Preservative-Free versus Benzalkonium Chloride–Preserved Latanoprost Ophthalmic Solution in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: A Phase 3 US Clinical Trial

**Background:** Glaucoma is a leading cause of irreversible blindness, and intraocular pressure (IOP) reduction is the mainstay of treatment. Prostaglandin analogs like latanoprost are first-line therapy, but chronic exposure to the preservative benzalkonium chloride (BAK) in multidose formulations can cause ocular surface disease, dry eye, and poor adherence. Preservative-free latanoprost (T2345) was developed to avoid these effects. This US phase 3 trial evaluated the efficacy and safety of T2345 compared to BAK-preserved latanoprost (BPL) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).

**Methods:** This prospective, randomized, multicenter, observer-masked, parallel-group noninferiority trial enrolled 335 patients from 31 US sites. Eligible patients (aged ≥18 years) had POAG or OHT with IOP ≤18 mm Hg on latanoprost monotherapy for ≥4 weeks. After a ≥72-hour washout (median 7 days), patients were randomized 1:1 to T2345 (n=165) or BPL (n=170). The study eye was the eye with lower IOP at baseline. Study drugs were instilled once daily at 8 PM for 84 days. The primary efficacy endpoint was between-group comparison of mean IOP at 8 AM, 10 AM, and 4 PM on Days 15, 42, and 84. Noninferiority required the 95% CI of the difference to be within ±1.5 mm Hg at all 9 time points and within ±1.0 mm Hg at the majority. Safety outcomes included treatment-emergent adverse events (TEAEs), ocular signs, and comfort assessments.

**Key Results:** The ITT population included 334 patients (164 T2345, 170 BPL). Mean baseline diurnal IOP was 18.8 mm Hg (T2345) and 19.2 mm Hg (BPL). At Day 84, mean diurnal IOP was 16.3 mm Hg (T2345) and 15.7 mm Hg (BPL), representing reductions of 13.8% and 17.7%, respectively. For the primary endpoint in the per-protocol population, the 95% CI was within 1.5 mm Hg at all 9 time points but within 1.0 mm Hg at only 1 time point (Day 84, 4 PM), so the noninferiority criteria were not fully met. However, in the contralateral (worse) eye, the 95% CI was within 1.5 mm Hg at all time points and within 1.0 mm Hg at 5/9 time points. Additional analyses (MMRM, using screening IOP as baseline) met both noninferiority criteria. The proportion of patients with IOP <18 mm Hg at Day 84 was 73.1% (T2345) vs 78.8% (BPL). Safety: Ocular TEAEs occurred in 13.9% of T2345 patients vs 22.5% of BPL patients. Treatment-related ocular TEAEs were reported in 5.5% (T2345) vs 11.8% (BPL). The most common treatment-related TEAEs with T2345 were instillation site pain (1.8%), conjunctival hyperemia (1.2%), and instillation site pruritus (1.2%). With BPL, the most common were instillation site pain (4.7%), conjunctival hyperemia (2.4%), and punctate keratitis (1.8%). Serious TEAEs occurred in 0.6% (T2345) and 2.4% (BPL), none ocular or treatment-related. Comfort ratings were "very satisfactory" or "satisfactory" for ≥98.2% of patients in both groups.

**Clinical Implications:** Although the prespecified noninferiority criteria were not fully met in the primary analysis, T2345 demonstrated clinically meaningful IOP reduction (mean ~2.6 mm Hg from baseline) and maintained IOP below 18 mm Hg in most patients. The numerically lower incidence of ocular TEAEs and treatment-related events with T2345 suggests improved tolerability, which may enhance adherence and reduce ocular surface disease risk. The FDA approved T2345 based on the totality of evidence, including this trial and the European pivotal trial. T2345 offers a preservative-free alternative for patients requiring latanoprost, particularly those sensitive to BAK or at risk for ocular surface disease.