Pilocarpine HCl 1.25% for treatment of presbyopia after laser vision correction: pooled analysis of two phase 3 randomized trials (GEMINI 1 and 2).

PURPOSE: To evaluate the efficacy of topical pilocarpine HCl 1.25% (Pilo) in treating presbyopia in individuals with or without a history of laser vision correction (laser-assisted in situ keratomileusis [LASIK] or photorefractive keratectomy [PRK]). SETTING: Multiple clinical sites. DESIGN: Pooled analysis of 2 identically designed prospective, randomized, vehicle-controlled studies (GEMINI 1 and 2). METHODS: Adults aged 40 to 55 years with presbyopia received once-daily Pilo or vehicle bilaterally for 30 days. Responder rates for ≥3-line improvement in mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA) were determined on day 30. RESULTS: Among participants with a history of LASIK/PRK (n = 39 in the Pilo group, n = 41 in the vehicle group), responder rates for ≥3-line improvement in DCNVA on day 30 at hours 0.25, 0.5, 1, 3, 6, 8, and 10, respectively, were 16.7%, 38.9%, 41.7%, 37.8%, 16.2%, 13.9%, and 8.3% with Pilo and 0.0%, 2.6%, 10.5%, 5.1%, 7.7%, 2.6%, and 0.0% with vehicle. Responder rates in the LASIK/PRK subgroup were significantly higher with Pilo than vehicle at hours 0.25 ( P = .0087), 0.5 ( P = .0001), 1 ( P = .0022), and 3 ( P = .0005). In contrast, there were no significant differences in responder rates between Pilo-treated participants with and without LASIK/PRK. Among non-LASIK/PRK participants in the Pilo group (n = 336), responder rates for ≥3-line improvement in DCNVA on day 30 at hours 0.25, 0.5, 1, 3, 6, 8, and 10, respectively, were 16.8%, 32.7%, 39.0%, 28.0%, 17.4%, 12.6%, and 10.5%. CONCLUSIONS: Pilo treatment effectively and similarly improved DCNVA in presbyopes with or without a history of laser vision correction.

Omidenepag Isopropyl in Latanoprost Low/Nonresponders With Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 3, Nonrandomized, Two-Phase, Open-Label Study.

PRCIS: This study demonstrates the efficacy and safety of once-daily 0.002% omidenepag isopropyl (OMDI) in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) who do not respond or respond poorly to latanoprost. PURPOSE: The purpose of this study was to evaluate the intraocular pressure (IOP)-lowering efficacy and safety of OMDI in latanoprost low/nonresponders with POAG or OHT. MATERIALS AND METHODS: Phase 3, nonrandomized, 2-phase, open-label, multicenter study (NCT03697811) in the United States. Key inclusion criteria included individuals aged 18 years or above, POAG or OHT diagnosis in both eyes, IOP ≥22 mm Hg in ≥1 eye, and ≤34 mm Hg in both eyes at all time points. Overall, 107 patients were enrolled; 104 completed treatment. Included a screening period (≤35-day washout period and 8-week latanoprost run-in period) and a 3-month treatment period comprising one drop of OMDI 0.002% once daily in both eyes. The primary study endpoint was changed from baseline in the mean diurnal (MD) IOP at month 3. Safety endpoints included incidence of adverse events, serious adverse events, and adverse drug reactions. RESULTS: At baseline (visit 4), 75 (70.1%) patients had POAG, 32 (29.9%) had OHT, and 68 (63.6%) had prior use of prostaglandin/prostaglandin analogs (37.4% of whom used latanoprost). The mean (SD) baseline MD IOP was 23.34 mm Hg (2.12). The mean (SD) 3-month (visit 7) MD IOP change from baseline (following latanoprost run-in period and OMDI treatment period) was an additional decrease of 2.96 mm Hg (2.83) ( P <0.0001). No significant safety issues were reported during OMDI treatment. CONCLUSIONS: These data demonstrate OMDI efficacy and safety in latanoprost low/nonresponders with POAG or OHT, suggesting OMDI is a treatment option in the patient population in this study.

Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

A randomized, vehicle-controlled, Phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1).

PURPOSE: Dry eye disease (DED) symptoms can negatively impact quality of life (QoL). AR-15512, a transient receptor potential melastatin 8 (TRPM8) agonist, was evaluated as a potential therapy for DED. METHODS: In a Phase 2b study, patients with DED were randomized 1:1:1 to 0.0014% AR-15512, 0.003% AR-15512, or vehicle twice daily for 12 weeks. Eligibility criteria included DED signs and symptoms of prespecified severity levels. Outcomes assessed were DED signs (Schirmer score ± anesthetic, ocular surface staining, hyperemia), symptoms (Ocular Discomfort [ODS-VAS], Symptoms Assessment iN Dry Eye [SANDE], Eye Dryness-VAS, Ocular Pain-VAS), QoL-VAS, and adverse events. Co-primary endpoints were changes from baseline in ODS-VAS and anesthetized Schirmer score at Day 28. RESULTS: 0.003% AR-15512 (n = 122) was associated with early and sustained improvements in unanesthetized Schirmer score (Days 1 and 14, p < 0.0001), as well as improvements in ocular surface staining (Days 14 and 84, p ≤ 0.0365) and hyperemia (Day 84, p < 0.0215). Statistically significant improvements in symptoms were observed for the 0.003% concentration on SANDE (Days 14, 28, and 84, p ≤ 0.0254), ODS-VAS (Day 84, p = 0.0281), Eye Dryness-VAS (Day 84, p = 0.0302), and multiple QoL measures (Days 14, 28, and 84, p < 0.05). There were no significant differences between active and vehicle groups for the co-primary endpoints. The most common adverse events were burning and stinging upon instillation. CONCLUSIONS: Although predefined co-primary study endpoints were not met, AR-15512 demonstrated statistically significant improvements in DED signs, symptoms, and disease-related QoL.

Plasma Pharmacokinetic Parameters of Dexamethasone Following Administration of a Dexamethasone Intracanalicular Insert in Healthy Adults.

PURPOSE: Intracanalicular dexamethasone insert is a resorbable sustained-release polyethylene glycol-based hydrogel insert delivering a 0.4 mg tapered dose of dexamethasone for up to 30 days to the ocular surface. It is FDA-approved for treating inflammation and pain after ocular surgery. It has also been studied for ocular surface diseases such as allergic conjunctivitis. This study assessed the plasma pharmacokinetic (PK) parameters of dexamethasone following intracanalicular insertion. PATIENTS AND METHODS: Study subjects (N=16) were healthy adults. A dexamethasone insert was unilaterally placed into the canaliculus, and blood samples were obtained for analysis 1 hour prior to insertion and 1, 2, 4, 8, 16, 24 hours and 4, 8, 15, 22 and 29 days after insertion. Safety analyses included slit lamp and dilated fundus examinations, best corrected visual acuity, intraocular pressure (IOP) and adverse events (AEs). RESULTS: Plasma results were below the lower limit of quantitation (LLOQ) at all time points in five subjects (31.3%). Among subjects with quantifiable plasma concentrations, Cmax was <1 ng/mL (range, 0.05 to 0.81 ng/mL), AUC0-last ranged from 0.13 to 7.18 h∙ng/mL, and Tmax ranged from 4.0 to 163.0 hours. Mean (SD) IOP increased from 16.3 (1.4) mmHg at baseline to 19.3 (3.2) at Day 22 but returned to baseline after treatment. No changes occurred in dilated fundus, punctum, or visual acuity examinations. CONCLUSION: The dexamethasone 0.4 mg insert results in minimal systemic exposure following intracanalicular administration.

Phase 3 Randomized Study of Efficacy and Safety of a Dexamethasone Intracanalicular Insert in Patients With Allergic Conjunctivitis.

PURPOSE: The purpose of this study was to evaluate the efficacy and safety of a dexamethasone intracanalicular ocular insert for the treatment of allergic conjunctivitis. DESIGN: Multicenter, randomized, double-masked, placebo-controlled, Phase 3 clinical trial. METHODS: Subjects with allergic conjunctivitis were randomized 1:1 to receive a dexamethasone insert or a placebo insert in both eyes and were evaluated using a modified version of the conjunctival allergen challenge (CAC) model. After inserts were placed in office, a series of 4 closely spaced post-insertion CACs were conducted at weeks 1, 2, and 4 across approximately 30 days. Primary efficacy endpoints, assessed at week-1 CAC-day 8, were reported by subjects of ocular itching at 3, 5, and 7 minutes post CAC and investigator-evaluated conjunctival redness at 7, 15, and 20 minutes post CAC. RESULTS: For the primary endpoints, dexamethasone inserts showed statistically significantly lower mean ocular itching scores than placebo at all time points (P <.001), with differences favoring dexamethasone inserts over placebo (0.86, 0.98, and 0.96 units at 3, 5, and 7 minutes, respectively) and statistically significantly lower conjunctival redness scores at 20 minutes (P <.05) but not at 7 or 15 minutes (P ≥.05). Results also showed statistically significantly less itching and conjunctival redness at 31 and 29 of 33 other time points, respectively (P <.05). There were no serious adverse events; 1 subject had elevated intraocular pressure in both eyes. CONCLUSIONS: Data presented in this study demonstrate the potential for a single, physician-administered dexamethasone intracanalicular insert to provide relief of ocular itching for up to 4 weeks in subjects with allergic conjunctivitis, while maintaining a favorable safety profile.

Effect of alcaftadine 0.25% on ocular itch associated with seasonal or perennial allergic conjunctivitis: a pooled analysis of two multicenter randomized clinical trials.

PURPOSE: Seasonal and perennial allergic conjunctivitis represent the majority of cases of ocular allergy. This analysis was designed to evaluate the efficacy and safety of once-daily alcaftadine 0.25% in preventing ocular itching associated with seasonal or perennial allergic conjunctivitis. SUBJECTS AND METHODS: Pooled data from two double-masked, multicenter, placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis were analyzed. Subjects randomized to receive treatment with alcaftadine 0.25% or placebo were challenged with seasonal (grass, ragweed, trees) or perennial (cat dander, cat hair, dog dander, dust mites, cockroach) allergens, 16 hours after treatment instillation. The primary efficacy measure was subject-evaluated mean ocular itching at 3 minutes post-CAC. Secondary measures included ocular itching at 5 and 7 minutes post-CAC. The proportion of subjects with minimal itch (itch score <1) and zero itch (itch score =0), and safety were also assessed. RESULTS: A total of 189 subjects enrolled in the two studies were treated with alcaftadine or placebo. Overall, 129 subjects were challenged with seasonal allergens and 60 subjects were challenged with perennial allergens. Alcaftadine 0.25% achieved a statistically significant reduction in mean itch score at 3, 5, and 7 minutes post-CAC compared with placebo in subjects challenged with seasonal allergens (P<0.0001 at all time points) and those challenged with perennial allergens (P<0.0001 at all time points). A higher percentage of subjects treated with alcaftadine compared with placebo achieved minimal itch (P≤0.001 versus placebo at all time points) and zero itch (P<0.05 at all time points except 7 minutes for perennial) when challenged with either seasonal or perennial allergens. No treatment-related or serious adverse events were reported. CONCLUSION: Once-daily alcaftadine 0.25% ophthalmic solution was well tolerated and demonstrated effective relief of ocular itching in subjects challenged with allergens classic for triggering either seasonal or perennial allergic conjunctivitis.

Ocular itch relief with alcaftadine 0.25% versus olopatadine 0.2% in allergic conjunctivitis: pooled analysis of two multicenter randomized clinical trials.

INTRODUCTION: The efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated. METHODS: Pooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score<1) and zero itch (itch score=0) was also assessed. RESULTS: A total of 284 subjects were enrolled in the two studies. At 3 min post-CAC and 16 h after treatment instillation, alcaftadine 0.25% achieved a significantly lower mean itch score compared with olopatadine 0.2% (0.50 vs. 0.87, respectively; P=0.0006). Alcaftadine demonstrated a significantly lower mean itch score over all time points compared with olopatadine (0.68 vs. 0.92, respectively; P=0.0390); both alcaftadine- and olopatadine-treated subjects achieved significantly lower overall mean ocular itching scores compared with placebo (2.10; P<0.0001 for both actives). Minimal itch over all time points was reported by 76.1% of alcaftadine-treated subjects compared with 58.1% of olopatadine-treated subjects (P=0.0121). Treatment with alcaftadine 0.25% and olopatadine 0.2% was safe and well tolerated; no serious adverse events were reported. CONCLUSION: Once-daily alcaftadine 0.25% ophthalmic solution demonstrated greater efficacy in prevention of ocular itching compared with olopatadine 0.2% at 3 min post-CAC (primary endpoint), and over all time points, 16 h post-treatment instillation. Alcaftadine and olopatadine both provided effective relief compared with placebo and were generally well tolerated.

Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study.

PURPOSE: To assess the efficacy and safety of lifitegrast ophthalmic solution 5.0% compared with placebo in subjects with dry eye disease. DESIGN: Prospective, randomized, double-masked, placebo-controlled, parallel arm, multicenter clinical trial. PARTICIPANTS: A total of 588 adult subjects with dry eye disease. METHODS: Eligible subjects were randomized 1:1 to receive topically administered lifitegrast (5.0%) or placebo (vehicle) twice daily for 84 days after a 14-day open-label placebo run-in period. After enrollment (day 0), subjects were evaluated at days 14, 42, and 84. Key objective (fluorescein and lissamine staining scores [Ora scales]) and subjective (Ocular Surface Disease Index [OSDI], 7-item visual analog scale, and ocular discomfort score [Ora scale]) measures were assessed at all visits. MAIN OUTCOME MEASURES: The primary objective efficacy measure (sign) was mean change from baseline inferior corneal staining score (ICSS) at day 84. The co-primary subjective efficacy measure (symptom) was the mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index (VR-OSDI). Supportive measures included corneal fluorescein scores (superior, central, total region) and conjunctival lissamine scores (nasal, temporal, total region) and symptom scores at day 84. RESULTS: The study met the primary objective efficacy ICSS end point in demonstrating superiority of lifitegrast compared with placebo (P = 0.0007). Lifitegrast significantly reduced corneal fluorescein staining (superior, P = 0.0392; total cornea, P = 0.0148) and conjunctival lissamine staining (nasal, P = 0.0039; total conjunctiva, P = 0.0086) at day 84 versus placebo. Significant (P < 0.05) improvements in nasal and total lissamine scores were observed at day 14 and maintained through day 84. The study did not meet the co-primary subjective VR-OSDI measure (P = 0.7894). However, significant improvements were observed at day 84 in ocular discomfort (P = 0.0273) and eye dryness (P = 0.0291), the most common and severe symptoms reported at baseline in both groups. There were no unanticipated or serious ocular adverse events (AEs). The most frequent reported ocular AEs were transient intermittent instillation site symptoms (irritation, discomfort) primarily on the initial lifitegrast dose at day 0. CONCLUSIONS: Lifitegrast ophthalmic solution 5.0% significantly reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily over 84 days.

A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye.

PURPOSE: To investigate the efficacy and safety of an investigational integrin antagonist (SAR 1118) ophthalmic solution compared to placebo (vehicle) in subjects with dry eye disease. DESIGN: Multicenter, prospective, double-masked, placebo-controlled trial. METHODS: A total of 230 dry eye subjects selected with use of a controlled adverse environment were randomized 1:1:1:1 to receive SAR 1118 (0.1%, 1.0%, 5.0%) or placebo eye drops twice daily for 84 days. Principal eligibility criteria included exacerbation in corneal staining and ocular symptoms with controlled adverse environment exposure, no active lid margin disease, and Schirmer test (mm/5 min) >1 and <10. Ocular signs and symptoms (Ocular Surface Disease Index, OSDI) were assessed at day 14, 42, and 84. No supplemental artificial tears were allowed. Primary outcome measure was inferior corneal staining score at day 84. RESULTS: A dose response for the corneal staining score (P = .0566) was observed for SAR 1118 at day 84 compared to placebo. Mean change from baseline to day 84 showed significant improvements (P < .05) in corneal staining score, total OSDI, and visual-related function OSDI scores for SAR 1118 compared to placebo; improvements in tear production and symptoms were observed as early as day 14 (P < .05). Adverse events were mild and transient in nature with no serious ocular adverse events. SAR 1118 5.0% showed increased instillation site adverse events relative to placebo but were limited to the initial dose. CONCLUSION: SAR 1118 demonstrated improvements in signs and symptoms of dry eye compared to placebo and appears safe when administered over 84 days.