Evaluation of cardiac parameters and other safety outcomes of brolucizumab treatment in patients with neovascular age-related macular degeneration.

This was a prospective, single-dose, single-arm, open-label, non-randomized, multicenter clinical study to determine cardiovascular safety after a single brolucizumab 6 mg intravitreal injection in neovascular age-related macular degeneration patients (N = 14). Electrocardiogram (ECG) data were collected at different time points using 12-lead Holter and standard ECG, and patients were followed up to 8 days (end of study) for any signs of ocular and non-ocular adverse events (AEs). No clinically meaningful changes were observed in cardiac parameters. No patient had a ≥30 msec change from baseline in heart rate-corrected QT using Fridericia's formula (QTcF), and no patient had a new QTcF value of ≥450 msec between 20 and 24 h after treatment. No deaths or serious AEs were reported during the study period. These results are in line with the absence of new cardiovascular safety signal based on the ECG recordings collected over the first year of the pivotal studies performed with brolucizumab in DME. Trial Registration: ClinicalTrials.gov identifier: NCT03954626.

RANIBIZUMAB VERSUS VERTEPORFIN PHOTODYNAMIC THERAPY IN ASIAN PATIENTS WITH MYOPIC CHOROIDAL NEOVASCULARIZATION: BRILLIANCE, a 12-Month, Randomized, Double-Masked Study.

PURPOSE: To evaluate the efficacy and safety of 2 dosing regimens of ranibizumab 0.5 mg versus verteporfin photodynamic therapy in Asian patients with visual impairment due to myopic choroidal neovascularization. METHODS: Eligible patients (aged ≥18 years) were randomized 2:2:1 to Group I (n = 182; ranibizumab treatment guided by visual acuity stabilization criteria); Group II (n = 184; ranibizumab treatment guided by disease activity); or Group III (n = 91; verteporfin photodynamic therapy on Day 1; from Month 3, ranibizumab/verteporfin photodynamic therapy/both treatment guided by disease activity). RESULTS: The mean average best-corrected visual acuity change from baseline to Month 1 through Month 3 was significantly higher in Groups I/II versus Group III (Group I/II: +9.5/+9.8 letters vs. Group III: +4.5 letters; both P < 0.001). Group II was statistically noninferior to Group I for the mean average best-corrected visual acuity change from baseline to Month 1 through Month 6 (10.7 vs. 10.4 letters; P < 0.001). Over 12 months, the mean number of ranibizumab injections received by Groups I/II/III was 4.6/3.9/3.2. CONCLUSION: In Asian patients, ranibizumab treatments demonstrated superior efficacy versus verteporfin photodynamic therapy at Month 3, and the beneficial treatment effects persisted at Month 12. Ranibizumab was well-tolerated and demonstrated a good safety profile.

Sustained Benefits from Ranibizumab for Central Retinal Vein Occlusion with Macular Edema: 24-Month Results of the CRYSTAL Study.

PURPOSE: To assess the efficacy and safety profile of an individualized, stabilization criteria-driven regimen of ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: A 24-month, prospective, open-label, single-arm, multicenter study. PARTICIPANTS: A total of 357 patients. METHODS: Patients received monthly ranibizumab 0.5 mg injections (minimum, 3 injections) until stable visual acuity (VA) was maintained for 3 consecutive months. Thereafter, ranibizumab 0.5 mg injections were administered if monitoring indicated a loss of VA due to disease activity. The primary outcome results have been published previously. MAIN SECONDARY OUTCOME MEASURES: Mean change from baseline at months 1 through 24 in best-corrected VA (BCVA) in the overall population and in subgroups categorized according to baseline BCVA, CRVO duration, or presence of macular ischemia. RESULTS: The baseline mean BCVA was 53.0 letters and baseline mean CRVO duration was 8.9 months (median, 2.4 months). The mean (standard deviation) gain in BCVA from baseline with ranibizumab 0.5 mg at month 24 was 12.1 (18.60) letters (P < 0.0001). Best-corrected VA gains at month 24 were similar in patients with or without baseline macular ischemia (mean change, 11.1 and 12.9 letters, respectively). The mean BCVA gain at month 24 was higher in patients with CRVO duration <3 months (13.2 letters) compared with that in those with CRVO duration >9 months (10.5 letters). Patients with lower baseline BCVA had larger mean BCVA gains at month 24 (≤39 letters; 18.5 letters) than those with higher baseline BCVA (40-59/≥60 letters; 13.9/7.2 letters), although the absolute BCVA values at month 24 were higher in patients with higher baseline BCVA. The mean (standard deviation) and median number of ranibizumab injections up to month 23 were 13.1 (6.39) and 15.0 injections, respectively. No new ocular or nonocular safety events were reported. CONCLUSION: An individualized, stabilization criteria-driven dosing regimen of ranibizumab 0.5 mg led to sustained BCVA gains for up to 24 months in patients with CRVO. The presence of macular ischemia at baseline did not influence VA gains. Shorter duration of CRVO at baseline was associated with better VA gains. Safety findings were consistent with those reported in previous ranibizumab studies in patients with CRVO.

Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion: 24-Month Results of the BRIGHTER Study.

PURPOSE: To evaluate the long-term (24-month) efficacy and safety of ranibizumab 0.5 mg administered pro re nata (PRN) with or without laser using an individualized visual acuity (VA) stabilization criteria in patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). DESIGN: Phase IIIb, open-label, randomized, active-controlled, 3-arm, multicenter study. PARTICIPANTS: A total of 455 patients. METHODS: Patients were randomized (2:2:1) to ranibizumab 0.5 mg (n = 183), ranibizumab 0.5 mg with laser (n = 180), or laser (with optional ranibizumab 0.5 mg after month 6; n = 92). After initial 3 monthly injections, patients in the ranibizumab with or without laser arms received VA stabilization criteria-driven PRN treatment. Patients assigned to the laser arm received laser at the investigator's discretion. MAIN OUTCOME MEASURES: Mean (and mean average) change in best-corrected visual acuity (BCVA) and central subfield thickness (CSFT) from baseline to month 24, and safety over 24 months. RESULTS: A total of 380 patients (83.5%) completed the study. Ranibizumab with or without laser led to superior BCVA outcomes versus laser (monotherapy and combined with ranibizumab from month 6; 17.3/15.5 vs. 11.6 letters; P < 0.0001). Ranibizumab with laser was noninferior to ranibizumab monotherapy (mean average BCVA change: 15.4 vs. 15.0 letters; P < 0.0001). However, addition of laser did not reduce the number of ranibizumab injections (mean injections: 11.4 vs. 11.3; P = 0.4259). A greater reduction in CSFT was seen with ranibizumab with or without laser versus laser monotherapy over 24 months from baseline (ranibizumab monotherapy -224.7 µm, ranibizumab with laser -248.9 µm, laser [monotherapy and combined with ranibizumab from month 6] -197.5 µm). Presence of macular ischemia did not affect BCVA outcome or treatment frequency. There were no reports of neovascular glaucoma or iris neovascularization. No new safety signals were identified. CONCLUSIONS: The BRIGHTER study results confirmed the long-term efficacy and safety profile of PRN dosing driven by individualized VA stabilization criteria using ranibizumab 0.5 mg in patients with BRVO. Addition of laser did not lead to better functional outcomes or lower treatment need. The safety results were consistent with the well-established safety profile of ranibizumab.

VISUAL ACUITY OUTCOMES OF RANIBIZUMAB TREATMENT IN PATHOLOGIC MYOPIC EYES WITH MACULAR RETINOSCHISIS AND CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To investigate visual and morphological outcome in eyes with MRS and choroidal neovascularization (CNV) secondary to pathologic myopia treated with intravitreal (IVT) ranibizumab. METHODS: Post hoc analysis of the patients included in the RADIANCE trial (n = 277) was performed to evaluate the impact of MRS on the functional outcome in patients with myopic choroidal neovascularization (mCNV) undergoing intravitreal ranibizumab injections. RESULTS: Prevalence of MRS in pathologic myopia population is 6%. Respective patients were generally older than patients without MRS. Study eyes with MRS at baseline (BL) showed an initially poor treatment response after 3 months (mean change in best corrected visual acuity (BCVA) was 2.8 ± 12.4 letters, P = 0.009). After 12 months of treatment however, the mean change in BCVA was 7.1 ± 14.5 early treatment diabetic retinopathy study (ETDRS) letters (P = 0.025). Patients with MRS at baseline received more intravitreal injections than the other RADIANCE patients without MRS (MRS, n = 15 eyes: 5.8 ± 2.1 vs. RADIANCE non-MRS [n = 207 eyes]: 4.0 ± 2.9; P = 0.0001). CONCLUSION: Improvement of visual acuity is delayed and reduced after 3 months intravitreal ranibizumab in eyes with MRS and myopic choroidal neovascularization compared to eyes without MRS. More ranibizumab injections are needed in eyes with MRS to gain comparable BCVA at Month 12.

Individualized Stabilization Criteria-Driven Ranibizumab versus Laser in Branch Retinal Vein Occlusion: Six-Month Results of BRIGHTER.

PURPOSE: To compare the 6-month efficacy and safety profile of an individualized stabilization criteria-driven pro re nata (PRN) regimen of ranibizumab 0.5 mg with or without laser versus laser alone in patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). DESIGN: A 24-month, prospective, open-label, randomized, active-controlled, multicenter, phase IIIb study. PARTICIPANTS: A total of 455 patients. METHODS: Eligible patients were randomized 2:2:1 to receive ranibizumab (n = 183), ranibizumab with laser (n = 180), or laser only (n = 92). Patients treated with ranibizumab with or without laser received a minimum of 3 initial monthly ranibizumab injections until visual acuity (VA) stabilization, and VA-based PRN dosing thereafter. In the ranibizumab with laser and laser-only groups, laser was given at the investigator's discretion at a minimum interval of 4 months and if VA was <79 letters. MAIN OUTCOME MEASURES: Mean change from baseline at month 6 in best-corrected visual acuity (BCVA) (primary end point) and central subfield thickness, and safety over 6 months. Exploratory objectives were to evaluate the influence of baseline BCVA, disease duration, and ischemia on BCVA outcomes at month 6. RESULTS: Baseline mean BCVA was 57.7 letters, and mean BRVO duration was 9.9 months. Ranibizumab with or without laser was superior to laser only in improving mean BCVA from baseline at month 6 (14.8 and 14.8 vs. 6.0 letters; both P < 0.0001; primary end point met). Patients with a shorter BRVO duration at baseline had a higher mean BCVA gain than those with a longer BRVO duration. Patients with a poor baseline VA had a better BCVA gain than those with a higher baseline VA, although final BCVA was lower in those with poor baseline VA. In the ranibizumab with or without laser groups, the presence of some macular ischemia at baseline did not influence mean BCVA gains. There were no new ocular or nonocular safety events. CONCLUSIONS: Ranibizumab with an individualized VA-based regimen, with or without laser, showed statistically significant superior improvement in BCVA compared with laser alone in patients with BRVO. Overall, there were no new safety events other than those reported in previous studies.

A 2-Year, Phase IV, Multicentre, Observational Study of Ranibizumab 0.5 mg in Patients with Neovascular Age-Related Macular Degeneration in Routine Clinical Practice: The EPICOHORT Study.

Purpose. To assess the safety profile of ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (nAMD) in routine clinical practice. Methods. This 2-year, multicentre, observational study was conducted to capture real-world early practice and outcomes across Europe, shortly after European licensing of ranibizumab for nAMD. Being observational in nature, the study did not impose diagnostic/therapeutic interventions/visit schedule. Patients were to be treated as per the EU summary of product characteristics (SmPC) in effect during the study. Key outcome measures were incidence of selected adverse events (AEs), treatment exposure, bilateral treatment, compliance to the EU SmPC, and best-corrected visual acuity (BCVA) over 2 years. Results. 755 of 770 patients received treatment. Ranibizumab was generally well tolerated with low incidence of selected AEs (0%-1.9%). Patients received 6.2 (mean) injections and 133 patients received bilateral treatment over 2 years. Protocol deviation to treatment compliance was reported in majority of patients. The observed decline in mean BCVA (Month 12, +1.5; Month 24, -1.3 letters) may be associated with undertreatment as suggested by BCVA subgroup analysis. Conclusion. The EPICOHORT study conducted in routine clinical practice reinforces the well-established safety profile of ranibizumab in nAMD. In early European practice it appeared that the nAMD patients were undertreated.

RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia.

OBJECTIVE: To compare the efficacy and safety of ranibizumab 0.5 mg, guided by visual acuity (VA) stabilization or disease activity criteria, versus verteporfin photodynamic therapy (vPDT) in patients with visual impairment due to myopic choroidal neovascularization (CNV). DESIGN: Phase III, 12-month, randomized, double-masked, multicenter, active-controlled study. PARTICIPANTS: Patients (N = 277) with visual impairment due to myopic CNV. METHODS: Patients were randomized to receive ranibizumab on day 1, month 1, and thereafter as needed guided by VA stabilization criteria (group I, n = 106); ranibizumab on day 1 and thereafter as needed guided by disease activity criteria (group II, n=116); or vPDT on day 1 and disease activity treated with ranibizumab or vPDT at investigators' discretion from month 3 (group III, n = 55). MAIN OUTCOME MEASURES: Mean average best-corrected visual acuity (BCVA) change from baseline to month 1 through months 3 (primary) and 6, mean BCVA change and safety over 12 months. RESULTS: Ranibizumab treatment in groups I and II was superior to vPDT based on mean average BCVA change from baseline to month 1 through month 3 (group I: +10.5, group II: +10.6 vs. group III: +2.2 Early Treatment Diabetic Retinopathy Study [ETDRS] letters; both P<0.0001). Ranibizumab treatment guided by disease activity was noninferior to VA stabilization-guided retreatment based on mean average BCVA change from baseline to month 1 through month 6 (group II: +11.7 vs. group I: +11.9 ETDRS letters; P<0.00001). Mean BCVA change from baseline to month 12 was +13.8 (group I), +14.4 (group II), and +9.3 ETDRS letters (group III). At month 12, 63.8% to 65.7% of patients showed resolution of myopic CNV leakage. Patients received a median of 4.0 (group I) and 2.0 (groups II and III) ranibizumab injections over 12 months. No deaths or cases of endophthalmitis and myocardial infarction occurred. CONCLUSIONS: Ranibizumab treatment, irrespective of retreatment criteria, provided superior BCVA gains versus vPDT up to month 3. Ranibizumab treatment guided by disease activity criteria was noninferior to VA stabilization criteria up to month 6. Over 12 months, individualized ranibizumab treatment was effective in improving and sustaining BCVA and was generally well tolerated in patients with myopic CNV.

The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration.

OBJECTIVE: To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN: Twenty-four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS: Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. METHODS: Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best-corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). MAIN OUTCOME MEASURES: Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. RESULTS: Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. CONCLUSIONS: The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study.

OBJECTIVE: To demonstrate noninferiority of a quarterly treatment regimen to a monthly regimen of ranibizumab in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: A 12-month, multicenter, randomized, double-masked, active-controlled, phase IIIb study. PARTICIPANTS: Patients with primary or recurrent subfoveal CNV secondary to AMD (353 patients), with predominantly classic, minimally classic, or occult (no classic component) lesions. INTERVENTION: Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection). MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 12 and the incidence of adverse events (AEs). RESULTS: In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 µm in 0.3 mg quarterly, -105.6 µm in 0.5 mg quarterly, and -105.3 µm in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group). There were 9 ocular serious AEs and 3 deaths; 1 death was suspected to be study related (cerebral hemorrhage; 0.5 mg quarterly group). The incidences of key arteriothromboembolic events were low. CONCLUSIONS: After 3 initial monthly ranibizumab injections, both monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with CNV secondary to AMD. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The safety profile was similar to that reported in prior ranibizumab studies.

Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study.

OBJECTIVE: The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS: This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age>18 years, type 1 or 2 diabetes, central retinal thickness [CRT]≥300 µm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n=51 each) or sham (n=49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n=151, patients receiving≥1 injection). RESULTS: At month 12, mean±SD BCVA improved from baseline by 10.3±9.1 letters with ranibizumab and declined by 1.4±14.2 letters with sham (P<0.0001). Mean CRT reduction was 194.2±135.1 µm with ranibizumab and 48.4±153.4 µm with sham (P<0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P<0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS: Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

Effect of Xalatan(R) and Cosopt(R) on the vascular tone of quiescent isolated pig ciliary arteries.

BACKGROUND: To investigate whether dilutions of the commercially available Xalatan(R) or Cosopt(R) induce vasoconstrictions in isolated quiescent porcine ciliary arteries. MATERIAL AND METHODS: Contractions measured with a myograph system (isometric force measurement) were expressed in percent of 100 mM potassium chloride(KCl)-induced contraction (mean +/- standard error). In preliminary experiments, vessels were contracted with 100 mM KCl after previous exposures to different dilutions of Xalatan(R) (1/250 to 1/50) or Cosopt(R) (1/500 to 1/5). In a further series of experiments, vessels were exposed in a cumulative manner to different dilutions of Xalatan(R) or Cosopt(R) (1/50 000 to 1/166). RESULTS: Contractions induced by 100 mM KCl were not significantly affected by previous exposure to Xalatan(R) or Cosopt(R) at dilutions higher than 1/166 and 1/50, respectively. However, at the lower dilutions tested, 100 mM KCl-induced contractions were significantly (p < 0.001) and markedly inhibited (1/50 Xalatan(R): 22.1 +/- 2.8 %; 1/5 Cosopt(R): 24.8 +/- 4.6 %). In quiescent vessels, diluted (1/50 000 to 1/166) preparations of Xalatan(R) induced, in a dilution-dependent manner, statistically significant (p < 0.05) but, however very small (3.2 +/- 1.0 %) contractions in comparison to Cosopt(R) (- 0.6 +/- 0.2 %). CONCLUSIONS: Although on the basis of these in vitro experiments no clinical interpretation should be made, at very high dilutions that did not affect KCl-induced contractions, Xalatan(R), but not Cosopt(R), had a very small vasoconstrictive effect in isolated quiescent porcine ciliary arteries. At low dilutions, responses to KCl were inhibited, possibly in relation to an unclear effect of the excipients of Xalatan(R) and Cosopt(R).