Alexandros Sagkriotis

Treatment Frequency and Dosing Interval of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration in Routine Clinical Practice in the USA.

Purpose To compare treatment patterns of intravitreal ranibizumab and aflibercept for the management of neovascular age-related macular degeneration (nAMD) in a real-world setting over the first 12 months of treatment. Methods A proprietary clinical database was used to identify treatment-naïve patients with nAMD in the USA with claims for ranibizumab or aflibercept between November 1, 2011 and November 30, 2013 and with follow-up of at least 12 months. Patients were considered treatment-naïve if they had no anti-VEGF treatment code for 6 months before the index date. Mean numbers of injections and of non-injection visits to a treating physician were compared between the two treatment cohorts (ranibizumab or aflibercept). In addition, the mean interval between doses was also investigated. Results Patient characteristics were similar for those receiving either ranibizumab (n = 5421) or aflibercept (n = 3506) at the index date. The mean (± standard deviation) numbers of injections received by patients treated with ranibizumab (4.9 ± 3.3) or aflibercept (5.2 ± 2.9) were not clinically different. The mean number of non-injection visits was 2.8 ± 2.8 and 2.1 ± 2.5 for ranibizumab and aflibercept, respectively. Mean dosing interval was 51.0 days (± 41.8 days) in patients receiving ranibizumab and 54.1 days (± 36.0 days) in those receiving aflibercept. Results were robust to sensitivity analyses for definition of treatment-naïve, length of follow-up and treatment in the index eye only. Conclusions Limited data exist regarding real-world treatment patterns of aflibercept for the management of nAMD. Our results suggest that, in routine clinical practice, patients receive a comparable number of injections in the first year of treatment with ranibizumab or aflibercept.

Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship.

Examine the efficacy of a competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model.

Ranibizumab prefilled syringes: benefits of reduced syringe preparation times and less complex preparation procedures.

Purpose A recently developed ranibizumab prefilled syringe (PFS) eliminates several preparatory steps versus the standard vial-based method, and is expected to reduce syringe preparation time (SPT) and enhance procedural simplicity for intravitreal injections. Methods Syringe preparation times for the ranibizumab PFS and vial were recorded during standard treatment sessions at 2 centers, without randomization. The duration of each step in preparing the syringe was recorded. At each center, total SPT (mean total duration of all syringe preparation steps) for each method was compared using a 2-tailed t test. Results In total, 97 SPTs were analyzed across both centers. Center 1 SPTs were 46 seconds (PFS) versus 75 seconds (vial; difference, 29 seconds; p<0.001). Center 2 SPTs were 46 seconds (PFS) versus 63 seconds (vial; difference, 17 seconds; p<0.001). This equates to a 27%-39% reduction in SPT when using the PFS rather than the vial, resulting mostly from the reduced number of syringe preparation steps associated with the PFS. Conclusions Syringe preparation times for ranibizumab intravitreal injections are significantly shorter with the PFS than with the vial. The time saved by using the PFS may benefit physicians and nurses, and the simplicity of the injection preparation process with the PFS is advantageous.

Intravenous Dosing as an Alternate Approach to Safely Achieve Supratherapeutic Exposure for Assessments of Cardiac Repolarization: A Randomized Clinical Trial with Mavoglurant (AFQ056)

PURPOSE The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high Cmax values while controlling tolerability. METHODS This study was a randomized, placebo- and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). FINDINGS Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmax values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association between mavoglurant plasma concentrations and ΔΔQTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. IMPLICATIONS This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.