Desmond Thompson

Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab

PURPOSE To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. DESIGN Analyses from 2 randomized, active-controlled, phase III trials. PARTICIPANTS A total of 2457 patients with NVAMD. METHODS Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. MAIN OUTCOME MEASURES Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (≥5 mmHg) was also evaluated. RESULTS Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%-78%), 50% (95% CI, 19%-70%), and 69% (95% CI, 45%-84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase ≥5 mmHg was 31% (95% CI, 8%-48%), 38% (95% CI, 17%-54%), and 47% (95% CI, 27%-61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. CONCLUSIONS Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group.

Intraocular pressure in patients with neovascular age-related macular degeneration switched to aflibercept injection after previous anti-vascular endothelial growth factor treatments.

Purpose: To assess for change in intraocular pressure (IOP) in neovascular age-related macular degeneration patients switched to aflibercept after receiving previous treatments of intravitreal bevacizumab or ranibizumab. Methods: This is a retrospective chart review of the first 53 patients (53 eyes) treated with at least 2 injections of 2 mg in 0.05 mL of aflibercept by March 6, 2013, after at least 2 previous injections of 0.5 mg in 0.05 mL of ranibizumab with or without previous injections of 1.25 mg in 0.05 mL of bevacizumab. The analysis was restricted to the first such sequence within each patient. The last previous anti-vascular endothelial growth factor injection before the switch to aflibercept was ranibizumab in all cases included in the study. Each person served as his or her own control. The pre-aflibercept IOP in the before state (treatment with bevacizumab or ranibizumab) was the preinjection IOP measure before dilation at the visit of the first aflibercept injection. Statistical analysis was performed using Microsoft Excel. Results: There were 41 patients who were first treated with ranibizumab followed by aflibercept and 12 patients treated with ranibizumab and bevacizumab followed by aflibercept. For each of these sequences, IOP in the treated eye during treatment with aflibercept (the after state) was computed in 3 different ways: the first IOP, the last IOP, and the mean IOP for the period when treated with aflibercept. The pooled data showed a mean pre-aflibercept (the before state) IOP of 14.87 that decreased to a mean first IOP of 14.57, mean last IOP of 13.79, and a mean IOP of 14.14 during aflibercept treatment. The inference is based on the pooled analysis. The 95% confidence interval for the differences (after minus before) were −0.30 (−1.12 to 0.52), −1.08 (−1.83 to −0.32), and −0.73 (−1.30 to −0.17) for the first, last, and mean IOPs, respectively. The corresponding P values were 0.46 for the first, 0.006 for the last, 0.01 for the mean IOP during the aflibercept treatment period. Conclusion: Intraocular pressure was found to be significantly lower in patients switched to aflibercept after previous treatments with ranibizumab and/or bevacizumab. Aflibercept may have a more favorable IOP safety profile in patients previously on other anti-vascular endothelial growth factor treatments.

Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials

Low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 monoclonal antibody alirocumab may be affected by background statin dose due to increased PCSK9 levels with higher statin doses. Data from 8 Phase 3 trials conducted with background statin (n = 4629) were pooled by alirocumab dose (75 or 150 mg every 2 weeks) and control (placebo/ezetimibe), and analyzed by background statin type/dose. Overall, 58.4% received high-dose statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg, simvastatin 80 mg), 28.6% moderate-dose statins (atorvastatin 20–<40 mg, rosuvastatin 10–<20 mg, simvastatin 40–<80 mg), and 12.9% low-dose statins (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <40 mg). Mean baseline PCSK9 levels were higher with high versus moderate and low statin doses (318.5 vs 280.6 ng/mL). Baseline LDL-C levels were similar across pools, regardless of statin intensity. No associations were observed between statin type/dose and LDL-C % change from baseline or % of patients achieving LDL-C goals at Week 24 for alirocumab versus control (interaction P-values non-significant). Incidence of adverse events was similar for alirocumab versus control, except for a higher rate of injection-site reactions with alirocumab. In summary, alirocumab provided consistent LDL-C reductions and was generally well tolerated independent of background statin type/dose.

Effect of Fluid Status at Week 12 on Visual and Anatomic Outcomes at Week 52 in the VIEW 1 and 2 Trials

BACKGROUND AND OBJECTIVE To evaluate effect of retinal fluid status at week 12 on visual and anatomic outcomes at week 52 in patients with neovascular age-related macular degeneration from the VIEW studies. PATIENTS AND METHODS Post-hoc analysis included 1,465 eyes treated with intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) 2 mg every 4 weeks (2q4) or every 8 weeks following three initial monthly injections (2q8) or ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg every 4 weeks (Rq4), which had known retinal fluid status at weeks 12 and 52. RESULTS At 12 weeks, 512 (35%) eyes had fluid and 953 (65%) were fluid-free. Two hundred three (41.5%), 148 (29.8%), and 161 (33.5%) eyes had fluid in Rq4, 2q4, and 2q8, respectively. Best-corrected visual acuity (BCVA) change at week 52 from baseline was independent of retinal fluid status at week 12 or treatment assignment. Eyes were more likely to remain fluid-free at week 52 if absent of fluid at week 12. CONCLUSION At week 52, 2q4, 2q8, and Rq4 improved BCVA independent of fluid status at week 12.

Assessment of the 1% of Patients with Consistent < 15% Reduction in Low-Density Lipoprotein Cholesterol: Pooled Analysis of 10 Phase 3 ODYSSEY Alirocumab Trials

PurposeClinical trials of statins and other lipid-lowering therapies (LLTs) often report large inter-individual variations in their effects on low-density lipoprotein cholesterol (LDL-C). We evaluated apparent hyporesponsiveness to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab (defined as < 15% LDL-C reduction from baseline at all timepoints) using data from 10 Phase 3 trials (3120 hypercholesterolemic patients).MethodsThis report assessed the LDL-C percent reduction from baseline at weeks 4–104 (depending on study), and alirocumab serum levels and antidrug antibodies, in patients with apparent hyporesponsiveness.ResultsAmong the 3120 patients evaluated, 98.9% responded to alirocumab, and 33 (1.1%) had < 15% LDL C reduction at all measured timepoints. Pharmacokinetics data indicated that 13/33 apparent hyporesponders had not received alirocumab; no pharmacokinetics data were available for 14/33, and 6/33 had detectable alirocumab. For the six patients with confirmed alirocumab receipt, the degree of adherence to pre-study concurrent LLTs could not be determined after study start; one of these patients had persistent antidrug antibodies.ConclusionsApparent hyporesponsiveness to alirocumab appeared to be due to lack of receipt of alirocumab determined by serum alirocumab levels, possible lack of adherence to concurrent LLTs, a theoretical and rare possibility of biological non-responsiveness due to persistent antidrug antibodies, or other causes, as yet unidentified.

Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials

BACKGROUND AND AIMS Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). METHODS Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy. RESULTS Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions versus controls. CONCLUSIONS Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG).