Acrizanib

A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration

Purpose: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. Design: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. Methods: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. Main outcome measure: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. Results: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. Conclusion: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.

[Eye Drops Instead of Intravitreal Injections? The Dream of Treating Macular Diseases by Topically Administered Drugs]

Background The introduction of VEGF inhibitors revolutionized treatment for age-related macular degeneration. However, it requires regular intravitreal (IVT) injections. Hence, replacement of IVT injections by topical, non-invasive eye drop treatment is subject to intensive research. Material and Methods Literature and database research on topical therapies for neovascular AMD. Results Several clinical projects with topical inhibitors of the VEGF pathway were initiated recently. Several candidate molecules were investigated and should have an efficacy potential in neovascular AMD given their ability to block the VEGF pathway. Preclinical experiments were quite promising. Still, translation into the clinical application has not been successful thus far. Differences in preclinical and clinical pharmacokinetics are assumed to be the major barrier to successful translation. In addition, specific algorithms for monitoring of disease activity are required for successful clinical implementation; otherwise, a topical therapy may reduce the IVT injection number, but patients would not gain independence through fewer office visits. Discussion It is required to refine the scientific basis including preclinical models and screening cascades. This will enable targeted selection of future candidates for clinical development.