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Jay S Pepose,1,2 Paul J Hartman,3 Harvey B DuBiner,4 Marc A Abrams,5 Robert J Smyth-Medina,6 Sayoko E Moroi,7 Alan R Meyer,8 Mina P Sooch,8 Reda M Jaber,8 Konstantinos Charizanis,8 Seth A Klapman,8 Arin T Amin,8 Jonah E Yousif,8 Eliot S Lazar,9 Paul M Karpecki,10 Charles B Slonim,11 Marguerite B McDonald12 1Pepose Vision Institute, St. Louis, MO, USA; 2Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; 3Department of Ophthalmology, University of Rochester, Rochester, NY, USA; 4Clayton Eye Center, Morrow, GA, USA; 5Case Western Reserve University, Cleveland, OH, USA; 6North Valley Eye Medical Group, Mission Hills, CA, USA; 7The Ohio State University Wexner Medical Center, Columbus, OH, USA; 8Ocuphire Pharma Inc, Farmington Hills, MI, USA; 9elCON Medical, Buffalo, NY, USA; 10Kentucky College of Optometry, University of Pikeville, Pikeville, KY, USA; 11Oculos Development Services, LLC, Tampa, FL, USA; 12Department of Ophthalmology, New York University Langone Medical Center, New York, NY, USACorrespondence: Konstantinos CharizanisOcuphire Pharma, Inc., 37000 Grand River Ave, Farmington, MI 48335, USATel +1 (352) 328 9117Email kcharizanis@ocuphire.comPurpose: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population.Patients and Methods: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia.Results: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥ 1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo.Conclusion: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.Keywords: IOP, presbyopia, night vision disturbances, dim light vision disturbances, pupil diameter, ORION-1

SIGNIFICANCE After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations. PURPOSE The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication. METHODS In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points. RESULTS Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours. CONCLUSIONS Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile.