Low-Dose Pilocarpine Improves Vision in Vehicle-Controlled Presbyopia Trials

SAN DIEGO -- A low-dose formulation of pilocarpine significantly improved visual acuity in presbyopia without adversely affecting distance vision, results of two randomized trials showed.

As compared with a vehicle control, twice as many patients randomized to CSF-1 met the primary endpoint of ≥3 lines of improvement in near visual acuity without a loss of ≥1 line in corrected distance visual acuity 1 hour after dosing at 8 days (40.1% vs 19.1%). Results were similar for the key secondary endpoints of distance-corrected near visual acuity (DCNVA) 2 hours after the first dose, 1 hour after the second dose, and 2 hours after the second dose.

On day 15, significantly more patients treated with CSF-1 maintained at least a 2-line improvement in DCNVA from 20 minutes to 8 hours, encompassing both doses, reported Marjan Farid, MD, of the University of California Irvine, at the American Society of Cataract and Refractive Surgery meeting.

"A significantly greater percentage of participants who received CSF-1 gained three or more lines from baseline across all timepoints on days 8 and 15 without compromising distance vision," said Farid. "CSF-1 achieved optimal pupil size in the 2-3 millimeter range. CSF-1 was well tolerated, with no serious adverse events."

Headache is a common side effect with pilocarpine. Responding to a question during the discussion that followed her presentation, Farid said headache was not a major issue.

In 2021, a 1.25% formulation of pilocarpine (Vuity) received FDA approval as the first treatment for presbyopia. Primary support for the approval came from two phase III randomized, placebo-controlled trials showing that significantly more patients treated with self-administered, once-daily pilocarpine met the primary endpoint of ≥3 lines of improvement in visual acuity at day 30 without a loss of at least one line in distance visual acuity. No serious adverse events (AEs) were reported, but headache was the most commonly reported minor AE.

CSF-1 is a preservative-free, low-dose formulation of pilocarpine, a muscarinic cholinergic agonist that improves visual acuity by means of pupil modulation. The formulation, administered twice daily, is designed to improve near vision without adversely affecting distance vision while achieving a favorable safety profile.

Farid reported findings from the identically designed NEAR-1 and NEAR-2 randomized, vehicle-controlled trials involving a combined total of 613 adults ages 45-64 with presbyopia. The primary endpoint was ≥3-line improvement in mesopic DCNVA without loss of ≥1 line of corrected distance visual acuity on day 8, 1 hour after the first dose. The key secondary endpoint was the same as the primary endpoint but with assessment 2 hours after the first dose and 2 hours after the second dose.

An additional secondary endpoint was the proportion of patients with ≥3-line improvement in DCNVA on day 15. Exploratory endpoints were pupil diameter on day 15 and the proportion of patients with ≥2-line improvement on day 15.

The results showed that the trial met the primary endpoint, demonstrating a significant increase in patients with ≥3-line improvement 1 hour after the first dose on day 8 with CSF-1 versus vehicle (P<0.0001). The trials also met the key secondary endpoints (P<0.0001 for all comparisons):

• 2 hours post-dose one: 39.8% vs 18.8%
• 1 hour post-dose two: 49.5% vs 16.1%
• 2 hours post-dose two: 42.4% vs 17.4%

CSF-1 also maintained a statistically significant reduction in pupil size 20 minutes to 8 hours after dosing.

Farid said 1.3% of participants treated with CSF-1 in both studies reported moderate treatment-related AEs (TRAEs). No serious AEs occurred in either trial. The most common TRAEs were headache (6.8%), instillation-site pain (5.8%), and blurred vision (3.6%).

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