Combinations of Pilocarpine and Oxymetazoline for the Pharmacological Treatment of Presbyopia: Two Randomized Phase 2 Studies

PURPOSE: To determine the safety, efficacy, and tolerability of combinations of pilocarpine (Pilo) and oxymetazoline (Oxy) ocular drops dosed once daily and identify the optimal concentration of each for the pharmacologic treatment of presbyopia. DESIGN: Two concurrent Phase 2, multicenter, double-masked, randomized, vehicle-controlled studies, 1 short-term and 1 extended study. PARTICIPANTS: Emmetropic individuals affected by presbyopia and in good general health. METHODS: Uncorrected near visual acuity (UNVA) was measured throughout both studies with various concentrations and combinations of Pilo (0%, 0.5% 1.0%, and 1.5%) and Oxy (0%, 0.0125%, 0.05%, and 0.125%). For safety, uncorrected distance visual acuity (UDVA) was measured, treatment-emergent adverse events (TEAEs) were recorded, and a temporal/supraorbital headache assessment was completed. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change from baseline in UNVA. RESULTS: In the short-term study, Pilo was shown to produce a significant dose response in the average increase of letters (P < 0.001), whereas Oxy did not have a significant impact (P = 0.4797). The addition or increase in concentration of Oxy did not reduce incidence or severity of headaches when compared with Pilo alone. Efficacy results from the extended study supported the results from the short-term study. As early as 15 minutes postadministration, a dose response could be seen, with peak effect at 1 hour. Peak improvement increased from day 1 to day 14 and was maintained up to day 28. The most common TEAE was headache. There was no clinically significant reduction in UDVA. A polynomial regression model was developed and determined that the optimal concentration range of Pilo is between 1.16% and 1.32%. CONCLUSIONS: On the basis of the results of the 2 Phase 2 studies, AGN-190584, a reading drop containing an optimized concentration of pilocarpine HCl (1.25%) delivered using a proprietary formulation, was developed and is currently under investigation in Phase 3 studies.