A Phase 1 safety study with GAL-101 eye drops was successfully completed in 40 healthy subjects and 30 glaucoma patients, in a randomized, double-masked, placebo-controlled single center study. All subjects received 16 days eye-drop application during 12 visits including a safety follow-up at day 23. Dosage of the eye drops was up to the maximum possible, thrice daily 3 drops in a row with 5 min interval using either placebo solution, 5 mg/ml GAL-101 or 20 mg/ml GAL-101 in an ascending dose regimen. The results of this study demonstrated an excellent safety and tolerability profile of the GAL-101 eye drops. All 70 randomized subjects completed the study and adverse events occurred at low frequencies across the treatment and control groups. As with preclinical experiments, no influence of the drug on IOP was observed, and no interaction with IOP lowering treatments was seen. Plasma concentrations were barely detectable, and less than 5% of the administered dose was eliminated in urine, establishing a comfortable safety margin compared to the animal toxicology studies. The Phase 1 study protocol was accepted by FDA and considered sufficient to support the start of large clinical studies in glaucoma and dry AMD patients.
GAL-101 is now being prepared for a Phase 2 program in glaucoma, and in dry AMD. The glaucoma neuroprotection study design was developed and validated with leading glaucoma experts and aims at treatment of first patients in H2/2019. The primary efficacy parameter of the Phase 2 neuroprotection study is based on clinically significant slowing of the progression of visual field loss, which FDA accepted in a previous pre-IND meeting as a potentially pivotal endpoint. The optimized study design draws on intensive statistical modeling using a large database of data from actual patients, which led to optimization of the inclusion/exclusion criteria for rapidly progressing patients resulting in a 12 months trial duration.
For a slowly progressing chronic disease like glaucoma, in which long-term therapeutic efficacy is dependent on patient compliance over decades, eye drops would offer a clearly advantageous route of application, so eye drops delivery of GAL-101 has been investigated thoroughly. Noting that other small molecules, such as topical NSAIDs, steroids, and topical carbonic anhydrase inhibitors are sometimes used in treating retinal disorders like macular edema when applied as eye drops, we tested topical application of GAL-101 in several animal models. Pharmacologically active levels in the retina were shown, paralleled by excellent efficacy, and without any significant toxicity. Extended ocular pharmacokinetics was studied using animal models. After application of GAL-101 eye drops 20mg/ml, various ocular tissues were analyzed. After only 5 minutes, the GAL-101 concentration in the retina had reached 1000 nM, which is 30-fold above the concentration required for target binding, and even after two hours the concentrations were still in the active range likely to support sustained effect. This excellent delivery to the retina was shown to be via the sclera and choroid to the back of the eye, not via the anterior chamber and vitreous. Recent publications have reported a similar route of retinal delivery for two other small molecules (SF0166 and PAN-90806), both under development as eye drops for the treatment of wet AMD. The use of eye drops would represent a major paradigm shift for the neuroprotective treatment of retinal diseases including glaucoma, as this would certainly be preferred by patients, provide a major compliance advantage versus intraocular injection, and almost certainly be safer.