Researchers have pursued topical treatments for retinal disease like the Holy Grail, only to find the quest as daunting as King Arthur’s mythical adventures. But in ophthalmology, its seekers have become emboldened with the release last month of Phase I/II data of a topical candidate SciFluor Life Sciences has in development. 

SciFluor unveiled the positive top-line results of SF0166 for the topical treatment of diabetic macular edema. In 40 patients with DME who were randomized to one of two dose strengths (2.5% and 5%), the safety endpoint was achieved with no drug-related serious adverse events. Ocular adverse events were recorded in the treated eyes of six patients; all were mild, and only one was considered possibly drug-related. The patients self-administered the agent as an eye drop twice a day for 28 days. 

More importantly, SF0166 demonstrated biological activity in both dosage groups, with 53 percent of patients demonstrating a reduction in retinal thickness and improvements in visual acuity. Durability of RT response after the 28-day course of therapy was observed during the month of follow-up without treatment. 

SF0166 is a selective small-molecule inhibitor of integrins. Here Peter Kaiser, MD, provides insight into how SF0166 works and explores the potential for topical treatment for DME and age-related macular degeneration. Dr. Kaiser holds the Chaney Family Endowed Chair in Ophthalmology Research and is a staff physician of the vitreoretinal faculty at the Cleveland Clinic Cole Eye Institute.

The mechanism of action in his own words
SF0166 blocks integrins, primarily integrin αvβ3, which is found in both DME and AMD. As the name of the company would suggest, the key feature of this formulation is that the drug is fluorinated. Fluorination of the drug improves the lipophilicity, slows metabolism and improves interactions with ligands. Preclinical studies have shown sustained levels in the retina after topical administration for up to eight hours.

What are the physiological challenges of getting active agents from the sclera to the retina?
The biggest issue is the cornea. Basically, the agent needs to have a special electrical charge for these molecules to cross through the eye. The eye is designed not to allow things to penetrate it. The past paradigm for topical agents was to put the active ingredients into an artificial-tear drop, but that didn’t add anything to the charge of the drop to make it pass through the eye’s defenses. 

Newer topical therapies are working on better ways to overcome these defenses to reach the posterior segment. For example, Ohr Pharmaceuticals is in Phase III with a topical therapy for AMD, and Kala Pharmaceuticals has completed a preclinical study of its lead compound KPI-285 for wet AMD. This really brings a new era in topical treatment.
What else is happening in this space to generate interest in the potential for integrin antagonism for retinal disease?

Allegro Ophthalmics has in development Luminate that also acts to inhibit integrins and disrupt the production of vascular endothelial growth factor. Two different Phase II studies showed Luminate to be non-inferior to monthly bevacizumab (Avastin, Roche/Genentech). Phase III studies will be starting shortly. Thrombogenics is also starting studies with its integrin inhibitor. 

What’s appeal of topical treatment for DME? 
Retina specialists are getting “injected out.” A therapy that offers similar efficacy and better safety in the form of a drop is a welcome addition. Moreover, a prescription eye drop comes out of a different bucket of health-care spending and it moves it away from the doctor having to administer and store the medication; the doctor writes a prescription, and the patient goes to the pharmacy to get it.

How will drops for retinal disease overcome compliance issues characteristic of glaucoma therapy?
The reason glaucoma compliance is poor is because glaucoma patients have no idea they’re losing vision. They have to remember every day to take a drop that may sting or burn and they don’t see any benefit. There’s no change in vision. 

In DME and AMD, we know that patients come in for up to monthly injections because they know if they miss the treatments, they’ll start to lose vision. That’s why the compliance rate for an eye drop in retinal disease is going to be vastly different from glaucoma­—because if patients stop taking it, they’re going to notice a decrease in vision.

What’s the next step in the development of SF0166?
Results of the DME trial will be presented at the American Academy of Ophthalmology meeting, and the results for the AMD trial will be completed shortly thereafter. The anticipation is that full analysis of the DME results combined with the hopefully positive AMD results will help determine which dosing groups will proceed into the Phase IIb trials.  RS