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

Abstract 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.

effects that could be serious, especially for patients with diabetes or the elderly (including patients with nAMD) who are at an increased risk for cardiovascular (CV) adverse events (AEs). 6,7 Pivotal clinical studies have confirmed the positive benefit risk profile of ocular anti-VEGF therapy and the number of reported systemic/cardiovascular incidences with these anti-VEGFs are low overall. 6,7 Furthermore, no significant association between ocular intravitreal (IVT) anti-VEGF administration and CV concerns has been established to date. [7][8][9] Brolucizumab, a single-chain antibody fragment, has recently been approved for the treatment of nAMD in the USA, Canada, Australia, Japan, and the EU, based on the confirmatory results from the Phase III HAWK and HARRIER trials. 10 The unique molecular design of brolucizumab allows for a concentrated molar dosing in one IVT injection, effective tissue penetration, and increased duration of action. [10][11][12][13] Based on currently available pre-clinical and clinical data, brolucizumab shows no potential to cause cardiac liabilities, especially due to its low molecular weight and high affinity for the VEGF-A receptor, which enables a rapid and more effective target tissue penetration, resulting in very low systemic exposure and faster systemic clearance. 12,13 Patients with nAMD on average are elderly and often have accompanying concomitant diseases, including CV comorbidities. 6,7 These comorbidities are also noticeably higher in other indications, e.g., diabetic macular edema (DME) 7 and retinal vein occlusion (RVO), 7 for which brolucizumab is currently under development.
Here, we aimed to investigate the CV safety and effects on ECGderived parameters after a single IVT injection of brolucizumab 6 mg in patients with nAMD.

| MATERIAL S AND ME THODS
This was a prospective, single dose, single-arm, open-label, nonrandomized multicenter clinical study to collect 12-lead ECG data after a single IVT injection of brolucizumab 6 mg in patients with nAMD. 1004_MedEye Associates). The study protocol, the patient's information, and consent form were approved by the Advarra (an Independent Ethics Committee). The study number at Advarra is Pro00033738; study was approved to the protocol allowed limit of 10-15 patients.
The study adhered to the Declaration of Helsinki and was reviewed by the Independent Ethics Committees or Institutional Review Board for each center. Written informed consent was obtained from each patient before screening. The detailed study protocol is available in the File S1. There were no formal hypotheses for this study and all statistical analyses were descriptive in nature.

| Baseline and demographic characteristics
All 14 patients with nAMD who enrolled across 3 sites in the US completed the study. At baseline, their median age was 77.0 years; all enrolled patients were Caucasian with 12 (86%) of Hispanic or

What is already known about this subject
• Systemic adverse events have periodically been raised as a concern for anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD) patients, especially because they present with comorbidities, such as diabetes and hypertension, often associated with advanced age.

What this study adds
• This is to our knowledge the first clinical study to describe the effect of intravitreal anti-VEGF treatment (brolucizumab 6 mg) on multiple 12-lead ECG-derived parameters in nAMD patients. The results from this study further corroborate previously published safety results with brolucizumab in nAMD.
• No clinically significant changes were observed in cardiac parameters of nAMD patients after administration of a single 6 mg dose of brolucizumab intravitreal injection.
Latino ethnicity; 8 (57%) were female. Mean systolic blood pressure, diastolic blood pressure, and HR of all patients were within normal range at baseline as per the inclusion criteria ( Table 1). The enrolled patients presented with a medical history of hypertension (n = 5), hypercholesterolemia (n = 6), diabetes (n = 2), and hyperlipidemia (n = 1); however, no patient received medication that could have an effect on their QT interval at study start or during the study.

| Primary outcomes
The 12-lead Holter ECG provided comprehensive ECG data starting ~1 h before IVT injection to 48 h after, capturing the approximate time at which maximum systemic concentration was expected (median T max = ~24 h post-dose). 14 The mean values for the Holter ECG-assessed cardiac parameters, including HR, PR, QRS, and QTcF intervals, remained within normal ranges at all time-points (Table 2) and no notable changes from baseline were observed for these parameters 20-24 h post-treatment with 6 mg brolucizumab.  (Table 3).
No clinically significant changes from baseline were noted in PR, QRS, QTcF, and HR when assessed using a standard 12-lead ECG, which was consistent with the Holter ECG findings ( Table 2).

| Secondary outcomes
There were no deaths or non-ocular AEs reported during the study or the follow-up period (Day 31). No clinically relevant changes in vital signs or ECG abnormalities were observed during the study.
Of the 14 enrolled patients, 1 patient experienced an ocular AE (increased intraocular pressure) of moderate severity, possibly related to study treatment. This event was transient (lasting for 1 min) and resolved without sequelae after a paracentesis was performed.

| DISCUSS ION
The findings of this study showed that no clinically relevant changes on 12-lead Holter ECG or standard 12-lead ECG derived parameters were observed within 48 h following a single IVT injection of brolucizumab 6 mg in patients with nAMD. Furthermore, no significant safety concerns were identified during the study.
Systemic AEs have periodically been raised as a concern for anti-VEGF therapy in nAMD patients, especially since they present with comorbidities, such as diabetes and hypertension, often associated with advanced age. Biotherapeutics, such as anti-VEGF monoclonal antibodies or antibody fragments, are not expected to have any cardiac liabilities; therefore, a thorough cardiac safety assessments are generally not required for these drugs. 15 While a large body of evidence supports the safety of ocular anti-VEGFs, such as ranibizumab and aflibercept, in nAMD with no increased risk of SAEs particularly, CV related AEs. [3][4][5][7][8][9] Georgakopoulos et al. confirmed that a single dose of aflibercept did not affect biomarkers associated with CV risks (homocysteine, total cholesterol, triglycerides, HDL-c, LDL-c and CRP) in AMD patients. 16 Furthermore, the safety data from real world populationbased studies 17,18 on intravitreal anti-VEGFs agents (ranibizumab, aflibercept and bevacizumab) in patients with AMD, found no consistent evidence that intravitreal anti-VEGF therapy was associated with increased risk of stroke, MI, or death. Drugs in general, may increase the risk for cardiovascular events via effects on the vascular tone (e.g., hypertension), rheological effects (e.g., prothrombotic effects) or by affecting cardiac electrophysiology. 19 Our study in-  [10][11][12][13] Preclinical and clinical studies have also confirmed no known systemic safety issues with brolucizumab. [10][11][12][13] Furthermore, recent real-world evidences of brolucizumab treatment in nAMD patients did not report any new safety signals specific to CV events; however, none of them specifically investigated any ECG-related cardiac parameters. 20,21 This present study is the first to describe the effect of intravitreal anti-VEGF treatment (brolucizumab 6 mg) on multiple 12-lead  Note: Safety analysis set.

TA B L E 1 Demographics and baseline characteristics
Abbreviations: ECG, electrocardiogram; HR, heart rate; IVT, intravitreal; N, total number of patients; R, replicates; SD, standard deviation.
The mean of the triplicate ECG values (R = 3) was calculated for each patient at each timepoint.

| Limitations
This study was non-randomized, limited by a small sample size, and lack of control group. Furthermore, the time to maximum concentration (T max ) of brolucizumab was estimated based on the previous pharmacokinetic assessments, nevertheless, the continuous ECG monitoring over 48 h ensured a comprehensive assessment of T max in all patients.

| CON CLUS IONS
To conclude, it was a small descriptive study to prospectively eval-

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C S S TATEM ENT
The study adhered to the Declaration of Helsinki and was reviewed by the Independent Ethics Committees or Institutional Review Board for each center. Written informed consent was obtained from each patient before screening. The detailed study protocol is available in the File S1.