When Ohr Pharmaceutical Inc. announced the topline results from the Phase IIb IMPACT study evaluating OHR-102 (0.2% squalamine lactate ophthalmic solution) combination therapy with ranibizumab (Lucentis, Genentech) for the treatment of wet age-related macular degeneration (AMD), the company acknowledged the overall study failed to meet its primary endpoint.

However, 42 percent of the subgroup of patients with classic-containing choroidal neovascularization (CNV) on the combination therapy achieved three or more lines of vision improvement, compared with only 28 percent in the ranibuzimab monotherapy arm. Ohr believes these data justify Phase III trials in wet AMD. Thomas A. Ciulla, MD, chief clinical investigator of IMPACT, answered questions via e-mail.

Q Can you describe the mechanism of action of OHR-102?

A Squalamine is a small-molecule drug, which has been shown to inhibit multiple angiogenic growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). It does so through a novel intracellular mechanism, which involves uptake by active endothelial cells and binding and displacement of calmodulin.1 It simultaneously shuts down these growth factors, unlike current intravitreal retina medications, which inhibit the target via extracellular binding. Squalamine has been shown to inhibit ocular neovascularization in animal models.2-4

Q Trials of topical agents for retinal disease have a history of failing. Why is this different?

A Squalamine was originally developed as an intravenous drug. In Phase II trials, it demonstrated a biological effect, a dose response and a visual acuity benefit.5 Due to its rapid clearance, pharmacokinetics and impractical delivery, it was not pursued further. While many previously studied topical agents for the treatment of retinal disease failed to show efficacy, OHR-102 is a proprietary formulation designed to improve trans-scleral permeability and increase retention of squalamine lactate in the targeted choroidal tissue, thus providing sustained anti-angiogenic concentrations in the posterior segment.
Q Was the subgroup you describe as working pre-specified?

A The IMPACT study included treatment-naïve subjects with wet AMD; 142 patients with classic or occult-only CNV were enrolled, with a wide range of visual acuities and lesion sizes, and 128 completed the nine-month study. The key endpoints were number of p.r.n. ranibizumab injections, mean change in visual acuity, percentage of subjects with three-line visual acuity gain and safety.  

In a prespecified subgroup of patients with lesions containing classic CNV (squalamine n=37, Lucentis monotherapy n=28), mean gains in visual acuity at month nine were 11 letters in the squalamine combination arm vs. five letters in the Lucentis-only arm. The classic-containing CNV population represented approximately two-thirds of the total wet-AMD patient population.  

Q What biology would explain why the drug would work in classic CNV but not occult?

A Classic CNV lesions typically grow aggressively and may be well-suited for squalamine combination therapy, but this may not be the entire story. The IMPACT study data also demonstrated that lesions with smaller occult CNV components (<10 mm2), including occult-only lesions, had a similar benefit to what was seen in the classic CNV group, suggesting that the size of the occult component may play a bigger role in predicting the optimal patient population for treatment. Therefore, this treatment could be useful in both classic as well as occult-containing lesions.

Q What is the unmet need in the wet AMD space beyond the anti-angiogenesis and anti-permeability effects of existing anti-VEGF drugs?

A There is unmet need for treatments for patients who present later with more mature CNV. While anti-VEGF addresses endothelial cells, anti-PDGF may address pericytes in these more mature CNV lesions. Attacking these pericytes would potentiate anti-VEGF treatment. Anti-fibrosis and neuroprotection are other areas of unmet need.  RS

1. Connolly B, Desai A, Garcia CA, et al. Squalamine lactate for exudative age-related macular degeneration. Ophthalmol Clin North Am. 2006;19:381-391.
2. Ciulla TA, Criswell MH, Danis RP, et al. Squalamine lactate reduces choroidal neovascularization in a laser-injury model in the rat. Retina. 2003;23:808-814.
3. Genaidy M, Kazi AA, Peyman GA, et al. Effect of squalamine on iris neovascularization in monkeys. Retina. 2002;22:772-778.
4. Higgins RD, Yan Y, Geng Y, et al. Regression of retinopathy by squalamine in a mouse model. Pediatr Res. 2004;56:144-149.  
5. Ciulla TA, Oliver A, Gast M. Squalamine lactate for the treatment of age-related macular degeneration. Expert Rev Ophthalmol. 2007;2:165-175.