid leakage into the retina. This disruption can be caused by increased levels of vascular endothelial growth factor (VEGF) in pathological conditions such as DME and NVAMD, as well as mutations of Norrin/Wnt pathway components in diseases such as FEVR.
When the Norrin/Wnt signaling pathway is stimulated, the FZD4/LRP5/TSPAN12 receptor/co-receptor complex clusters and is activated, turning on the downstream beta-catenin pathway. This leads to the expression of proteins essential for the restoration of tight junctions and vascular barrier function, while proteins that are involved in vascular permeability are inhibited, including those induced by elevated levels of VEGF (4).
Restoret® is a Norrin mimetic that binds to FZD4 and LRP5 receptors with high specificity and affinity to potently activate the downstream beta-catenin pathway and restore vascular barrier function (3). Restoret® exhibits superior potency and therapeutic activity in restoring BRB compared to Norrin and can effectively activate the b-catenin signaling without binding to the co-receptor TSPAN12. This mechanism has been shown to resolve vascular leakage regardless of the root cause: increased levels of vascular endothelial growth factor (VEGF) expression in pathological conditions such as DME and NVAMD or a number of diseases involving Norrin/Wnt pathway mutations (1,2,4).
Upon exposure to Restoret®, paracellular tight junctions between endothelial cells are restored and vascular leakage is efficiently suppressed. Restoration of the BRB promotes the removal of harmful blood components, resolution of retinal edema, and a return to normal retinal homeostasis function. As a result, Restoret® treatment can restore vision by addressing the leakage-driven unmet need seen in retinal diseases characterized by breakdown of the BRB.

References:

  1. 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.
  2. 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.
  3. 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.
  4. 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.