Glaucoma - Next Generation Therapeutics: Impossible to Possible

The future of next generation therapeutics for glaucoma is strong. The recent approval of two novel intraocular pressure (IOP)-lowering drugs with distinct mechanisms of action is the first in over 20 years. However, these are still being administered as topical drops. Efforts are underway to increase patient compliance and greater therapeutic benefits with the development of sustained delivery technologies. Furthermore, innovations from biologics- and gene therapy-based therapeutics are being developed in the context of disease modification, which are expected to lead to more permanent therapies for patients. Neuroprotection, including the preservation of retinal ganglion cells (RGCs) and optic nerve is another area that is actively being explored for therapeutic options. With improvements in imaging technologies and determination of new surrogate clinical endpoints, the therapeutic potential for translation of neuroprotectants is coming close to clinical realization. This review summarizes the aforementioned topics and other related aspects

Using healthcare databases to explore associations between drugs and progression of open angle glaucoma

We sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs

Non-invasive molecular tracking method that measures ocular drug distribution in non-human primates

Intravitreal (IVT) injection has become the standard route for drug administration in retinal diseases. However, the ability to measure biodistribution of ocular therapeutics in large species remains limited, due to the invasive nature of some techniques or their lack of spatial information. The aim of this study was to develop in cynomolgus monkeys a non-invasive fluorescence imaging technology that enables tracking of IVT-dosed drugs and could be easily translated into humans. Here, we show a proof-of-concept for labeled ranibizumab with observed half-lives of 3.34 and 4.52 days at the retina and in the vitreous, respectively. We further investigate a long acting anti-VEGF antibody, which remains as an agglomerate with some material leaking out until the end of the study at Day 35. Overall, we were able to visualize and measure differences in the in vivo behavior between short and long-acting antibodies, demonstrating the power of the technology for ocular pharmacokinetics

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.

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.A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.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.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.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.In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy

A phase I/II study to evaluate the safety, tolerability and early efficacy of MGV354 in healthy subjects and in patients with ocular hypertension or glaucoma

Purpose: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. Design: Double-masked, prospective, randomized and vehicle-controlled three-part multicenter study with 98 subjects (ClinicalTrials.gov NCT02743780). Methods: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2). Part 3 evaluated IOP-lowering efficacy of the MTD administered nightly for one week in 50 patients with minimum IOP of 24mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at Day 8 compared to baseline. Results: There was no difference in favor of MGV354 for IOP lowering; change from Baseline to Day 8 in mean diurnal IOP was -0.6 mmHg for MGV354-treated patients and -1.1 mmHg for Vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common AEs reported following MGV354 administration in all the three parts was conjunctival and ocular hyperemia. Conclusions: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to Vehicle in lowering IOP based upon the study’s main outcome measure. MGV354 produced ocular hyperemia consistent with target engagement in the conjunctiva, but human glaucomatous trabecular meshwork may have levels of oxidized sGC that are too low to benefit from MGV354

Complement factor B is critical for sub-RPE deposit formation in a model of DHRD/ML with features of age-related macular degeneration

EFEMP1 R345W is a protein misfolding-prone mutation causing Doyne honeycomb retinal dystrophy/Mallatia Leventinese (DHRD/ML), a rare blinding disease with similar clinical pathology to a common disease of age-related macular degeneration (AMD). Aged Efemp1R345W/R345W knock-in mice (Efemp1ki/ki mice) develop deposits on the basal side of retinal pigment epithelial cells, which is complement C3- dependent. We assessed alternative complement pathway component factor B (FB) in sub-RPE deposit formation in Efemp1ki/ki mice. RNA-seq analysis of Efemp1ki/ki mice comparing to Efemp1+/+ reveals increased unfolded protein response in posterior eye cups, decreased mitochondrial function in neural retina (both by 3-month-old), and increased inflammatory pathways in both tissues (at 17-month-old). Aged Efemp1ki/ki mice also exhibits elevated ocular complement protein activation with around two-fold (p<0.05) elevation of breakdown products iC3b and Ba by Western blot analysis. Proteomics analysis of eye lysate confirmed similar Efemp1 R345W-dysregulated pathways as detected by RNA-seq. Cfb deficiency partially normalizes these biological pathway changes in the eyes of female Efemp1ki/ki mice. Female Efemp1ki/ki mice dosed with a small molecule FB inhibitor from 10- to 12-month-old reduced sub-RPE deposits by 65% (p=0.051). Male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females and no elevation of ocular complement activation, therefore not affected by FB inhibitor. Sub-RPE deposits/drusen, seen in Efemp1ki/ki mice, are a common early clinical feature of DHRD/ML and AMD. The broader effect on Efemp1ki/ki mice by either Cfb deficiency or oral FB inhibition suggest that systemic inhibition of the alternative complement pathway is potentially an effective strategy for treatment of dry AMD and DHRD/ML