Preclinical Studies Show Brimochol Effectively Modulates Pupil Size

Brimochol was effective at reducing pupil size for 12 hours in an animal model and had a greater effect on pupil size than carbachol alone, according to research presented at the annual meeting of the American Academy of Optometry (AAO 2021) held in Boston and virtually, November 3 to 6.

Brimochol (Visus Therapeutics) is a fixed combination of carbachol (acholinergic miotic agent) and brimonidine (an alpha-2 agonist) that is under investigation as a pupil-modulating agent for the treatment of presbyopia. 

The investigators conducted 2 preclinical studies in an animal model to evaluate the pharmacokinetics and pharmacological effects on pupil size of the fixed combination compared with carbachol 2.75% alone. 

For the first study, in the treatment group, Dutch belted rabbits (n=4) were dosed with 1 drop of brimochol in 1 eye and phosphate-buffered saline (PBS) in the other. In the control group, 4 rabbits were dosed with carbachol 2.75% in 1 eye and PBS in the other. 

Pupil diameter of conscious animals was measured using a digital pupillometer (NeurOptics VIP-200) at baseline and various timepoints after dosing. Ocular toxicity was assessed as measures of hyperemia (score of 0-3) and chemosis (conjunctival swelling, score of 0-4) at 15 minutes and 2 hours after dosing using the Hackett McDonald scoring system. 

For the second study, the maximum concentration (Cmax) for carbachol in the iris ciliary body (ICB) was measured in 8 rabbits using liquid chromatography and tandem mass spectrometry.

Under high mesopic conditions, brimochol and carbachol alone reduced pupil size relative to baseline by a mean of 2.3±0.14 mm vs 3.45±0.49 at 0.5 hours, 4.60±0.14 vs 2.30±0.57 at 1 hour, 2.50±0.80 vs 1.43±0.64 at 2 hour, 1.65±0.87mm vs 0.83±0.32 at 4 hours, 1.33±0.73 vs 0.28±0.35 at 6 hours, 1.05±0.95 vs 0.38±0.41 at 8h 0.53±0.75 vs 0.18±0.49 at 10 hours, 0.90±0.80 vs 1.03±0.66 at 12 hours, and 1.33±0.25 vs 0.68±-0.43 mm at 24 hours, respectively. The differences between the brimochol and carbachol-alone groups were statistically significant at 1 hour (P =.031) and 6 hour (P =.041). Similar results were observed under other lighting conditions. 

In the brimochol and carbachol-only groups, the mean hyperemia scores were 0±0 vs 0±0 at baseline, 0±0 vs 0.75±0.5 at 0.25 hours (P =.024), and 0.25±0.5 vs 0.75±0.5 at 2 hours (P =.207), respectively. In the brimochol and carbachol-only groups, the mean chemosis scores were 0±0 vs 0±0 at baseline, 0±0 vs 0.75±0.5 at 0.25 hours (P =.024), and 0±0 vs 0.5±0.58 at 2 hours (P =.134), respectively. 

The Cmax (at 2 hours) for brimochol in ICB was 32.8 ng/g compared with 17.8 ng/g for carbachol alone (P =.159). The investigator observed a trend toward higher Cmax and area under the curve at all time points through 12 hours following dosing.

“Brimochol demonstrated effectiveness at reducing pupil size in rabbits for 12 hours and had a greater effect on pupil size than carbachol 2.75% alone,” concluded investigator Milton Hom, OD, FAAO. “The addition of brimonidine appears to counter hyperemia and chemosis compared to carbachol alone. Perhaps by altering aqueous dynamics, the addition of brimonidine also tends to increase the Cmax of carbachol.”

Reference

Hom M. Pharmacokinetics and pharmacodynamics of brimochol. Paper Presented at: American Academy of Optometry 2021; November 3-6, 2021. Presentation Board #91.