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SAN FRANCISCO -- A noninvasive treatment for diabetic macular edema (DME) produced early evidence of efficacy in a study reported here.

Best corrected visual acuity (BCVA) improved by more than seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters as early as 6 weeks after the start of treatment with OCS-01, twice as many as a control group. The improvement was maintained at 12 weeks. Additionally, central subfoveal thickness (CST) declined rapidly and significantly more compared with the control eye drops.

The treatment was not associated with any unexpected safety issues, said Hani Salehi-Had, MD, of Retina Associates of Southern California in Huntington Beach, at the American Academy of Ophthalmology meeting.

"OCS-01 has the potential to address the unmet need of a noninvasive treatment for diabetic macular edema," he said. "Induction with six and maintenance with three drops a day was a very effective dosing regimen that led to improvement in visual acuity, reduction in central macular thickness, and an increase in the number of patients who gained at least three letters of vision."

During a discussion that followed the presentation, an early question centered on the potential treatment burden associated with OCS-01.

"Six times a day as an induction dose, that's quite a high frequency," said Carolyn Pan, MD, of Stanford University Medical Center in California. "Even at three drops a day maintenance, our glaucoma colleagues have challenges with compliance. How do you see this being solved in patients who are used to coming in once a month, but now have to do drops six times a day or three times a day?"

Salehi-Had acknowledged that the induction regimen requires "quite frequent" application of the eye drops and suggested a motivated patient population might mitigate some of the concern about adherence.

"The diabetic patient population is young," he said. "If you're offering a patient that's in their working career an injection every month versus taking eye drops at home, I think most patients are willing to accept that."

"Compliance obviously is going to be an issue that we're not going to know as much about in the clinical trial setting," Salehi-Had noted. "But these are always intention-to-treat trials, so all patients are included in the dataset, and we've seen positive results. I'm hoping this will be translated into the real world."

Suber Huang, MD, of the Retina Center of Ohio in Cleveland, asked how a treatment applied to the anterior segment penetrates all the way to the retina.

The cyclodextrin component of the formulation encapsulates dexamethasone into a single complex that leads to a much higher concentration than would normally be found in the tear film of the aqueous layer, Salehi-Had explained.

"You have a very high concentration, and as this breaks down, because of the gradient of this concentration, it's able to deliver the hydrophobic molecule to the mucous layer and beyond, and the molecule now has a chance to get in [the retina]," he continued. "It's just getting through the first aqueous layer."

"When we studied this compound in rabbit eyes, we saw that the concentration gradient is also very high in the scleral, so we believe the route of delivery is through the sclera and through the choroid to the retina," Salehi-Had added. "The concentrations are actually less in the vitreous than in the retina."

Investigators in the phase II/III DIAMOND trial evaluated OCS-01 in 148 patients with DME, and randomized 2:1 to active treatment versus vehicle. For the first 6 weeks, participants applied eye drops or vehicle six times a day, followed by 6 weeks of maintenance with three drops per day.

The primary endpoint was change in ETDRS letters during the 6-week induction phase. Other endpoints included mean change in BCVA at 12 weeks, proportion of patients with at least a three-line gain in BCVA at 6 and 12 weeks, mean change in CST at 6 and 12 weeks, and adverse events (AEs).

The study population had a DME duration of about 2 years, mean baseline BCVA of about 57 letters, mean CST of about 450 µm, and mean intraocular pressure of 15 mmHg.

At 6 weeks the mean change in BCVA was 7.2 letters (P-0.007 versus baseline) with the OCS-01 group and 3.1 in the control group. At 12 weeks the mean BCVA had increased slightly in both the OCS-01 (7.6 letters, P=0.016) and vehicle arms (3.7 letters).

About a fourth of patients allocated to OCS-01 had at least a three-line gain in ETDRS at 6 and 12 weeks versus 9.8% and 7.5%, respectively, in the control group (P=0.015, P=0.009). CST remained almost unchanged through 8 weeks in the control arm before declining by 16 µm at 12 weeks. CST declined within the first 2 weeks in the OCS-01 arm, reached a maximum decrease of 63.6 µm at 6 weeks (P<0.0001 vs control), and averaged 61.6 µm lower at 12 weeks (P=0.004).

OCT-01 led to BCVA improvement at 6 weeks in patients with phakic and pseudophakic lens status (6.9, 7.8 EDTRS letters).

The most common treatment-emergent AEs (TEAEs) with OCS-01 were diabetic retinal edema (10%), increased IOP (14%), and hypertension (10%). The only serious ocular TEAE was a single case of vitreous hemorrhage.

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