Topical squalamine a promising treatment for RVO-induced ME

December 1, 2014

A proof-of-concept trial was launched to determine the safety and efficacy of squalamine lactate ophthalmic solution in eyes with macular edema secondary to branch and central retinal vein occlusion.

 

Take home

A proof-of-concept trial was launched to determine the safety and efficacy of squalamine lactate ophthalmic solution in eyes with macular edema secondary to branch and central retinal vein occlusion.

 

 

By Michelle Dalton, ELS; Reviewed by John J. Wroblewski, MD

Chambersburg, PA-Topical squalamine lactate ophthalmic solution, in synergy with intravitreal ranibizumab, may reduce the need for chronic injection therapy in eyes with retinal vein occlusion (RVO)-induced macular edema, said John J. Wroblewski, MD.

Dr. Wroblewski and Allen YH Hu, MD, both with Cumberland Valley Retina Specialists, Chambersburg, PA, launched a proof-of-concept trial designed to determine the safety and efficacy of squalamine lactate ophthalmic solution in eyes with macular edema secondary to branch and central retinal vein occlusion (BRVO and CRVO, respectively).

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“Squalamine eye drops have the potential to significantly advance the treatment of wet age-related macular degeneration (AMD) and RVO through a unique mechanism of action which may provide distinct or additional benefits to the anti-vascular endothelial growth factor (VEGF) agents currently used to treat these patients,” Dr. Wroblewski said.

Study details

Dr. Wroblewski initiated the investigator sponsored, single site trial “to determine the biological effect of squalamine lactate ophthalmic solution in eyes with macular edema secondary to BRVO and CRVO,” he said. “Squalamine is known to inhibit multiple protein growth factors and it is now well established that agents with anti-VEGF properties have benefit for patients with RVO and improve visual acuity. The eye-drop formulation of squalamine may provide a non-invasive approach that is more convenient for patients and physicians.”

 

The group used spectral domain optical coherence tomography (OCT) to evaluate the retina, and used best-corrected Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity as a primary end point.

Dr. Wroblewski enrolled 20 treatment naïve patients with macular edema due to RVO: nine with non-ischemic CRVO, eight with BRVO and three with hemi-central RVO. Average patient age for the three groups was 69, 68, and 71 years, respectively. Average symptom duration at baseline was 9, 6, and 8 weeks for the three groups, respectively.

Eyes with ETDRS vision 20/40 to 20/320 and SD-OCT central foveal thickness greater than 300u were included. Eyes with greater than 50% disruption of the foveal capillary ring as defined by fluorescein angiography were excluded. All 20 patients received topical squalamine for the first 10 weeks of treatment, with two injections of ranibizumab given at week 2 and week 6.

At week 10, the average EDTRS letter gain was +18.2 for CRVO, +18.1 for BRVO, and +32.3 for HRVO. In addition, 80% of patients achieved gains of ≥3 lines in visual acuity, with 40% of patients achieving gains of ≥4 lines in visual acuity. Overall, mean ETDRS visual acuity at week 10 was 20/32 for all groups and there was a mean improvement in central foveal thickness on OCT from 723 to 270 μm.

At week 10, 7/9 CRVO eyes (77.7%), and all BRVO and HRVO eyes had central foveal thickness measurements of 300μ or less (4 weeks following injection #2) with all of the BRVO/HRVO eyes having a CFT of 280 μm or less. Only one patient out of the 20 required an injection of ranibizumab at week 10 using predefined OCT-based rescue criteria.

An extension study randomly assigned 1:1 at week 10 to either continue administering squalamine or discontinue drops for the remainder of the 38-week study, with rescue injections of ranibizumab allowed, Dr. Wroblewski said, who added none of the patients exited the study or its extension component. The primary and secondary endpoints include visual acuity parameters, need for rescue retreatments, retinal thickness, vascular leakage and change in area of non-perfusion.

The combination of topical squalamine lactate drops and intravitreal ranibizumab 0.5mg led to “rapid central visual acuity recovery and macular deturgescence (95% early responders),” Dr. Wroblewski said.

 

“The early effect on visual acuity, edema, and percentage of early responders appears to be better than those seen in historical monthly ranibizumab retinal vein occlusion trials,” he said.

About squalamine

Squalamine is an anti-angiogenic small molecule with a novel intracellular mechanism of action, which counteracts multiple growth factors and pathways implicated in the angiogenic process, including VEGF, platelet-derived growth factor, and basic fibroblast growth factor, developer Ohr Pharmaceutical has said.

Squalamine lactate sequesters intracellular calmodulin, rendering VEGF, platelet-derived growth factor (PGDF) and basic fibroblast growth factor (bFGF) inactive, the company has noted. PDGF is known to be significantly elevated in aqueous samples of CRVO and bFGF is known to be significantly elevated in aqueous samples of BRVO, Ohr added.

Squalamine, using an intravenous administration in over 250 patients in phase I and phase II trials for the treatment of wet AMD, showed “favorable biological effect and maintained and improved visual acuity outcomes,” according to Ohr.

In May 2012, the Squalamine Eye Drop program was granted fast track designation by the FDA. Other investigator-sponsored studies are evaluating squalamine for proliferative diabetic retinopathy and diabetic macular edema.

 

John J. Wroblewski, MD

P: 301/665-1712

This article was adapted from Dr. Wroblewski’s presentation during the 2014 meeting of American Society of Retina Specialists. Dr. Wroblewski is a member of Ohr Pharmaceutical’s scientific advisory board.