VISUS THERAPEUTICS RECENTLY shared the results of its BRIO-1 phase 3 study evaluating Brimochol PF, a fixed-dose combination of carbachol 2.75% and brimonidine tartrate 0.1% in a preservative-free vehicle, for the temporary treatment of presbyopia.

This is the first phase 3 presbyopia trial in which the medication was compared to another active ingredient. In this crossover study, 182 emmetropic patients ages 45-80 (including pseudophakes) were enrolled at 15 U.S. sites. After screening, they were randomized to a single dose of Brimochol PF, carbachol monotherapy, or brimonidine monotherapy; visual acuity and pupil size were measured repeatedly over the next 10 hours. At 2 subsequent visits, on days 4 and 7, patients were switched to each of the other drugs. Thus, each subject was exposed to all three formulations on different days, and the same subject’s response to each could be compared directly.

The results are impressive. First, Brimochol PF met the primary endpoint established by the FDA for all studies of presbyopia-correcting drops: a ≥15 ETDRS letter gain (3 lines) from baseline in binocular uncorrected near visual acuity under mesopic conditions, without a ≥5 ETDRS letter loss (1 line) in binocular uncorrected distance visual acuity. Brimochol PF met this endpoint at 1, 2, 4, and 6 hours. Even at 10 hours after a single dose, patients still had a 2-line gain. No loss of distance vision was observed in any of the 3 study arms. In fact, subjects experienced a small gain (2 letters) in uncorrected distance vision.

In addition to the subjective acuity gains, Brimochol PF also had an objective effect on the pupil, achieving a statistically significant reduction in pupil size compared to active controls at all time points out to 10 hours (Figure 1). We see that the miotic effect gradually diminishes by the end of the day, which is important for patients to be able to safely drive home from work in the dark. Contrary to some reports, a sub-2.0-mm pupil was not necessary to achieve the desired near vision gains.

The combination drug outperformed both of its single-agent components out to 8 hours, passing the important “contribution of elements” test that the FDA requires. Carbachol is quite an effective miotic on its own, but the addition of brimonidine prolongs its efficacy. We also know that brimonidine in a lower dose formulation (0.025%) has been approved for eye whitening. Patients receiving Brimochol PF in this study reported no hyperemia at all, while the carbachol group did report redness.

Tolerability is very important for any elective, topical treatment for presbyopia, so I was excited to see there was no tradeoff between duration and tolerability with Brimochol PF. There were no treatment-related serious adverse events and no discontinuations due to adverse events in the study. Headache was reported by less than 10% of people, and about 14% of patients experienced transient irritation on instillation. All patients filled out a questionnaire after the 10-hour study visit evaluating their impressions of the drops. Patients reported that they were highly likely (score of 7/10) to use the drop every day and that they found the duration of effect to be “just right,” ie, neither too short nor too long.

A second phase 3 study, BRIO-II, is already under way to evaluate Brimochol PF vs vehicle for daily use over a full year, setting the stage for the drop to be considered by the FDA as early as next year. In my experience, patients with presbyopia want a comfortable, once-daily eye drop that can improve near vision throughout a full workday—and we saw in this study that Brimochol PF provides just that. If approved in the future, it will become an important new option for our patients who are struggling with presbyopia. ■

Dr. Donnenfeld practices at Ophthalmic Consultants of Long Island in Garden City, NY. He serves on the Visus Board of Directors and is chair of the company’s medical advisory board.