Phase 3, Randomized Study Comparing Intracameral Bimatoprost Implant 15 µg and Selective Laser Trabeculectomy in Patients with Open-Angle Glaucoma or Ocular Hypertension.

Purpose: We evaluate the safety and intraocular pressure (IOP)-lowering effect of 15-µg bimatoprost implant (higher dose than the currently approved product) compared with selective laser trabeculoplasty (SLT) in patients with open-angle glaucoma or ocular hypertension. Methods: Randomized, phase 3, 12-month, multicenter, paired-eye, patient- and efficacy evaluator-masked noninferiority study. Patients with inadequate IOP control were randomized to receive 360° SLT (day 1) or up to 3 administrations of 15-µg bimatoprost implant (day 4, weeks 16 and 32) in the primary eye and the alternative treatment in the contralateral eye. The primary endpoint was IOP change from baseline at weeks 4, 12, and 24. Results: At weeks 4, 12, and 24, mean IOP change from baseline ranged from -7.01 to -6.65 mm Hg in implant-treated eyes (N=138) and -6.45 to -6.26 mm Hg in SLT-treated eyes (N=138). Differences in IOP change from baseline ranged from -0.70 to -0.25 mm Hg favoring implant; the upper limit of the 95% confidence interval of the difference (implant minus SLT) was <1.0 mm Hg at all 3 visits. The probability of requiring no additional (rescue) IOP-lowering treatment in implant-treated versus SLT-treated eyes was 93.6% versus 86.5% at day 180 and 74.6% versus 77.1% at day 360. Corneal endothelial cell loss was more common in implant-treated eyes and typically occurred after repeated implant administration. Conclusion: Bimatoprost implant 15 µg met prespecified criteria for statistical and clinical noninferiority to SLT in lowering IOP, and after 1, 2, or 3 administrations, demonstrated a duration of IOP lowering similar to SLT. Bimatoprost implant 15 µg was associated with corneal adverse events in some patients, especially after repeated administrations at a fixed interval, and has been discontinued from development. A lower dose strength of implant (bimatoprost implant 10 µg, Durysta) is US Food and Drug Administration-approved for single administration.

Single Administration of Bimatoprost Implant: Effects on 24-Hour Intraocular Pressure and 1-Year Outcomes.

PURPOSE: To evaluate the effects of a single bimatoprost implant administration on 24-hour intraocular pressure (IOP) lowering at 8 weeks, and 1-year IOP-lowering efficacy and safety outcomes. DESIGN: Multicenter, open-label, 12-month, phase 3b study (NCT04285580). PARTICIPANTS: Adults with open-angle glaucoma or ocular hypertension. METHODS: Participants (n = 31) received 10-µg bimatoprost implant in the study eye on day 1; IOP (sitting and/or supine) was measured with pneumatonometry every 2 hours throughout a 24-hour period at baseline and week 8. IOP was measured by Goldmann applanation tonometry (GAT) at hour 0 (8 am ± 1 hour) at baseline, weeks 8 and 16, and months 6, 9, and 12. MAIN OUTCOME MEASURES: The primary endpoint was the week-8 hour-matched change from baseline in habitual position IOP over 24 hours assessed with pneumatonometry. Hour 0 IOP change from baseline measured with GAT in study eyes that received no additional (rescue) IOP-lowering treatment, treatment-emergent adverse events (TEAEs), and central corneal endothelial cell density (CECD) were evaluated through 12 months. RESULTS: The mean (standard deviation [SD]) baseline IOP at hour 0 was 24.2 (2.70) mmHg and 25.3 (7.15) mmHg by GAT and pneumatonometry, respectively. Pneumatonometer measurements of IOP taken over 24 hours at week 8 with the participant in habitual position (sitting from 8 am to 10 pm, supine from 12 am to 6 am) showed consistent IOP lowering through the day and night and reduced fluctuation in IOP. The range in IOP measurements over 24 hours was reduced from baseline by a mean (SD) of -1.6 (2.98) mmHg. All 31 bimatoprost implant-treated participants completed the 12-month study; 23 (74%) required no rescue IOP-lowering treatment. The mean (SD) IOP reduction from baseline at month 12 in nonrescued eyes was -4.3 (3.35) mmHg. The most common TEAE was conjunctival hyperemia (incidence 35.5%, 11/31). No implant-treated eye had a ≥ 15% loss in CECD from baseline. CONCLUSIONS: A single intracameral administration of the bimatoprost implant lowered IOP in the habitual position consistently throughout the day and night at week 8. The majority of participants continued to have reduced IOP for 1 year without additional therapy. The 1-year safety profile was favorable. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Randomized Phase IIb Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of repeat injections of Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400-µg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: A phase IIb, randomized, multicenter, double-masked, sham-controlled, 30-month study (BEACON). PARTICIPANTS: Patients diagnosed with GA secondary to AMD and multifocal lesions with total area of > 1.25 mm2 and ≤ 18 mm2 in the study eye. METHODS: Enrolled patients were randomized to treatment with intravitreal injections of 400-µg Brimo DDS (n = 154) or sham procedure (n = 156) in the study eye every 3 months from day 1 to month 21. MAIN OUTCOME MEASURES: The primary efficacy endpoint was GA lesion area change from baseline in the study eye, assessed with fundus autofluorescence imaging, at month 24. RESULTS: The study was terminated early, at the time of the planned interim analysis, because of a slow GA progression rate (∼ 1.6 mm2/year) in the enrolled population. Least squares mean (standard error) GA area change from baseline at month 24 (primary endpoint) was 3.24 (0.13) mm2 with Brimo DDS (n = 84) versus 3.48 (0.13) mm2 with sham (n = 91), a reduction of 0.25 mm2 (7%) with Brimo DDS compared with sham (P = 0.150). At month 30, GA area change from baseline was 4.09 (0.15) mm2 with Brimo DDS (n = 49) versus 4.52 (0.15) mm2 with sham (n = 46), a reduction of 0.43 mm2 (10%) with Brimo DDS compared with sham (P = 0.033). Exploratory analysis showed numerically smaller loss over time in retinal sensitivity assessed with scotopic microperimetry with Brimo DDS than with sham (P = 0.053 at month 24). Treatment-related adverse events were usually related to the injection procedure. No implant accumulation was observed. CONCLUSIONS: Multiple intravitreal administrations of Brimo DDS (Gen 2) were well tolerated. The primary efficacy endpoint at 24 months was not met, but there was a numeric trend for reduction in GA progression at 24 months compared with sham treatment. The study was terminated early because of the lower-than-expected GA progression rate in the sham/control group. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN: Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data. PARTICIPANTS: The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters. METHODS: At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630). MAIN OUTCOME MEASURES: Efficacy measures included stable vision (<15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs). RESULTS: For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 µm, -146 µm, and -142 µm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. CONCLUSIONS: Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.

Double-Masked, Randomized, Phase 2 Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. Methods: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients (n = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). Results: In the abicipar 1 mg (n = 25), abicipar 2 mg (n = 23), and ranibizumab (n = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 µm at week 16 and 116, 103, and 138 µm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. Conclusions: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.