Age-Related Macular Degeneration (Amd)
EUnetHTA Joint Action 3 WP4
Relative effectiveness assessment of pharmaceutical technologies
BROLUCIZUMAB FOR THE TREATMENT OF ADULTS WITH NEOVASCULAR (WET) AGE-RELATED MACULAR DEGENERATION (AMD)
Project ID: PTJA09
Version 1.0, 12/03/2020
Dec2015 ©EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 1 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
DOCUMENT HISTORY AND CONTRIBUTORS
Version Date Description V0.1 28/01/2020 First draft V0.2 24/2/2020 Input from dedicated reviewers has been processed V0.3 10/03/2020 Input from medical editor and manufacturer(s) has been processed V1.0 12/03/2020 Final assessment report
Disclaimer This Joint Assessment is part of the project / joint action ‘724130 / EUnetHTA JA3’ which has received funding from the European Union’s Health Programme (2014-2020). The content of this Assessment Report represents a consolidated view based on the consensus within the Authoring Team; it cannot be considered to reflect the views of the European Network for Health Technology Assessment (EUnetHTA), EUnetHTA’s participating institutions, the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.
Assessment team Author(s) Finnish Medicines Agency (Fimea), Finland Co-Author(s) Spanish Agency of Medicine and Sanitary Products (AEMPS), Spain Andalusian Unit for Health Technology Assessment (AETSA), Spain Dedicated French National Authority for Health (HAS), France Reviewer(s) Agency for Health Technology Assessment and Tariff System (AOTMiT), Poland Regione Emilia-Romagna (RER), Italy Association of Austrian Social Insurance Institutions (DVSV), Austria Observer HTA Department/EC Ukraine, Ukraine
March 2020 EUnetHTA Joint Action 3 WP4 1 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Further contributors
External experts Prof. João Barbosa Breda Answer specific question during the assessment Manufacturer(s) [v0.2] Novartis Preparation of the submission dossier Factual accuracy check Medical editor [v0.2] Compuscript Limited Responsible for medical editing of the report Patient(s) / patient organisation(s) / citizens Asociación Acción Visión España Provided input in response to the open call for patients (Spain) Input published on 20th May, 2019 Društvo MDSS Kranj (Slovenia) Fighting Blindness (Ireland) Macula Retina (Spain) Retina Bulgaria (Bulgaria) Retina International (Ireland) Retina Suisse (Swiss Confederation) Project Management Zorginstituut Nederland (ZIN), Coordination between involved parties throughout the assessment Netherlands Other [v0.1] EUnetHTA Senior Scientific Officer Support for the systematic literature review Giovanni Tafuri
Conflict of interest All authors and dedicated reviewers involved in the production of this assessment have declared they have no conflicts of interest in relation to the technology assessed according to the EUnetHTA Declaration of Interest and Confidentiality Agreement forms.
How to cite this assessment Please cite this assessment as follows:
EUnetHTA PTJA09. Authoring Team. Relative Effectiveness Assessment of pharmaceutical technologies. Brolucizumab for the treatment of adults with neovascular (wet) age-related macular degeneration (AMD). Joint Assessment. Diemen (The Netherlands): EUnetHTA; 2020. [date of citation]. 124 pages. Report No.: PTJA09. Available from: https //www.eunethta.eu
March 2020 EUnetHTA Joint Action 3 WP4 2 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
TABLE OF CONTENTS
DOCUMENT HISTORY AND CONTRIBUTORS ...... 1 TABLE OF CONTENTS ...... 3 LIST OF TABLES AND FIGURES...... 5 LIST OF ABBREVIATIONS...... 8 EXECUTIVE SUMMARY OF THE ASSESSMENT OF BROLUCIZUMAB ...... 10 INTRODUCTION ...... 10 OBJECTIVE AND SCOPE...... 10 METHODS ...... 10 RESULTS ...... 11 DISCUSSION ...... 14 CONCLUSIONS ...... 15 1 BACKGROUND ...... 16 1.1 OVERVIEW OF THE DISEASE OR HEALTH CONDITION ...... 16 1.2 CURRENT CLINICAL PRACTICE...... 17 1.3 FEATURES OF THE INTERVENTION ...... 18 2 OBJECTIVE AND SCOPE ...... 21 2.1 DEVIATIONS FROM THE PROJECT PLAN ...... 21 3 METHODS ...... 22 3.1 INFORMATION RETRIEVAL ...... 22 3.2 DATA EXTRACTION ...... 25 3.3 ROB ASSESSMENT ...... 25 3.4 EXTERNAL VALIDITY ...... 26 3.5 RESULTS AND ANALYSES FOR THE STUDIES INCLUDED ...... 26 3.6 PATIENT INVOLVEMENT ...... 28 4 RESULTS ...... 29 4.1 INFORMATION RETRIEVAL ...... 29 4.2 STUDIES INCLUDED IN THE ASSESSMENT ...... 31 4.3 EXCLUDED STUDIES ...... 35 4.4 CHARACTERISTICS OF THE STUDIES INCLUDED: DIRECT EVIDENCE ...... 35 4.5 OUTCOMES INCLUDED ...... 39 4.6 RISK OF BIAS ...... 40 4.7 EXTERNAL VALIDITY ...... 41 4.8 DIRECT EVIDENCE: RESULTS FOR CLINICAL EFFICACY AND SAFETY ...... 42 4.9 DIRECT SUPPORTIVE EVIDENCE: BROLUCIZUMAB 3 MG ...... 60 4.10 DIRECT SUPPORTIVE EVIDENCE: SUMMARY OF THE PHASE II OSPREY STUDY ...... 61 4.11 INDIRECT EVIDENCE: NMA RESULTS ...... 62 4.12 LITERATURE REVIEW: EVIDENCE OF BEVACIZUMAB AS A TREATMENT OPTION IN NAMD ...... 67 5 PATIENT INVOLVEMENT ...... 74 6 DISCUSSION ...... 75 6.1 DIRECT COMPARISONS ...... 75 6.2 INDIRECT COMPARISONS ...... 77 6.3 LITERATURE REVIEW OF BEVACIZUMAB ...... 77 6.4 PATIENT PERSPECTIVE ...... 77 7 CONCLUSIONS ...... 78 8 REFERENCES ...... 79
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APPENDIX 1: GUIDELINES FOR MANAGEMENT OF AMD ...... 86 APPENDIX 2: SEARCHES STRATEGIES FOR BEVACIZUMAB LITERATURE REVIEW ...... 89 STRATEGIES TO SELECT NMAS AND SRS ...... 89 STRATEGIES TO UPDATE THE INCLUDED NMAS AND SRS ...... 91 APPENDIX 3: SEARCHES PERFORMED BY THE INFORMATION SPECIALIST TO THE COMPLETENESS OF THE STUDY POOL ...... 93 SEARCH 1: SEARCH IN STUDY REGISTRIES FOR BROLUCIZUMAB ...... 93 SEARCH 2: SEARCH IN STUDY REGISTRIES FOR RANIBIZUMAB, BEVACIZUMAB AND AFLIBERCEPT ...... 94 SEARCH 3: SEARCH FOCUSED IN PUBMED ...... 95 APPENDIX 4: RESULTS FROM THE SCREENING OF THE SEARCHES OF BEVACIZUMAB..... 96 APPENDIX 5: STUDIES (SR OR NMA) THAT MET THE ELIGIBILITY CRITERIA FOR THE BEVACIZUMAB LITERATURE REVIEW ...... 97 APPENDIX 6: EXCLUDED ARTICLES FROM BEVACIZUMAB LITERATURE REVIEW ...... 110 APPENDIX 7: BASELINE CHARACTERISTICS OF HAWK AND HARRIER STUDY POPULATIONS...... 114 APPENDIX 8: POOLED RESULTS OF HAWK AND HARRIER STUDIES ...... 116 APPENDIX 9: CHECKLIST FOR CRITICAL APPRAISAL OF INDIRECT COMPARISONS – EVALUATION OF THE NMA PROVIDED BY MAH ...... 117 APPENDIX 10: CRITICAL APPRAISAL FOR THE SYSTEMATIC REVIEWS SELECTED FROM THE SLR OF BEVACIZUMAB ...... 120 APPENDIX 11: PROTOCOL DEVIATIONS IN HAWK AND HARRIER STUDIES ...... 123
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LIST OF TABLES AND FIGURES
Tables Table 0.1. Results for the change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF) ...... 12 Table 1.1. Features of the intervention and other treatment options ...... 19 Table 1.2. Administration and dosing of the technology and other treatment options ...... 20 Table 2.1. Scope of the assessment ...... 21 Table 3.1. Summary of information retrieval and study selection submitted by the MAH ...... 23 Table 3.2. PICO framework for the network meta-analysis ...... 24 Table 3.3. Selection criteria for the literature searches regarding bevacizumab ...... 25 Table 4.1. Study pool: list of relevant studies used for the assessment ...... 33 Table 4.2. Overview of trials included in the network meta-analysis ...... 34 Table 4.3. Characteristics of the studies included for direct comparison ...... 35 Table 4.4. Characterisation of the interventions and comparators...... 36 Table 4.5. Trial populations used for analysis of outcomes in the HAWK and HARRIER studies ...... 36 Table 4.6. DAA criteria for the HAWK and HARRIER studies ...... 38 Table 4.7. Risk of bias in the randomised HAWK and HARRIER studies ...... 40 Table 4.8. Risk of bias by outcome in the HAWK and HARRIER studies ...... 40 Table 4.9. Subject disposition in the HAWK and HARRIER studies ...... 42 Table 4.10. Change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS- LOCF, PPS-LOCF) ...... 44 Table 4.11. Selected secondary endpoints related to BCVA (LS mean estimates; proportion of patients) at and up to week 48 and week 96 (FAS-LOCF) ...... 45 Table 4.12. Change in CSFTns (μm) from baseline to week 48 for the study eye in HAWK and HARRIER (FAS-LOCF)...... 46 Table 4.13. LSMD in CSFTtot (μm) from baseline to weeks 48 and 96 for the study eye in HAWK and HARRIER (FAS-LOCF) ...... 48 Table 4.14. Proportion of subjects with IRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression...... 49 Table 4.15. Proportion of subjects with SRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression...... 50 Table 4.16. Number of injections from baseline to week 96 (SAF) ...... 53 Table 4.17. Mean change in VFQ-25 composite scores from baseline in HAWK and HARRIER studies (FAS-observed) ...... 53 Table 4.18. Ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF)...... 54 Table 4.19. Serious ocular adverse events up to week 96 for the study eye (SAF) ...... 55 Table 4.20. Non-ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF) ...... 55 Table 4.21. Serious non-ocular adverse events up to week 96 (≥3 patients in any treatment group) for the SAF ...... 57 Table 4.22. Death, SAE or AE leading to permanent study treatment discontinuation up to week 96 (SAF) ...... 58 Table 4.23. LSM estimates for the change in BCVA from baseline at weeks 12, 40 and 56 (FAS- LOFC) ...... 61 Table 4.24. LSM estimates for the change in CSFT (µm) from baseline at weeks 12, 40 and 56 (FAS-LOFC) ...... 62 Table 4.25. Summary of NMA results comparing MD in BCVA and OR of loss of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator. . 65 Table 4.26. Summary of NMA results comparing the MD in CRT and OR in gain of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator...... 66 Table 4.27. Treatment effect estimates: bevacizumab versus ranibizumab ...... 69 Table 4.28. AEs up to 1 year: bevacizumab versus ranibizumab ...... 70 Table 4.29. Treatment effect estimates ...... 72 Table 4.30. Adverse events: treatment versus comparator ...... 73 Table 5.1. Summary of patient involvement...... 74 Table A1. Overview of guidelines used for this assessment ...... 86
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Table A2. Information about the screening of the records from the searches of bevacizumab to include SRs and NMAs...... 96 Table A3. Information about the screening of the records from the searches to update included SRs and NMAs...... 96 Table A4. Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review . 97 Table A5. RCTs not included in the SR by Solomon 2019 which are considered in the other references and reasons for exclusion in Solomon SR...... 109 Table A6. Excluded articles, based on the full text, from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD...... 110 Table A7. Articles excluded, by title and abstract (full text not available), from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD...... 112 Table A8. Baseline characteristics of the study populations (FAS, excluding brolucizumab 3 mg group in HAWK study) ...... 114 Table A9. Summary of direct comparison results (pooled results) for HAWK and HARRIER studies116 Table A10. Evaluation of the NMA provided by MAH ...... 117 Table A11. Critical appraisal for the SRs selected from the SLR of bevacizumab ...... 120 Table A12. Protocol deviations by deviation category (RAN) in HAWK study - week 48 analysis .... 123 Table A13. Protocol deviations by deviation category (RAN) in HARRIER study - week 48 analysis 123
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Figures Figure 4.1. Flowchart of the selection process to identify systematic reviews and network meta- analyses...... 30 Figure 4.2. Flowchart of the process to select randomised controlled trials to update the systematic reviews included...... 31 Figure 4.3. PRISMA diagram...... 32 Figure 4.4. HAWK and HARRIER trial design...... 37 Figure 4.5. LSM change in BCVA from baseline to week 96 (FAS-LOCF)...... 45 Figure 4.6. LSM change in CSFTns (μm) from baseline by visit in HAWK (FAS-LOCF)...... 47 Figure 4.7. LSM change in CSFTns (μm) from baseline by visit in HARRIER (FAS-LOCF)...... 47 Figure 4.8. LSM change in CSFTtot (µm) from baseline by visit through to week 96 (FAS-LOCF). ... 48 Figure 4.9. Percentage of subjects with IRF by visit up to week 96 in HARRIER (FAS-LOCF)...... 49 Figure 4.10. Percentage of subjects with IRF visit to week 96 in HAWK (FAS-LOCF)...... 49 Figure 4.11. Percentage of subjects with SRF by visit up to week 96 in HARRIER (FAS-LOCF)...... 50 Figure 4.12. Percentage of subjects with SRF by visit up to week 96 in HAWK (FAS-LOCF)...... 50 Figure 4.13. Proportion of patients with sub-RPE fluid at weeks 16, 48 and 96 in HAWK and HARRIER (FAS-LOCF)...... 51 Figure 4.14. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HAWK (FAS efficacy/safety approach)...... 52 Figure 4.15. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HARRIER (FAS efficacy/safety approach)...... 52 Figure 4.16. Forest plot of summary statistics and ANOVA for change in BCVA from baseline to week 48 by subgroups of interest (FAS-LOCF) ...... 59 Figure 4.17. Proportion of patients maintained on Q12W dosing interval until week 48 (FAS)...... 60 Figure 4.18. OSPREY trial design...... 61 Figure 4.19. Quality assessment performed by the MAH for trials included in the NMA...... 63 Figure 4.20. Network for mean change in BCVA from baseline to 1 year...... 64 Figure 4.21. RoB summary: judgements for each RoB item for each study comparing bevacizumab versus ranibizumab included by Solomon et al...... 68 Figure 4.22. Cochrane RoB results for individual studies on nAMD included by Pham et al...... 68
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LIST OF ABBREVIATIONS
AE Adverse event AMD Age-related macular degeneration ANOVA Analysis of variance BCVA Best corrected visual acuity CHMP Committee for Medicinal Products for Human Use CI Confidence interval CFT Central foveal thickness CMT Central macular thickness CNV Choroidal neovascularisation CRD Centre for Reviews and Dissemination CrI Credibility interval CRT Central retinal thickness CSFT Central subfield thickness CSFTns Central subfield thickness of the neurosensory retina CSFTtot Total central subfield thickness CSR Clinical study report DAA Disease activity assessment DIC Deviance information criterion EMA European Medicines Agency EQ-5D European Quality of Life-5 Dimensions ETDRS Early Treatment Diabetic Retinopathy Study EUnetHTA European Network for Health Technology Assessment EU-CTR European Clinical Trials Register FAS Full analysis set GRADE Grading of Recommendations, Assessment, Development and Evaluation HR Hazard ratio HRQoL Health-related quality of life ICTRP International Clinical Trials Registry Platform IRF Intraretinal fluid ITT Intention to treat IVT Intravitreal LOCF Last observation carried forward LP Loading phase LS Least squares LSM Least squares mean LSMD Least squares mean difference MA Marketing authorisation MAH Marketing authorisation holder MD Mean difference MeSH Medical Subject Headings nAMD Neovascular age-related macular degeneration NA Not applicable NEI VFQ-25 National Eye Institute Visual Function Questionnaire-25 NMA Network meta-analysis NR Not reported OR Odds ratio QxW Every x weeks QoL Quality of life PCV Polypoidal choroidal vasculopathy
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PDT Photodynamic therapy PICO Patients, Intervention, Comparators, Outcomes instrument PP Per protocol PPS Per protocol set PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRN Pro re nata PRNX Pro re nata and extend RAN All randomised analysis set RCT Randomised controlled trial RD Risk difference REA Relative effectiveness assessment RoB Risk of bias RPE Retinal pigment epithelium RR Relative risk SAE Serious adverse event SAF Safety analysis set SD Standard deviation SE Standard error SLR Systematic literature review SPC Summary of product characteristics SR Systematic review SRF Subretinal fluid Sub-RPE Subretinal pigment epithelium TREX Treat and extend VA Visual acuity VEGF Vascular endothelial growth factor wAMD Wet age-related macular degeneration
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EXECUTIVE SUMMARY OF THE ASSESSMENT OF BROLUCIZUMAB
Introduction
Age-related macular degeneration (AMD) is a chronic eye disease characterised by progressive degeneration of the macula, the area of the retina responsible for sharp, central vision. The late stages of disease progression in AMD are further classified into two types: neovascular (nAMD) and atrophic AMD (1). nAMD is characterised by leaking of fluid due to the formation of abnormal blood vessels underneath the macula. This phenomenon, known as choroidal neovascularisation (CNV), is the defining feature in nAMD and occurs in response to abnormally high levels of vascular endothelial growth factor (VEGF).
Left untreated, AMD can lead to rapid, irreversible vision loss. nAMD is the leading cause of severe vision loss and legal blindness among individuals aged >65 years in Europe, North America, Australia and Asia (2, 3). Prevalence estimates suggest that nAMD affects approximately 1.7 million people in Europe (4, 5). The estimated incidence of late AMD in Europe in 2013 was between 2.9 and 3.7 per 1000 person-years (6). Since the introduction of anti-VEGF therapies, there has been a reduction in the incidence of blindness and visual impairment due to nAMD (7, 8).
The aim of nAMD treatment with drugs that are currently available is to resolve the accumulation of retinal fluid and subsequently recover and/or preserve visual function, while slowing disease progression. According to clinical guidelines, first-line treatment for nAMD is intravitreal (IVT) anti-VEGF agents (2, 9-15). Two authorised anti-VEFG treatment options for nAMD are currently available in Europe: aflibercept (Eylea®) (16) and ranibizumab (Lucentis®) (17). A third anti-VEGF product, bevacizumab (Avastin®) (18), is frequently used off-label for nAMD. In clinical trials, the anti-VEGF therapies currently in use maintain visual acuity (VA) in approximately 90% of patients over 2 years (19- 22). The choice of agent and regimen should be individualised, taking into account clinical criteria, patient preferences and health care system characteristics.
Brolucizumab (Beovu®) is a humanised single-chain Fv inhibitor of VEGF-A (23). A single-chain Fv is an autonomous binding agent that comprises only the variable domains of the monoclonal antibody (joined by a short flexible linker peptide) that are responsible for binding to its receptor (24). Brolucizumab is indicated in adults for the treatment of nAMD. Treatment consists of a loading phase (LP) of three consecutive 6-mg injections every 4 weeks (Q4W), followed by a maintenance phase of injections Q8W or Q12W, depending on disease activity.
Objective and scope
The aim of this EUnetHTA Joint Relative Effectiveness Assessment (REA) is to compare the clinical effectiveness and safety of brolucizumab in the target patient population with relevant comparators. The target patient population and relevant comparators (based on the requirements of EUnetHTA Partners) are defined in the project scope. The project scope can be found in Table 2.1.
Methods
Direct evidence The evidence base for the drug under assessment provided by the marketing authorisation holder (MAH) was reviewed by the information specialist on the authoring team. Search strategies were checked for appropriateness and the results of information retrieval included in the MAH’s submission dossier were checked for completeness against a search in study registries. Supplementary searches were conducted to check for possible incompleteness of the study pool.
Direct evidence used for assessment of the clinical effectiveness and safety was extracted from the submission dossier and verified against the clinical study reports (CSRs) or other original documentation provided in the submission dossier. The methods for data analysis applied by the MAH were checked against the requirements for the submission dossier and applicable EUnetHTA guidelines and assessed with regard to scientific validity. Assessment of the risk of bias (RoB; at both the study
March 2020 EUnetHTA Joint Action 3 WP4 10 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD level and outcome level) was conducted only for the randomised phase III studies using the Cochrane RoB tool, including relevant direct evidence on brolucizumab and aflibercept.
Indirect evidence Direct evidence was available only for comparison between brolucizumab and aflibercept. The MAH performed a network meta-analysis (NMA) to assess the relative effectiveness of brolucizumab versus aflibercept and ranibizumab. Standard pairwise meta-analyses based on direct comparisons were carried out between pairs of treatments when possible when two treatments were compared in two or more clinical trials. The NMA was conducted using a Bayesian framework. Both fixed-effects and random-effects models were developed and the one associated with the lowest deviance information criterion (DIC) was selected, unless the absolute difference between the DIC values of the two models was less than three points, then the fixed-effect model was chosen. Several sensitivity analyses were conducted to test the assumptions adopted within the base-case NMA. The methods for data analysis and synthesis applied by the MAH were assessed with regard to scientific validity. The structured checklist developed by Ortega et al. (25) was used to critically appraise the indirect comparisons.
Information retrieval for bevacizumab Bevacizumab was not included as a comparator in the NMA conducted by the MAH even though it had been identified as an important off-label comparator option through the Patients, Intervention, Comparators, Outcomes (PICO) survey and the authoring team had specifically requested its inclusion. Therefore, the authoring team (with support from the EUnetHTA Senior Scientific Officer) performed a systematic literature review (SLR) of bevacizumab in nAMD. The aim of this literature search was to find comprehensive systematic reviews (SRs) and NMAs of randomised controlled trials (RCTs). The quality of the SRs was assessed using the AMSTAR-2 checklist (26).
Patient involvement At the start of this Joint Assessment, EUnetHTA conducted an open call for patient organisations. The information gathered from the open call was used to inform the scope of this assessment and in particular the outcomes to be considered.
Results
Direct evidence: results of direct comparison between brolucizumab and aflibercept The clinical evidence is mainly based on two double-blind noninferiority RCTs: HAWK and HARRIER. In these trials brolucizumab 6 mg was compared with aflibercept 2 mg (HAWK also included a brolucizumab 3 mg arm). Results of HAWK and HARRIER studies are presented separately because pooled results were not available.
The study-level RoB was assessed as low for both the HAWK and HARRIER studies. At the outcome level, the RoB was low for most of the outcomes and unclear for some of the outcomes such as visual function–related QoL (measured using the National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]) and some of the safety outcomes.
The following key results were observed during the assessment:
The change in best corrected VA (BCVA) from baseline to 48 weeks was noninferior with brolucizumab compared to aflibercept (Table 0.1). In addition, no differences in the change in BCVA from baseline to 96 weeks were observed between brolucizumab and aflibercept; The mean change in the central subfield thickness of the neurosensory retina (CSFTns) from baseline to week 48 did not differ between the brolucizumab 6 mg and aflibercept 2 mg groups. The mean change in total central subfield thickness (CSFTtot) showed statistically significant difference between brolucizumab 6 mg compared to aflibercept 2 mg groups at weeks 16, 48 and 96. The absolute difference at the end of week 96 was 26 µm in HAWK and 43 µm in HARRIER, with lower mean measures in the brolucizumab groups. In general, lower CSFT measures potentially indicate better anatomical outcome;
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In the HAWK and HARRIER studies, 56% and 51% of the patients, respectively, in the brolucizumab 6 mg arm remained on the Q12W regimen up to week 48; Over 96 weeks, the mean number of injections was 10.2 for brolucizumab versus 11.3 for aflibercept in HAWK, and 10.9 for brolucizumab versus 12.1 for aflibercept in HARRIER study. The difference in the mean number of active injections administered in the brolucizumab and aflibercept treatment arms in HAWK and HARRIER was between 1 and 1.5. During the study, patients in the aflibercept 2 mg arm were treated at a fixed dose of Q8W and lengthening of the dosing interval was not allowed. In the brolucizumab arm, the dosing interval (Q8W or Q12W in the maintenance phase) was based on disease activity assessment (DAA). The slight difference in the mean number of injections might be driven by differences in the dosing intervals between the brolucizumab and aflibercept arms (protocol difference); Both HAWK and HARRIER showed a similar change in visual function–related quality of life (VFQ-25 score) from baseline for both brolucizumab 6 mg and aflibercept 2 mg. No statistical comparisons were performed between the brolucizumab and aflibercept arms; Serious adverse events (SAEs) were rare. Conjunctival haemorrhage and reduced VA were the most frequent ocular adverse events (AEs) across all treatment arms in HAWK and HARRIER. These AEs are known effects of anti-VEGF drugs administered via the IVT route. In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report (27); Results for subgroup analyses for the primary endpoint of change in BCVA from baseline to week 48 showed no difference between brolucizumab 6 mg and aflibercept 2 mg, irrespective of baseline disease characteristics or demographics. For the outcome of mean change in BCVA, the subgroup with poorer baseline VA (≤55 letters) experienced a greater change in the least squares (LS) mean change in BCVA (9.6 for brolucizumab 6 mg vs. 10.3 for aflibercept 2 mg) than the subgroups with better baseline VA (56–70 letters: change 7.1 vs. 7.0; ≥71 letters: change 2.4 vs. 2.4, respectively), but there was no difference between brolucizumab 6 mg and aflibercept 2 mg groups.
Table 0.1. Results for the change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF) Trial name HAWK (NCT02307682) HARRIER (NCT02434328) Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg (n=360) 2 mg (n=360) 6 mg (n=370) 2 mg (n=369) Change in BCVA from baseline to week 48 Mean (SD) 6.4 (14.40) 7.0 (13.16) 6.9 (11.47) 7.6 (12.47) Median (range) 7.5 (69, 52) 8.0 (57, 54) 8.0 (57, 38) 8.0 (37, 50) 95% CI for mean 4.9, 7.9 5.6, 8.3 5.8, 8.1 6.3, 8.9 Pairwise ANOVA (brolucizumab 6 mg vs. aflibercept 2 mg) LSM (SE) 6.6 (0.71) 6.8 (0.71) 6.9 (0.61) 7.6 (0.61) 95% CI for LSM 5.2, 8.0 5.4, 8.2 5.7, 8.1 6.4, 8.8 LSMD (SE) 0.2 (1.00) 0.7 (0.86) 95% CI for LSMD 2.1, 1.8 2.4, 1.0
p-value for treatment 0.4199 0.8695 difference (2-sided) p-value for noninferiority (4- <0.0001 0.0001 letter margin; 1-sided) Source: HAWK clinical study report, HARRIER clinical study report, Dugel et al. 2020 (28). Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; FAS=full analysis set; LOCF=Last observation carried forward; LSM=least squares mean; LSMD=least squares mean difference; SD=standard deviation; SE=standard error
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Indirect evidence: NMA results The quality of the NMA provided by the MAH was evaluated by the assessment team using the tool developed by Ortega et al (25). Quality assessment of the individual trials was perfomed by the MAH. The main limitation of the NMA is related to the external validity and applicability of the results and conclusions obtained, because one of the relevant comparators from the European perspective has not been considered.
In the base-case NMA, the main focus was comparison between brolucizumab 6 mg and different dosing schemes for aflibercept 2 mg and ranibizumab 0.5 mg. For the main outcome, mean change in BCVA, no differences were observed in any of the comparisons from baseline to year one or baseline to year two. For the following outcomes there were some differences favouring brolucizumab:
Patients losing at least 15 letters from baseline to 1 year: difference in one of the seven dosing schemes assessed for ranibizumab; Patients gaining at least 15 letters from baseline to 1 year: difference in two of the seven dosing schemes assessed for ranibizumab; Mean change in central retinal thickness from baseline to 1 year: difference in four of the four dosing schemes assessed for ranibizumab and two of the two dosing schemes assessed for aflibercept; Mean change in central retinal thickness from baseline to 2 years: difference in three of the four dosing schemes assessed for ranibizumab and two of the three dosing schemes assessed for aflibercept.
There were no differences in the overall rate of treatment discontinuation. Indirect comparison of AEs was not provided.
Overall, the credibility and validity of NMA rest on a few key assumptions (homogeneity, transitivity and consistency assumptions) and have well-known limitations that should be taken into account in drawing conclusions from these results. In this NMA, some simplifying assumptions were made for practical reasons. These include assuming equivalence between the dosing regimens at year one and year two for the treatments in VIEW 1&2 studies. The other key assumptions were as follows: (1) central retinal thickness (CRT), central foveal thickness (CFT), CSFT and central macular thickness (CMT) were considered as the same measure; and (2) equivalence was assumed for assessment times between 48 and 52 weeks for 12-month outcomes, and between 96 and 104 weeks for 24-month outcomes. Furthermore, the NMA results are reported as mean differences only, and not as absolute values or absolute changes. Therefore, it is difficult to evaluate the clinical relevance of the NMA results. However, despite the above limitations the methodological approach and conduct of the NMA can be considered adequate.
Results for the bevacizumab literature search Two applicaple SRs (29, 30) that included bevacizumab as a comparator in the treatment of nAMD were identified in the literature search. According to the AMSTAR-2 tool, the SR by Solomon et al. is a low quality review and the SR by Pham et al. a critically low quality review. However, the main limitations of the SRs are related to the level of details included in the methodology description of the SRs, and the authors of this REA consider that the results are robust enough to derive some conclusions on the effectiveness of bevacizumab in this setting.
Results for the meta-analysis by Solomon et al. showed that bevacizumab and ranibizumab were similar in terms of vision-related outcomes and numbers of AEs among participants followed for at least 1 year (30). Similarly, the SR by Pham et al. revealed no difference in vision related outcomes between bevacizumab and ranibizumab or between ranibizumab and aflibercept (29). The authors estimated that the mean difference between bevacizumab and aflibercept in terms of the change in BCVA suggests no difference between these tretments.
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Results from patient involvement Seven patient organisations completed the EUnetHTA patient survey. The key message was that patients with AMD often lose their autonomy and mobility and experience many difficulties in daily life. With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. The availability of other modes of administration would also be appreciated (e.g., drops or tablets).
Discussion
The aim of this assessment was to compare the clinical effectiveness and safety of brolucizumab for the treatment of nAMD with relevant comparators. In the EUnetHTA PICO survey, aflibercept, ranibizumab and bevacizumab were identified as relevant comparators.
The efficacy and safety of brolucizumab were directly compared only with aflibercept in an RCT setting. Two phase III noninferiority RCTs demonstrated that brolucizumab was noninferior to aflibercept for the change in BCVA. The RoB for these studies was considered low.
The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns regarding anti-VEGF treatments, at least for 2 years of use. In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report (27). However, in real life most AMD patients need treatment for more than 2 years and some patients will need to be treated simultaneously for both eyes, so the safety of long-term use and systemic exposure needs to be monitored.
Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences for the main outcome (mean change in BCVA) or for most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since indirect comparison between these two treatments was not formally conducted.
Regarding the direct evidence, the following key limitations were identified during the assessment:
In both the HAWK and HARRIER trials, the study eye for each patient had to be treatment-naïve for any anti-VEGF agents. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. The therapeutic indication for brolucizumab has no limitations in terms of prior anti-VEGF treatments; The first three loading doses of brolucizumab are given Q4W. During maintenance treatment, the dosing interval is based on disease activity and injections are given Q12W or Q8W. At the start of the LP it is not possible to know which patients will be able to remain on Q12W dosing. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who are able to remain on Q12W dosing; In the HAWK and HARRIER trials the treatment duration and follow-up time were up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years; Aflibercept was the only comparator in the HAWK and HARRIER trials. The MAH provided an NMA that included ranibizumab as a comparator. In many European countries bevacizumab is one of the primary treatment options for nAMD. However, brolucizumab has not been compared with bevacizumab either directly or indirectly; Brolucizumab has been compared only to aflibercept 2 mg at fixed Q8W dosing and not to other dosing schemes (e.g., pro re nata [PRN] or treat and extend [TREX]) commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn regarding the treatment burden (injection frequency) between these two regimens. Further investigations involving comparable treatment regimens would be needed;
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Data on general health-related QoL (HRQoL; e.g., European Quality of Life-5 Dimensions [EQ- 5D]) are not available. However, vision-related QoL (measured using NEI VFQ-25) was included.
Conclusions
Two pivotal phase III RCTs showed the noninferiority of brolucizumab in comparison to aflibercept in terms of visual function measured as BCVA in the treatment of patients with nAMD. Brolucizumab 6 mg Q8W or Q12W has only been compared to aflibercept 2 mg dosed at fixed intervals of Q8W and not to other dosing schemes commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn about treatment burden (injection frequency) between these two drugs. Consequently, it is unknown how brolucizumab compares with existing flexible dose regimens, so no advantages related to treatment burden can be anticipated with available data. Further investigations involving comparable treatment regimens would be needed.
In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events were higher for brolucizumab. These safety concerns were raised also in European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.
Evidence of the efficacy and safety of brolucizumab is based only on data for anti-VEGF treatment– naïve patients. There is no evidence regarding the efficacy and safety of brolucizumab in patients with nAMD previously treated with an anti-VEGF agent.
Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences in the main outcome (mean change in BCVA) or most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparisons between these two treatments were not formally conducted.
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1 BACKGROUND
1.1 Overview of the disease or health condition
AMD is a chronic eye disease characterised by progressive degeneration of the macula, the area of the retina responsible for sharp, central vision. Left untreated, AMD can lead to rapid, irreversible vision loss. Globally, 8.7% of all cases of blindness are attributed to AMD and it is the most common cause of blindness in developed countries (31, 32). Clinically, AMD is classified into early and late stages. The late stages of disease progression in AMD are further classified into two types: nAMD and atrophic AMD (1). Although nAMD represents only approximately 10% of all AMD cases, it accounted for approximately 90% of cases of severe vision loss due to AMD before the introduction of anti-VEGF therapies (33).
The risk of developing late AMD can be assessed using the risk scale derived from the Age-Related Eye Disease Study and based on a combination of retinal abnormalities. The risk of 5-year progression to late AMD is 0.5% for score 0 (normal ageing changes) to 50% for score 4 (34, 35). When one eye is affected, the risk of developing neovascularisation in the contralateral eye is 12.2% by 1 year and 26.8% by 4 years from initial diagnosis in the first eye (36).
1.1.1 Pathophysiology nAMD is an acute and rapidly progressing disease characterised by leaking of fluid due to the formation of abnormal blood vessels underneath the macula. This phenomenon, known as CNV, is the defining feature in nAMD and occurs in response to abnormally high levels of VEGF (37). The newly formed blood vessels are fragile and leak fluid, and progressive exudation from the macula can lead to separation of Bruch’s membrane, retinal pigment epithelium (RPE) and the retina, as well as accumulation of sub-RPE, subretinal fluid (SRF) and/or intraretinal fluid (IRF). This leads to generalised thickening of the retina (central subfield thickness [CSFT]) and the generation of cystic spaces (2, 38). Unresolved fluid accumulation leads to disruption of the anatomic architecture of the retina and ultimately leads to progressive, severe and irreversible vision loss due to photoreceptor degeneration (39).
1.1.2 Prevalence and incidence nAMD is the leading cause of severe vision loss and legal blindness among individuals aged >65 years in Europe, North America, Australia and Asia, and impacts an estimated 20–25 million people worldwide (2, 3). Prevalence reports have estimated that nAMD affects approximately 1.7 million people in Europe (4, 5). In developed nations, the estimated increase in population ageing is a contributing factor to the projected increase in nAMD prevalence, with the proportion of the population aged ≥60 years anticipated to increase and account for 35% of the population in Europe by 2050 (40). The estimated incidence of late AMD in Europe in 2013 was between 2.9 and 3.7 per 1000 person-years (6).
1.1.3 Symptoms and burden of the disease The early and intermediate stages of AMD usually occur without symptoms, with minimal or no vision loss. As the disease progresses into late AMD, the symptoms of nAMD include reduced VA, blurred vision, reduced contrast sensitivity, metamorphopsia, scotoma, photopsia and difficulties in dark adaptation (1, 41-44). nAMD is a debilitating, chronic disease that significantly impacts patients’ HRQoL, independence and functional ability. Several studies have shown that overall HRQoL is significantly associated with the degree of visual impairment suffered (45-47). Patients with nAMD commonly have difficulty in carrying out activities of daily living, increasing the likelihood that patients will require caregiver assistance; approximately 50% of patients with nAMD require caregiver support with instrumental daily activities (48). As a result, the nAMD-associated caregiver burden can be substantial. A study of nAMD patients found that the need for care increased with the level of visual impairment (49). The results showed that 35% and 37% of those with no visual impairment received formal and informal care, respectively, compared with 52% and 70% of those with moderate visual impairment and 56% and 89% of those with severe visual impairment.
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1.2 Current clinical practice
The aim of nAMD treatment with currently available drugs is to resolve the accumulation of retinal fluid and subsequently recover and/or preserve visual function, while slowing disease progression. Early detection of disease onset, prompt therapeutic intervention and continuous follow-up to detect fluid accumulation are critical, as vision loss becomes irreversible with delayed diagnosis and treatment (2).
Identification of VEGF as a major pathogenic feature in the development of nAMD has positioned anti- VEGF therapies as the standard of care for most patients. Older therapies, such as laser photocoagulation therapy and verteporfin photodynamic therapy (PDT), remain a therapeutic option for selected patients in whom VEGF inhibition is not advisable (2).
Two authorised anti-VEGF treatment options for nAMD are currently available in Europe: aflibercept (Eylea®) (16) and ranibizumab (Lucentis®) (17). A third anti-VEGF product, bevacizumab (Avastin®) (18), is frequently used off-label for nAMD. At the moment, ranibizumab is considered the reference standard for treatment in the European Society of Retina Specialists guidelines (2). The efficacy of aflibercept was demonstrated in two phase III studies in a noninferiority setting against ranibizumab (17). Noninferiority trials comparing bevacizumab with ranibizumab showed similar effects for maintaining or improving VA for the same treatment regimen (monthly injections or PRN), while anatomic endpoints favoured ranibizumab. SRs (19-22) concluded that there are no significant differences between the two drugs after 2 years of follow-up.
According to national (9-15) and European (2) guidelines, nAMD should be treated with anti-VEGF agents. The choice of agent and regimen should be individualised, taking into account clinical criteria, patient preferences and health care system characteristics. Patients are monitored at regular intervals and, in addition to fixed regimens, individualised dosing schemes are used. Flexible treatment strategies based on imaging findings include TREX (the interval between injections is extended when no CNV activity is observed) and PRN regimens (treatment is stopped when no activity is observed, and restarted when necessary); PRN and extend (PRNX) combines both strategies. Bevacizumab for off- label ophthalmologic use is covered in several European national health care systems. Informed consent after discussing the benefits, risks and off-label use of the drug is mandatory before administration of the drug (11, 13, 14, 50, 51). An overview of the management of the disease from country-specific and European guidelines is presented in Appendix 1: Guidelines for management of AMD.
Since the introduction of anti-VEGF therapies there has been a reduction in the incidence of blindness and visual impairment due to nAMD (7, 8). In clinical trials, the anti-VEGF therapies currently in use maintained VA in approximately 90% of patients over 2 years (52-54). In real-world settings it has been shown that anti-VEGF therapies preserve vision during the first year of treatment, with a gradual decline over time (55). Real-world evidence demonstrates that visual outcomes with current anti-VEGF therapies are related to injection frequency. Clinical trial dosing regimens for currently available anti- VEGF therapies are difficult to achieve in clinical practice and thus injections are not commonly administered at the recommended frequency. As a result, real-world visual outcomes vary among countries and are often less favourable than clinical study results (56-58). The prevalence of nonresponsiveness to anti-VEGF therapy in treatment-naïve patients has been assessed in retrospective studies. A study evaluating treatment with ranibizumab or aflibercept found that 22.4% of patients did not respond to treatment and 12.7% developed early tachyphylaxis, with no correlation between the type of anti-VEGF agent and nonresponse to therapy (59). A second study found that the prevalence of initial nonresponders to ranibizumab was 10.1% (60).
There are significant differences in costs among anti-VEGF drugs. As a result, on the basis of cost- effectiveness considerations, bevacizumab is often used as a first-line treatment in countries where it is available as a treatment option for nAMD, while ranibizumab or aflibercept is offered as second-line treatment. In situations or countries where off-label bevacizumab is not considered an option, treatment with ranibizumab or aflibercept is recommended. Sequential administration of different anti-VEGF agents is usual in clinical practice when clinical outcomes are not achieved with the first selected agent. However, the optimal sequence of treatment has not been established through RCTs.
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1.3 Features of the intervention
Brolucizumab (Beovu®) is a humanised single-chain Fv inhibitor of VEGF-A. A single-chain Fv is an autonomous binding agent that comprises only the variable domains of the monoclonal antibody (joined by a short flexible linker peptide) that are responsible for binding to its receptor (24). Features and administration of brolucizumab and other treatment options are presented in Table 1.1 and Table 1.2.
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Table 1.1. Features of the intervention and other treatment options Nonproprietary Brolucizumab Aflibercept Ranibizumab Bevacizumab name (active substance) Proprietary name Beovu® Eylea® Lucentis® Avastin® Registered EMA Brolucizumab is indicated in Aflibercept is indicated for Ranibizumab is indicated in adults for Bevacizumab does not have an EU indication adults for the treatment of adults for the treatment of the treatment of neovascular (wet) AMD marketing authorisation for neovascular neovascular (wet) AMD neovascular (wet) AMD AMD MAH Novartis Europharm Limited Bayer AG Novartis Europharm Limited Roche Registration GmbH Contraindications Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to the active substance Patients with active or suspected ocular or periocular infections. or to any of the excipients listed. Patients with active intraocular inflammation. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanised antibodies. Pregnancy. Drug class Anti-VEGF Pharmaceutical 120 mg/ml solution for injection 40 mg/ml solution for injection 10 mg/ml solution for injection in 25 mg/ml solution for infusion. formulation(s) in prefilled syringe. in prefilled syringe. prefilled syringe. Injections for ophthalmic use are 120 mg/ml solution for injection 10 mg/ml solution for injection. prepared by hospital pharmacies. Anatomical S01LA06 S01LA05 S01LA04 L01xC07 therapeutic chemical code Source: Summary of product characteristics for Beovu®, Eylea® and Lucentis®. Systematic reviews on anti-VEGF agents were consulted for the bevacizumab regimen (29, 30). Abbreviations: AMD=age-related macular degeneration; EMA=European Medicines Agency; VEGF=vascular endothelial growth factor.
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Table 1.2. Administration and dosing of the technology and other treatment options Active Brolucizumab Aflibercept Ranibizumab Bevacizumab substance Method of Intravitreal injection administration Doses 6 mg (0.05 ml) 2 mg (0.05 ml) 0.5 mg (0.05 ml) 1.25 mg (0.05 ml) Dosing According to the SPC: According to the SPC: According to the SPC: Dosing frequency according to frequency Initial treatment: one injection every Initial treatment: one injection Initial treatment: one injection available evidence is: 4 weeks for the first three doses. every 4 weeks for the first three every 4 weeks until maximum Initial treatment: one injection every 4 A disease activity assessment is doses. visual acuity is achieved and/or weeks for the first 3 months. suggested 16 weeks after Fixed regimen: the treatment there are no signs of disease Fixed regimen: one injection every 4 treatment initiation. interval is extended to 2 months. activity. weeks. In patients without disease activity, Treat-and-extend: based on Thereafter, monitoring and treatment every 12 weeks should physician’s judgement of visual treatment intervals should be be considered. and/or anatomic outcomes, determined by the physician and In patients with disease activity, injection intervals may be should be based on disease treatment every 8 weeks should be increased in 2- or 4-weekly activity, as assessed using visual considered. increments. acuity and/or anatomic Physicians may further Treatment intervals >4 months parameters. individualise treatment intervals between injections have not been according to on disease activity. studied. Standard length Treatment is continuous. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, it should be discontinued. of a course of treatment Dose No dose adjustments are necessary. adjustments Source: Summary of product characteristics for Beovu, Eylea and Lucentis. Systematic reviews on anti-VEGF agents were consulted for the bevacizumab regimen(29, 30). Abbreviations: SPC=summary of product characteristics.
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2 OBJECTIVE AND SCOPE
The aim of this EUnetHTA joint REA is to compare the clinical effectiveness and safety of brolucizumab in the target patient population with relevant comparators. The target patient population and relevant comparators (based on the requirements of EUnetHTA partners) are defined in the project scope below.
Table 2.1. Scope of the assessment Population Adults with neovascular (wet) age-related macular degeneration Intervention Brolucizumab (Beovu®) as an intravitreal injection at a dosage strength of 6 mg/0.05 ml Comparison Aflibercept (Eylea®) 2 mg/0.05 ml Ranibizumab (Lucentis®) 0.5 mg/0.05 ml Bevacizumab (Avastin®) 1.25 mg/0.05 ml1 Efficacy Best corrected visual acuity (treated eye)2 outcomes Anatomic parameters of disease activity: Central subfield thickness Choroidal neovascularisation area Subretinal fluid Intraretinal fluid/intraretinal cyst Subretinal pigment epithelium fluid Neurosensory retinal thickness Vision-related quality of life2 Health-related quality of life Treatment frequency of brolucizumab in loading/maintenance phase (e.g., proportion of patients maintained on dosing every 12 weeks through to week 48)2 Safety Adverse events due to treatment2 outcomes Any adverse events Serious adverse events Grade ≥3 adverse events Death as a serious adverse event Adverse events of special interest (e.g., ocular/non-ocular adverse events) Rates of discontinuation2 All causes Discontinuation due to adverse events Percentage of patients who discontinued the treatment by reason for discontinuation 1 At the time of publication of the Joint Assessment (March 2020), bevacizumab did not have an EU marketing authorisation for the indication under assessment. Bevacizumab is included as a comparator because of its importance identified in the EUnetHTA PICO survey; however its inclusion in the Joint Assessment should not be understood or quoted as a recommendation for its unlicensed use. 2 Outcomes related to issues particularly emphasised by patient organisations (please see patient involvement in Section 3.6 and Section 5).
2.1 Deviations from the Project Plan
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was not applied by either the MAH or the authors of this joint REA for rating the quality or certainty of the evidence (as high, moderate, low and very low certainty).
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3 METHODS
The assessment is mainly based on the data and analyses included in the submission dossier prepared by the MAH, received on 12th November 2019. During the assessment, the completeness of the data and analyses in the submission dossier was verified. Furthermore, the methods for data analysis and synthesis applied by the MAH were checked against the requirements for the submission dossier and applicable EUnetHTA guidelines and assessed with regard to scientific validity.
In addition, during the scoping phase the MAH indicated that no information about the off-label comparator bevacizumab would be included in the submission dossier. Since bevacizumab was identified as an important off-label comparator option for nAMD in several European countries in the PICO survey, the authoring team decided to perform an SLR with the support of the EUnetHTA Senior Scientific Officer.
3.1 Information retrieval
3.1.1 Information retrieval submitted by the MAH The evidence base with regard to the drug under assessment provided by the MAH was reviewed by the information specialist on the authoring team. Search strategies were checked for appropriateness and the results of information retrieval included in the MAH submission dossier were checked for completeness against a search in study registries and against the studies included in the regulatory assessment report. Supplementary searches were conducted to check for possible incompleteness of the study pool.
The MAH provided an SLR to identify relevant evidence of the efficacy and safety of brolucizumab versus authorised comparator therapies for the treatment of nAMD. The following electronic databases were included: EMBASE, MEDLINE, Medline-in-Process and the Cochrane Library. In addition to the searches of electronic databases, manual searches were also conducted for congress proceedings and clinical trials registries (US National Library of Medicine and EU Clinical Trials Register [EU-CTR]). An original search was conducted on 10th September 2018, with an update conducted on 13th June 2019. The manual searches covered the period between 2015 and 2019. Detailed search strategies for each electronic database and the search terms used for the manual searches are available in the appendices in the MAH submission dossier. Complete details of the search are available in Table 3.1.
The PICO selected for the SLR (Table 3.1) differed from the PICO proposed in the Project Plan (Table 2.1). Most notably, the PICO for SLR provided by MAH did not include bevacizumab as a comparator. In addition, PDT with verteporfin, laser photocoagulation therapy and macular surgeries were included as comparators; these were not selected in the Project Plan and are thus not considered relevant for this assessment.
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Table 3.1. Summary of information retrieval and study selection submitted by the MAH Element Details Inclusion Population: Patients aged ≥18 years with neovascular age-related macular degeneration criteria Intervention: Brolucizumab Comparators: Ranibizumab Aflibercept Photodynamic therapy with verteporfin Laser photocoagulation therapy Macular surgeries Outcomes: Visual acuity Other measures of visual acuity (blindness and gain/loss of ≥15 letters) Central retinal thickness Health-related quality of life Severe ocular and systemic adverse events Treatment discontinuation Injection and monitoring frequencies Study type: RCTs or crossover RCTs (if data presented at the time of crossover) of 44 weeks or longer Open-label extension studies of RCTs Publication type: peer reviewed published in journals or retrieved via hand searches on relevant websites Language: English Exclusion Population: Polypoidal choroidal vasculopathy (if >10% of population) criteria Intervention/comparators: intervention or comparator of interest not included in any arm of the trial Outcomes: outcomes that do not measure efficacy, safety or HRQoL Study type: SLRs, observational or real-world evidence studies, single-arm trials, nonrandomised trials, post hoc analyses, case studies, reviews Publication type: letters, editorials and conference abstracts Language: languages other than English Source: Submission dossier. Abbreviations: RCT=randomised controlled trial; SLR=systematic literature review.
3.1.2 Information retrieval for the NMA submitted by the MAH Following the identification of relevant studies from the clinical SLR, a feasibility assessment was conducted to assess the possibility of performing an NMA and of conducting baseline pooling analysis to estimate the absolute treatment effect for treatment regimens with more than one trial. The eligibility criteria for the NMA were based on the PICO criteria presented in Table 3.2.
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Table 3.2. PICO framework for the network meta-analysis Topic Description a Population Patients aged ≥18 years with neovascular age-related macular degeneration Intervention Brolucizumab Comparators Ranibizumab (Lucentis®) Aflibercept (Eylea®) Outcomes Mean change in best corrected visual acuity Mean change in central retinal thickness Proportion of patients gaining at least 15 letters on the ETDRS test Proportion of patients losing at least 15 letters on the ETDRS test Overall discontinuation Injection frequenciesb Adverse eventsb Study type and RCTs of 44 weeks or longer, crossover RCTs (if data presented at the time of crossover) duration Open-label extension studies of RCTs Source: Submission dossier. Abbreviations: ETDRS=Early Treatment Diabetic Retinopathy Study; RCT=randomised controlled trial. aStudies that enrolled patients with uncommon manifestations of neovascular age-related macular degeneration, including polypoidal choroidal vasculopathy, were excluded if these subtypes comprised >10% of the total population. bThese outcomes were evaluated through baseline pooling analysis only.
Only studies investigating therapies and doses licensed in the EU were included in the NMA. On the basis of these criteria, the treatments and doses considered in the NMA base-case analysis were brolucizumab 6 mg (and 3 mg) as the intervention of interest, and ranibizumab 0.5 mg and aflibercept 2 mg as comparators.
Different treatment regimens were also taken into account in the NMA using an attribute-based approach (e.g., PRN, TREX). Each treatment was evaluated separately by its treatment regimen, including whether an LP was used.
Regimen-based pooling was conducted for the mean change in BCVA, patients gaining at least 15 letters, patients losing at least 15 letters, injection frequency and AEs. Molecule-based pooling was conducted for discontinuation as well as AEs. The outcomes were analysed at both 1 and 2 years.
3.1.3 Information retrieval for bevacizumab Bevacizumab was not included as a comparator either in the SLR or in the NMA searches performed by the MAH, even though it had been identified as an important off-label comparator option in the PICO survey and the authoring team had specifically requested its inclusion.
Therefore, an exhaustive literature search was conducted for clinical review of bevacizumab in nAMD, which was developed by the information specialist with input from the authoring team. The selection criteria are presented in Table 3.3.
As the first step, the following bibliographic databases were searched (through the OVID interface): MEDLINE, Embase, the Cochrane Database of Systematic Reviews and the Centre for Reviews and Dissemination (CRD) database. The aim of these searches was to find comprehensive and high-quality SRs and NMAs of RCTs.
The literature search was performed on 24th October 2019 to identify studies meeting the predefined eligibility criteria in Table 3.3. The searches did not include language or publication year restrictions.
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Table 3.3. Selection criteria for the literature searches regarding bevacizumab Topic Description Population Adults with neovascular (wet) age-related macular degeneration Intervention Bevacizumab Comparators Brolucizumab, aflibercept, ranibizumab Outcomes Efficacy Best corrected visual acuity Anatomical parameters of disease activity Vision-related quality of life Health-related quality of life Safety Adverse events due to treatment Any adverse events Serious adverse events Grade ≥3 adverse events Death as a serious adverse event Adverse events of special interest (e.g., ocular/non-ocular adverse events) Rates of discontinuation All causes Discontinuation due to adverse events Percentage of patients who discontinued treatment by reason for discontinuation Design Systematic reviews or network meta-analyses that include RCTs Abbreviations: RCT=randomised controlled trial.
In a second step and to identify primary studies (RCTs), a systematic search of the OVID interface in MEDLINE and Embase was conducted to update the SRs or NMAs selected in the first step, taking into account the date of the search strategies in those reports until 19th November 2019.
Controlled vocabulary and keywords used in the search included terms for nAMD and the drugs of interest. Methodological filters were applied to limit retrieval to meta-analyses and SRs and to clinical controlled trials. The detailed search strategies are presented in Appendix 2: Searches strategies for bevacizumab Literature ReVIEW.
Once the search results were obtained, two researchers independently performed initial screening of the records (titles and abstracts) using the predefined inclusion and exclusion criteria. Conflicts regarding screening decisions between the two researchers were resolved via discussion and consensus.
The full-text articles of the records considered potentially relevant by title and abstract by both researchers were obtained and were reviewed independently to classify each record as “included” or “excluded”. Any discrepancies were resolved via discussion.
3.2 Data extraction
Information used for assessment of the clinical effectiveness and safety was extracted from the submission dossier and verified against the CSRs or other original documentation provided in the submission dossier. Information about the off-label comparator bevacizumab was extracted from the literature review conducted by the authoring team with support from the EUnetHTA Senior Scientific Officer.
3.3 RoB assessment
In accordance with EUnetHTA guideline recommendations (61), the quality rating tool developed by the Cochrane Collaboration (version 5.1.0) (62) was used to assess the RoB in randomised trials.
RoB at the study level was assessed for six different domains:
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The method used to generate the sequence for randomisation (random sequence generation); The method used to mask the sequence for allocation to treatment (allocation concealment); The measures used to ensure the blindness of the study with respect to treatment assignment (blinding of participants, medical personnel and outcome assessors); The completeness of the data for each outcome considered (incomplete outcome data); The selective description of the results (selective outcome reporting); Other sources of bias (e.g., bias due to early interruption of the study because of the benefits without an appropriate stopping rule, use of a nonvalidated measurement instrument, incorrect statistical analysis).
For each domain, two independent assessors judged the RoB (low risk, high risk or unclear) on the basis of the information retrieved from the full-text publications, the protocols and the submission dossier. RoB assessment (at both the study level and outcome level) was conducted only for the randomised phase III studies that included relevant direct evidence on brolucizumab and comparators.
Studies included in the NMA conducted by MAH were not individually assesed for RoB by the authoring team, but the MAH provided quality assessment for each trial.
The individual studies included in the SRs on bevacizumab were not assessed separately for RoB by the authors of this joint REA, as the RoB of the RCTs described in the SRs was already assessed for by the authors of the selected SRs. In addition, the quality of the SRs was assessed using the AMSTAR- 2 checklist (26). The AMSTAR-2 critical domains are as follows:
The protocol registered before commencement of the review; The adequacy of the literature search; The justification for excluding individual studies; The RoB for individual studies included in the review; The appropriateness of the meta-analytical methods; The consideration of RoB when interpreting the results of the review; The assessment of presence and likely impact of publication bias.
The critical appraisal of key issues in indirect comparisons, including comments for assessing the consequences of application to drug evaluation, was evaluated using a structured checklist developed by Ortega et al. (25). The checklist has two parts. The first consists of three eliminatory key questions while the second includes 17 items: five regarding quality, five regarding clinical issues and seven dealing with the methodology and statistics.
3.4 External validity
The external validity of the trials included was assessed using EUnetHTA guidelines on the applicability of evidence in the context of an REA of pharmaceuticals considering the following elements: population, intervention, comparator, outcomes, and setting (63, 64).
3.5 Results and analyses for the studies included
The information in the submission dossier on the study design, study methods, populations, endpoints (patient relevance, validity and operationalisation) and study results was evaluated. The results including direct evidence from phase III trials comparing brolucizumab and aflibercept form the basis for the results and assessment. The results of the two relevant reviews (including bevacizumab) identified in the literature review conducted by the authoring team are presented and summarised separately. Finally, the results from the NMA conducted by the MAH are presented and assessed as applicable.
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3.5.1 Meta-analysis and indirect evidence In the absence of head-to-head data for brolucizumab versus ranibizumab, an NMA was performed by the MAH to assess the relative effectiveness of brolucizumab versus aflibercept and ranibizumab.
Standard pairwise meta-analyses based on direct comparisons were carried out between pairs of treatments when possible for cases in which two treatments were compared in two or more clinical trials. Direct pairwise comparisons were conducted to assess the heterogeneity between studies when there was more than one study comparing the same treatments.
The NMA was conducted using a Bayesian framework that preserved the randomisation of each trial. The relative goodness of fit of the models was assessed using the deviance information criterion. Both fixed-effects and random-effects models were developed and the one associated with the lowest deviance information criterion (DIC) was selected, unless the absolute difference between the DIC values of the two models was less than three points, then the fixed-effect model was chosen.
The base-case NMA included studies with treatment-naïve patients (naïve to any anti-VEGF treatment) and mixed populations (treatment-naïve and previously treated with an anti-VEGF agent). All trials that were connected via common comparators to brolucizumab were included in the analyses. Outcomes included in the NMA are reported in Table 3.2.
During the assessment, the methods applied for the meta-analyses presented in the submission dossier and, if applicable, the justification for deviations from the procedures described above were evaluated.
Potential sources of heterogeneity in the studies included in the NMA were investigated and discussed with clinicians on the basis of the descriptive statistics. Analyses to determine the inconsistency of the assessment results were conducted.
Several sensitivity analyses were conducted to test the assumptions adopted in the base-case NMA. Sensitivity analyses were related to the networks of evidence, the time of assessment and the methodological choices made.
Networks of evidence A sensitivity analysis was conducted for trials that reported only the median change in BCVA and retinal thickness.
In addition, the following two sensitivity analyses were conducted on the basis of clinical expert opinion:
The RIVAL study was excluded from VA outcomes (mean change in BCVA and patients gaining or losing at least 15 letters) as patients in RIVAL had the highest mean BCVA at baseline and the results from this study appeared to be outlier values; The PIER and MARINA studies were excluded, as these two trials compared an active treatment to sham IVT, which could have introduced bias into the relative efficacy results versus results from studies comparing anti-VEGF treatments.
Time of assessment A sensitivity analysis was performed in which results before 52 weeks and 104 weeks were extrapolated. Given that time equivalence was assumed between 48 and 52 weeks for 1-year results and between 96 and 104 weeks for 2-year results, this analysis made it possible to identify if the results are highly influenced by this assumption.
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Methodological analyses The following methodological sensitivity analyses were run to test the effects of the model specifications chosen:
A sensitivity analysis was conducted regarding trials with imputed standard error from the baseline and final value: rather than correlation of 0.5, correlation of 0.7 between the baseline and the final value was assumed; Two sensitivity analyses were conducted regarding trials with an imputed standard error from the mean standard deviation of the other trials: o The minimum standard deviation instead of the mean; o The maximum standard deviation instead of the mean.
3.5.2 Subgroup analyses and other effect modifiers The following subgroups considered relevant for the analysis were: age category; sex (male and female); baseline BCVA categories; baseline CSFT category; baseline lesion type (predominantly classic, minimally classic, occult); baseline CNV lesion size; baseline lesion size by lesion type; and baseline fluid status (IRF, SRF, sub-RPE fluid).
During the assessment, the subgroup analyses examining potential effect modifiers presented in the submission dossier and the corresponding methods applied were evaluated.
3.6 Patient involvement
At the start of this joint REA, EUnetHTA conducted an open call for patient organisations. General questions were asked to elicit patients’ views on living with the disease, important outcomes to be considered in this assessment and expectations about the drug under assessment. The key questions and a summary of the answers are presented in Section 5.
European and national patient organisations were asked to provide an organisational perspective on the questions in English. In all parts of the open call, the term patient refers to anyone living with, or who has lived with, the condition for which the new medicine is indicated.
Seven patient organisations completed the survey: Asociación Acción Visión España (Spain); Društvo MDSS Kranj (Slovenia); Fighting Blindness (Ireland); Macula Retina (Spain); Retina Bulgaria (Bulgaria); Retina International (Ireland); and Retina Suisse (Swiss Confederation).
The information gathered from the open call was used to inform the scope of this assessment and in particular the outcomes to be considered. In Table 2.1, the outcomes related to issues particularly emphasised by patient organisation are identified.
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4 RESULTS
4.1 Information retrieval
4.1.1 Check for completeness of the literature search submitted by the MAH Overall, the authors considered that the search followed EUnetHTA guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
The study pool for the assessment was compiled on the basis of the following information sources reported by the MAH in the submission dossier:
Bibliographic databases (last search on 12th–13th June 2019); Study registries (the date when the search was run was not reported); A manual search (date when the search was carried out is not reported).
In general, the scope described by the MAH in the submission dossier presents one significant difference from the scope defined in the Project Plan: the MAH does not include bevacizumab as a comparator. In addition, CRT was the only outcome related to anatomic parameters of disease activity considered by the MAH.
The main concerns regarding the searches are as follows:
Firstly, the searches are not up to date (more than 3 months old) and do not meet the requirements from the Project Plan; therefore, newer evidence could be missing; Secondly, regarding clinical trial registries, the search syntax in the submission dossier includes the same strategy for both registries, and the two interfaces do not allow running the searches in the same way. Results for the search in all the study registries are not reported; therefore, this could not be checked.
Besides these main overall issues, other shortcomings were noted:
The flow chart results do not match with the hits shown in the search history appendix; Synonyms for the target intervention are missing; There are misspellings in the search strategies and search fields are missing in some strategy lines.
Overall, the information specialist questioned the completeness of the study pool. Thus, a search in study registries was performed to check the completeness of the study pool for RCTs with brolucizumab.
Check for completeness of the study pool for direct comparisons A search in study registries for brolucizumab (ClinicalTrials.gov, EU-CTR, ICTRP Search Portal, last search on 20th December 2019) was carried out (Appendix 3: Searches performed by the Information specialist to the completeness of the study pool).
The check did not identify any additional relevant study.
Check of completeness of the study pool for indirect comparisons with a common comparator A search in study registries (ClinicalTrials.gov, EU-CTR, ICTRP Search Portal, last search on 20th December 2019) was carried out (Appendix 3: Searches performed by the Information specialist to the completeness of the study pool).
A focused search (simple Boolean search as well as the “Similar articles” function in PubMed) was not possible because of inconsistencies on the platform on days when the information retrieval was checked
March 2020 EUnetHTA Joint Action 3 WP4 29 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD for the first time (16th–20th December 2019); this is why a focused search was run on 7th February 2020. The check did not identify any additional RCTs.
4.1.2 Results for the bevacizumab literature search In the first step of the literature search (conducted in October 2019) to identify SRs/NMAs regarding the relative efficacy and safety of treatment with bevacizumab in nAMD, 371 records were retrieved among the four databases (212 from MEDLINE, 22 from Embase, 12 from the Cochrane Database of Systematic Reviews and 125 from CRD). A flowchart of the selection process to identify SRs/NMAs is shown in Figure 4.1. The screening results with reasons for exclusion based on title and abstract are in Appendix 4: Results from the screening of the searches of bevacizumab. Fifty-six records were selected for full-text review. Thirty-five of those documents met the inclusion criteria. They are briefly described in Appendix 5: Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review. There was consensus between the two researchers in the selection of studies. The reasons for exclusion by full-text report are described in Appendix 6: Excluded articles from bevacizumab literature review.
Records identified in the searches n=371
Records after deleting duplicates n=300
Articles excluded based on title and abstract n=244
Potentially relevant articles retrieved for more detailed evaluation n=56
Full text not available, articles excluded based on abstract n=7
Articles excluded by full text n=14
Relevant articles included n=35
Figure 4.1. Flowchart of the selection process to identify systematic reviews and network meta-analyses.
The second step to update the SRs or NMAs identified in the first step searched for RCTs: 110 records were retrieved from the searches conducted in November 2019 (87 from MEDLINE and 23 from Embase). There were two duplicates. All the records were excluded by title or abstract. The flowchart of the selection process to identify RCTs is shown in Figure 4.2. The screening results with the reasons for exclusion based on title and abstract are in Appendix 4: Results from the screening of the searches of bevacizumab. No records were reviewed by full text, nor included from the searches in both databases.
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Citations identified in the searches n=110
Citations after deleting duplicates n=108
Articles excluded based on title and abstract n=108
Articles excluded by full text n=0
Relevant articles included n=0
Figure 4.2. Flowchart of the process to select randomised controlled trials to update the systematic reviews included.
4.2 Studies included in the assessment
4.2.1 Studies included from the literature search submitted by the MAH In literature search submitted by MAH, a total of 48 publications reporting on 38 RCTs were included in the SLR, as shown in the PRISMA diagram in Figure 4.3, extracted for four treatments: ranibizumab, aflibercept, brolucizumab and PDT. Three of these RCTs compared brolucizumab to a relevant comparator: HAWK (NCT02307682), HARRIER (NCT02434328) and OSPREY (NCT01796964).
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Figure 4.3. PRISMA diagram. Source: Submission dossier.
HAWK and HARRIER are phase III trials and OSPREY is a phase II trial. In all three studies the efficacy and safety of brolucizumab were compared to aflibercept.
The studies listed in Table 4.1 were included in the assessment. The OSPREY study was a phase II study and in the REA it has been handled as supportive evidence, as well as in the EMA market authorisation process and the REA submission dossier. It has a different primary outcome to HAWK and HARRIER. Thus, results from the OSPREY study are presented separately as supportive evidence in Section 4.10.
It is worth mentioning that in addition to the brolucizumab 6 mg dose, the HAWK study included a brolucizumab arm with a dose of 3 mg. The EMA has approved brolucizumab 6 mg for this indication and for this reason the scope for this assessment (Table 2.1) focuses on the brolucizumab 6 mg dose. Results from the brolucizumab 3 mg arm are described in brief as supportive evidence in Section 4.9.
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Table 4.1. Study pool: list of relevant studies used for the assessment Study Study category Study for Sponsored or Available documentation marketing third-party authorisation of the technology under assessment HAWK (NCT02307682) Yes Sponsored HAWK CSR Dugel et al. 2020 (28) CHMP Assessment Report HARRIER (NCT02434328) Yes Sponsored HARRIER CSR Dugel et al. 2020 (28) CHMP Assessment Report OSPREY (NCT01796964) Yes Sponsored OSPREY CSR Dugel et al. 2017 (65) CHMP Assessment Report Abbreviations: CSR=clinical study report; CHMP=Committee for Medicinal Products for Human Use.
4.2.2 Studies included from the NMA literature search submitted by the MAH Given the data availability and homogeneous populations in the trials identified, an NMA was determined to be feasible and was conducted on all outcomes of interest considered in the MAH’s PICO. The trials included in the base case are summarised in Table 4.2.
Overall, the studies were considered largely homogeneous, and representative of the target population and treatments. Potential sources of heterogeneity identified by the MAH were as follows:
Outcome measures: For continuous measures, only mean changes were included in the analyses, following a conservative approach. This led to exclusion of one trial (RABIMO); Previous treatment use: Among the trials included in the base case, most were conducted among treatment-naïve patients according to the inclusion criteria (defined as patients who are naïve to other anti-VEGF agents). Two studies did not report prior therapies but, since pegaptanib was the only authorised treatment at the time, it was considered that patients in the study were predominantly anti-VEGF–naïve and the studies were included in the analysis.
Heterogeneity in the relative treatment effects was assessed for each pairwise comparison using Cochran’s Q test and the I2 statistic. The significance for Cochran’s Q test was set at a level of 10%, or I2 >50%. Forest plots were generated for each comparison to illustrate heterogeneity.
Consistency between direct and indirect comparisons in the NMA was assessed.
The RCTs included in the NMA were qualitatively assessed using the CDR for assessing RoB in randomised trials. Overall, the evidence was of moderate to high quality. The greatest RoB was due to insufficient information identified in the publication during the quality assessment. The majority of studies did not have unexpected imbalances in drop-outs between groups.
Overall, the studies included in the NMA were considered largely homogeneous and representative of the target population and treatments. There was homogeneity among the trials included in the NMAs for the following baseline characteristics:
Age; Sex (proportion of males); VA (ETDRS); Retinal thickness (CRT, CMT, CSFT, CFT); CNV lesion size in disc areas and mm2; CNV lesion type (predominantly classic, minimally classic and occult).
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Table 4.2. Overview of trials included in the network meta-analysis Assessment Sample Blinding Author, year Trial name Phase Intervention Comparator time (months) size status Dugel 2017 12 OSPREY 90 II Double-blind LP → Bro 6 mg Q8W → Q12W LP → Afli 2 mg Q8W Dugel 2020 96 weeks HARRIER 739 III Double-blind LP → Bro 6 mg Q12W/Q8W LP → Afli 2 mg Q8W Dugel 2020 96 weeks HAWK 1078 III Double-blind LP → Bro 6 mg Q12W/Q8W LP → Afli 2 mg Q8W LP → Bro 3 mg Q12W/Q8W Martin 2011/ 12/24 CATT 1143 NR Single-blind Rani 0.5 mg Q4W Bev 1.25 mg Q4W Martin 2012 Rani 0.5 mg PRN Bev1.25 mg PRN Eldem 2015 12 SALUTE 77 IV Open-label LP → Rani 0.5 mg PRNX LP → Rani 0.5 mg PRN Feltgen 2017 12 RABIMO 40 IV Open-label LP→ Rani 0.5 mg Q8W LP → Rani 0.5 mg PRN Heier 2012/Yuzawa 2015/ 12/96 weeks VIEW 1 & 2/ 1217 III Double-blind Afli 0.5 mg Q4W → PRN Rani 0.5 mg Q4W → PRN Schmidt-Erfurth 2014 VIEW 1 & 2/ Afli 2 mg Q4W → PRN Pooled LP → Afli 2 mg Q8W → PRN Ho 2014 24 HARBOR 1089 III Double-blind Rani 0.5 mg Q4W LP → Rani 0.5 mg PRN LP → Rani 2 mg Q4W Rani 2 mg PRN Gillies 2019/ 12/24 RIVAL 278 III Double-blind LP → Rani 0.5 mg TREX LP → Afli 2 mg TREX Hunyor 2018 Kertes 2019 24 CAN-TREAT 580 NR Open-label LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W Regillo 2008 12 PIER 184 IIIb Double-blind LP → Rani 0.5 mg Q12W Sham IVT LP → Rani 0.3 mg Q12W Rosenfeld 2006/ 24 MARINA 716 III Double-blind Rani 0.5 mg Q4W Sham IVT Chang 2007 Rani 0.3 mg Q4W Silva 2017 12 TREND 650 IIIb Single-blind LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W Wykoff 2015/2017 12/24 TREX-AMD 60 IIIb Open-label LP → Rani 0.5 mg TREX Rani 0.5 mg Q4W Source: Submission dossier. Abbreviations: Aflib=aflibercept; Bro=brolucizumab; IVT=intravitreal; LP=loading phase of three initial monthly injections; NR=not reported; PRN=pro re nata dosing regimen; PRNX=PRN and extend dosing regimen; QXW=one injection every X weeks; Rani=ranibizumab; TREX=treat and extend dosing regimen.
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4.2.3 Studies included from the bevacizumab literature search Two SRs were described as relevant reviews used for assessment of bevacizumab, by Solomon et al. (30) (literature search up to January 2018) and Pham et al. (29) (literature search up to August 2017). This latter SR was considered because Solomon et al. did not include aflibercept among the drugs assessed.
Of the 35 articles included that met the eligibility criteria for the bevacizumab literature review, 33 were not further described in detail in the SR of the relative efficacy and safety of bevacizumab in patients with nAMD as the RCTs considered in those reviews are included in the most up-to-date and complete SR by Solomon et al. (30).
Appendix 6: Excluded articles from bevacizumab literature review includes a table that lists RCTs not included in the SR by Solomon et al. that were included in the other references and reasons for exclusion in the SR by Solomon et al. (30). The main reasons for not including the RCTs in the SR performed by Solomon et al. were follow-up of <1 year, dosing studies and studies with combination therapy. The exclusion of those studies is not considered to impact the applicability to our PICO.
A description of the two SRs included and a summary of their results are presented in Section 4.12.
4.3 Excluded studies
None of the studies in the literature search provided by the MAH was excluded for this assessment. The studies excluded from the SLR on bevacizumab and the reasons for their exclusion are described in Section 4.2.
4.4 Characteristics of the studies included: direct evidence
Table 4.3 and Table 4.4 describe the studies used for the assessment. HAWK and HARRIER are phase III multicentre RCTs comparing the efficacy and safety of brolucizumab versus aflibercept 2 mg in a noninferiority setting. Definitions for the analysis populations are provided in Table 4.5.
Table 4.3. Characteristics of the studies included for direct comparison Study Study Patient Brolucizumab Aflibercept Study Primary design population (patients (patients duration outcome randomised) randomised) HAWK Randomised, Treatment naïve Group 1: 3 mg Group 3: 2 96 Change (NCT02307682) double- patients aged (N=360) mg weeks in BCVA masked, ≥50 years; active Group 2: 6 mg (N=361) follow- from multicentre, CNV lesions (N=361) up baseline three-arm secondary to to week phase III AMD affecting 48 study (212 the central study centres subfield in the across 11 study eye; IRF countries) and/or SRF HARRIER Randomised, affecting the 6 mg (N=372) 2 mg 96 Change (NCT02434328) double- central subfield (N=371) weeks in BCVA masked, of the study eye; follow- from multicentre, BCVA between up baseline two-arm 78 and 23 to week phase III letters, inclusive, 48 study (147 in the study eye study centres at baseline using across 29 ETDRS testing countries) Source: European Medicines Agency public assessment report, submission dossier. Abbreviations: AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CNV=choroidal neovascularisation; ETDRS=Early Treatment Diabetic Retinopathy Study; IRF=intraretinal fluid; SRF=subretinal fluid.
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Table 4.4. Characterisation of the interventions and comparators Study Brolucizumab Aflibercept Treatment characteristics HAWK Group 1: 3 mg Group 3: 2 mg Loading: Monthly injections for the first 3 months (NCT02307682) Group 2: 6 mg (day 0, week 4 and week 8) across all groups. Maintenance: Q8W injections in aflibercept arm. In both brolucizumab arms the dosing frequency was either Q8W or Q12W, according to the patient’s disease activity. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit) HARRIER 6 mg 2 mg Loading: Monthly injections for the first 3 months (NCT02434328) (day 0, week 4 and week 8) across all groups. Maintenance: Q8W injections in aflibercept arm. In brolucizumab arm the dosing frequency was either Q8W or Q12W, according to the patient’s disease activity. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit) Source: Submission dossier. Abbreviations: Q8W=every 8 weeks; Q12W=every 12 weeks.
Table 4.5. Trial populations used for analysis of outcomes in the HAWK and HARRIER studies Analysis set Description All enrolled analysis All patients who signed informed consent and were assigned a subject number. set This analysis set was used to summarise subject disposition and pretreatment AEs. All randomised All patients who were randomised in the interactive response technology. analysis set (RAN) This analysis set was used to summarise protocol deviations, analysis restrictions, medical history and prior medications. Full analysis set All randomised patients who received at least one IVT injection of the study treatment. (FAS) The FAS served as the primary analysis set for all efficacy analyses, with LOCF imputation of missing/censored (after start of alternative anti-VEGF treatment) BCVA values. The FAS represented the analysis set that was as close as possible to the intent-to- treat principle of including all randomised patients. Safety analysis set All patients who received at least one IVT injection. (SAF) Per protocol analysis Subset of the FAS that excluded patients with protocol deviations and violations of set (PPS) analysis requirements that were expected to have a major effect on the validity of the assessment of efficacy at week 48. Source: Submission dossier. Abbreviations: AE=adverse event; BCVA=best-corrected visual acuity; IVT=intravitreal; LOCF=last observation carried forward; VEGF=vascular endothelial growth factor.
4.4.1 Trial design A schematic of the study design for the HAWK and HARRIER trials is presented in Figure 4.4. Both trials primarily followed the same study design, with the following differences:
Dosing of brolucizumab (in addition to brolucizumab 6 mg, HAWK also included a brolucizumab dose of 3 mg); Number of scheduled DAA visits; Potential dosing interval adjustments (from week 20, DAAs were conducted every 12 weeks in both trials; in HARRIER, additional DAAs occurred at weeks 28, 40, 52, 64, 76 and 88).
Both studies included screening visits (2–14 days before baseline) and a baseline visit (day 0), followed by monthly post-baseline study visits from week 4 until week 96. After confirmation of eligibility at baseline, patients were randomised to receive either brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg via IVT injection in a 1:1:1 ratio in HAWK, and randomised to receive either
March 2020 EUnetHTA Joint Action 3 WP4 36 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD brolucizumab 6 mg or aflibercept 2 mg via IVT injection in a 1:1 ratio in HARRIER. Monthly loading dose injections were given for the first 3 months (day 0, week 4 and week 8) across all arms of both trials, followed by maintenance dosing.
Figure 4.4. HAWK and HARRIER trial design. Randomisation was 1:1:1 in HAWK and 1:1 in HARRIER. Source: Dugel et al. 2020 (28). Supplementary material. Appendix 3. aHAWK only. bDisease activity assessments were conducted at prespecified visits by a masked investigator. Guidance for assessing disease activity (based on dynamic functional and anatomical characteristics) was given in the protocol; however, the final decision was made by the investigator. Abbreviations: q8w=every 8 weeks; q12w=every 12 weeks.
Maintenance dosing for aflibercept in both trials was administered at fixed 8-week intervals (Q8W). This was in line with the marketing authorisation for aflibercept for this indication at the time when the HAWK and HARRIER trials were designed. However, individualised aflibercept regimens were included in the SPC indication when the pivotal studies were ongoing. The aflibercept SPC allows further individualised dosing schedules and these regimens are commonly used in clinical practice (16).
Maintenance dosing for brolucizumab in both trials was Q12W/Q8W, where the treatment interval could be adjusted according to the patient’s individual treatment need from 12- to 8-week intervals on the basis of DAA. DAAs were performed by masked investigators at prespecified visits. At the week 16 visit, DAA was based on the decrease in BCVA and anatomic parameters (CSRT, IRF, intraretinal cysts). After week 16, DAA was based on the decrease in BCVA only. More detailed information on the DAA criteria is provided in Table 4.6. If disease activity was identified by the investigator at either of these DAAs, the dosing interval was adjusted to Q8W. Once patients were adjusted to a Q8W interval, they remained on that interval until the end of the study (week 96/exit) and could not return to a Q12W interval.
In both HAWK and HARRIER studies, sham injections were administered to establish an identical monthly injection schedule across treatment arms to maintain the masking and data integrity. Sham was administered by mimicking an IVT injection and using an injection syringe without a needle. (HAWK CSR, HARRIER CSR)
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Table 4.6. DAA criteria for the HAWK and HARRIER studies
a Study weeks DAA criteria Week 16 Decrease in BCVA of ≥5 letters compared with baseline Decrease in BCVA of ≥3 letters and CSFT increase ≥75 μm compared with week 12 Decrease in BCVA of ≥5 letters due to wAMD disease activity compared with week 12 New or worse IRF/intraretinal cysts compared with Week 12 b b Weeks 20, 28 , 32, 40 and 44 Decrease in BCVA of ≥5 letters due to wAMD disease activity compared with week 12 b b b Weeks 52 , 56, 64 , 68, 76 , Decrease in BCVA of ≥5 letters due to wAMD disease activity compared b with week 48 80, 88 and 92 Source: Submission dossier. a DAA criteria used to assign brolucizumab every 12 or 8 weeks dosing were developed based on findings from predictive data modelling combined with clinically meaningful vision and anatomic parameters of disease activity. Dynamic criteria identified in analyses of the PIER, EXCITE and CATT studies support DAA at week 16 for early determination of patients suited to dosing every 8 weeks and to minimise patient reassignment at later time points. Subsequent DAA visits coincide with every 12 weeks dosing visits to allow reassignment to every 8 weeks dosing if patients experience a BCVA decline due to wAMD at these time points. b Additional DAA visits were included in the HARRIER study owing to a health authority request. Abbreviations: BCVA=best-corrected visual acuity; CSFT=central subfield thickness; DAA=disease activity assessment; IRF=intraretinal fluid; wAMD=wet age-related macular degeneration.
4.4.2 Statistical methods for primary analyses of the HAWK and HARRIER studies The objectives were as follows:
The primary hypothesis was noninferiority in terms of the mean change in BCVA from baseline to week 48 (margin of 4 letters) with fewer injections; The first key secondary efficacy endpoint was the average change in BVCA from baseline over the period from week 36 to week 48; The statistical hypotheses for the primary and first key secondary efficacy endpoints were intended to demonstrate the noninferiority of brolucizumab to aflibercept.
Noninferiority was demonstrated (i.e., the null hypothesis was rejected) if the lower limit of the two-sided 95% CI for the corresponding treatment difference (brolucizumab [6 mg or 3 mg] vs. aflibercept 2 mg) was greater than 4 ETDRS letters.
In calculating the study power, a sample size of 297 patients per treatment arm was considered sufficient to demonstrate noninferiority (margin of 4 letters) of brolucizumab 3 mg/6 mg versus aflibercept 2 mg with respect to the change in BCVA from baseline to week 48 at a two-sided level of 0.05 with a power of approximately 90%, assuming equal efficacy and a common SD of 15 letters.
Power of at least 90% was expected for the first key secondary efficacy endpoint, assuming that averaging over the four time points would not lead to an increase in SD.
To account for a dropout rate of 10%, a total of 330 patients was planned for randomisation to each treatment arm (total of 990 randomised patients in HAWK and 660 in HARRIER).
In HARRIER study, hypothesis testing for secondary endpoints lack management of type one error and consequently multiplicity is not controlled for. Consequently, nominal statistical significances for superiority for these outcomes cannot be considered as confirmatory evidence.
In HAWK study, the analysis plan included additional hypotheses testing for superiority of brolucizumab versus aflibercept related to CSFT, retinal fluid, and disease activity. Correspondingly, the analysis plan also pre-specified a proper management of the global level in relation to the resulting multiple testing. As these hypotheses were derived from an independent source (HARRIER study) and were pre-
March 2020 EUnetHTA Joint Action 3 WP4 38 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD specified prior to unmasking of this study all related statistical significances for superiority provide confirmatory evidence. (27)
More details on confirmatory testing related to additional secondary endpoints in HAWK study are described in appendix 5 of Dugel et al. 2020 (28).
4.4.3 Follow-up duration and discontinuations The planned follow-up duration was 96 weeks in both HAWK and HARRIER. In the HAWK study, 10.5% of the patients (31 in the brolucizumab 3 mg arm, 37 in the brolucizumab 6 mg arm and 46 in the aflibercept arm) discontinued the study before week 48 when the primary outcome analysis was performed. In the HARRIER study, 6.6% of the patients (25 in the brolucizumab arm and 24 in the aflibercept arm) discontinued before week 48.
Overall, 171 subjects (15.8%) discontinued the study and 211 (19.5%) discontinued the study treatment before week 96 in HAWK. Withdrawal by subject was the most frequent reason for study (9.4% brolucizumab 6 mg arm, 6.4% aflibercept) or treatment (10.0% brolucizumab, 6.4% aflibercept) discontinuation. AEs were the second most frequent reason for study (2.2% brolucizumab, 3.3% aflibercept) or study treatment (3.6% brolucizumab, 3.9% aflibercept) discontinuation.
Similarly, 72 subjects (9.7%) discontinued the study and 95 (12.8%) discontinued the study treatment overall before week 96 in HARRIER. Withdrawal by subject was also the main reason for study (3.2% brolucizumab, 5.7% aflibercept) or study treatment (2.7% brolucizumab, 5.4% aflibercept) discontinuation. Adverse events were also the second most frequent reason for study (2.4% brolucizumab, 1.1% aflibercept) or study treatment (5.4% brolucizumab, 2.4% aflibercept) discontinuation.
In week 96 analysis, twelve patients (1.1 %) were lost to follow-up in HAWK and seven patients (0.9%) in HARRIER (HAWK CSR, HARRIER CSR). More details on subject disposition are presented in Table 4.9, in Section 4.8.
4.4.4 Baseline characteristics of the study populations Baseline characteristics of the patients in the HAWK and HARRIER studies are presented in Appendix 7: Baseline characteristics of HAWK and HARRIER study populations. The demographic and disease characteristics of patients were similar between the treatment arms in both trials. The mean age of patients included was 76.5 years (range 50–97 years) in HAWK and 75.1 years (range 50–95 years) in HARRIER, with the majority aged ≥75 years (HAWK 60.9%; HARRIER 56.4%) at the time of study entry. A greater percentage of the patients were female than male (HAWK 56.5%; HARRIER 57.1%) and the patients were predominantly white (HAWK 81.1%; HARRIER 92.2%). In the HAWK trial, 14.3% of patients were of Japanese ancestry. The majority of the patients had unilateral nAMD (HAWK 75.0%; HARRIER 70.8%) with occult CNV lesions (HAWK 57.7%; HARRIER 50.3%) at baseline.
Approximately 25%–31% of patients in each study arm had nAMD in both eyes. According to the HAWK and HARRIER study protocols, patients could received another anti-VEGF drug for the non-study eye. Therefore, the authoring team asked the MAH to provide information about this subgroup in the scoping document request. The MAH did not provide the requested information.
4.5 Outcomes included
The following outcomes were included in both pivotal RCTs (HAWK and HARRIER):
Change in BCVA baseline to week 48 and week 96; Proportion of patients maintaining Q12W dosing in the brolucizumab arms through to week 48; Treatment frequency (number of IVT injections in each treatment arm); Anatomic parameters of disease activity; Visual function–related QoL, assessed using NEI VFQ-25; Safety and tolerability of brolucizumab relative to aflibercept.
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In relation to the scope of the assessment (Table 2.1), data were available for all outcomes except HRQoL and grade ≥3 AEs.
4.6 Risk of bias
Table 4.7 and Table 4.8 describe the RoB in HAWK and HARRIER at the study level and for the relevant outcomes. At the study level, RoB was low in both HAWK and HARRIER. At the outcome level, RoB was low for most of the outcomes. There was some uncertainty related to three outcomes in both studies: visual function–related QoL, AEs due to treatment and rates of discontinuation. Explanations for these uncertainties are given in the footnotes to Table 4.8.
Table 4.7. Risk of bias in the randomised HAWK and HARRIER studies
Study
a b
study study
at
Random sequence sequence Random generation bias) (selection Allocation concealment bias) (selection of Blinding and participants personnel bias) (performance outcome of Blinding assessment bias) (detection outcome of Blinding assessment bias) (detection outcome Incomplete addressed data bias) (attrition reporting Selective bias) (reporting potential Other bias of sources bias Risk of level HAWK L L L L L L L L L HARRIER L L L L L L L L L aFor self-reported outcomes including pain, function and global assessment bFor assessor-reported outcomes. Abbreviations: H=high risk; L=low risk; U=unclear risk.
Table 4.8. Risk of bias by outcome in the HAWK and HARRIER studies
Trial
-
me level me
Blinding of of Blinding outcome assessment bias) (detection ITT principle appropriately implemented Selective outcome reporting unlikely potential Other bias of sources level) (outcome bias Risk of outco Change in BCVA baseline to week 48 and week 96 HAWK L L L L L HARRIER L L L L L Proportion of patients maintaining Q12W dosing in the brolucizumab arms through to week 48 HAWK L L L L L HARRIER L L L L L Anatomic parameters of disease activitya HAWK L L L L L HARRIER L L L L L Visual function–related QoL assessed using NEI VFQ-25 HAWK L Ud L L L/Ud HARRIER L Ud L L L/Ud Health-related QoL* HAWK - - - - - HARRIER - - - - - Safety: AEs due to treatmentb HAWK L L L Ue L / Ue HARRIER L L L Ue L / Ue Safety: rates of discontinuationc HAWK L L L Uf L / Uf HARRIER L L L Uf L / Uf
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*Data not available. aThis includes the following parameters: central subfield thickness, choroidal neovascularisation area, subretinal fluid, intraretinal fluid/intraretinal cyst, subretinal pigment epithelium fluid and neurosensory retinal thickness. Risk of bias was similar for all of these parameters and therefore they are reported as one group: “anatomic parameters of disease activity”. bThis includes the following outcomes: any AEs, serious AEs, grade ≥3 AEs, death as serious AE and AE of special interest (e.g., ocular/non-ocular AEs). cThis includes the following outcomes: rates of discontinuation for any reason, rates of discontinuation due to AEs and percentage of patients who discontinued the treatment by reason for discontinuation. dIt was unclear whether ITT principle was appropriately implemented. It was unclear how the missing values for the outcome were dealt with in the analysis. eIt was unclear whether there were some other potential sources of bias. AEs were not reported by grade categories (e.g., grade ≥3 AEs). This could be a minor shortcoming but the authoring team was unable to determine whether this was important or not. fIt was unclear whether there were some other potential sources of bias. Rates of discontinuation for any reason were not reported clearly, especially for discontinuations between weeks 48 and 96. In addition, the percentages of patients who discontinued the treatment by reason for discontinuation were not reported clearly. Abbreviations: H=high risk; L=low risk; U=unclear risk; AE=adverse event; BCVA=best corrected visual acuity; ITT=intention to treat; NEI VFQ-25=National Eye Institute Visual Function Questionnaire-25; Q12W=every 12 weeks; QoL=quality of life.
4.7 External validity
The external validity and evidence gaps for the HAWK and HARRIER studies were assessed in relation to the population, intervention, comparators and outcomes of this joint REA (Table 2.1).
Population In both HAWK and HARRIER, the study eye for each patient had to be treatment-naïve for any anti- VEGF agents. In clinical practice some patients do not experience a treatment response or their treatment response declines in the long run. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. The therapeutic indication for brolucizumab has no limitations in terms of prior anti-VEGF treatments. This means that brolucizumab can also be used as second- or third-line treatment even without clinical evidence.
Intervention The first three loading doses of brolucizumab are given every 4 weeks. During maintenance treatment the dosing interval is based on disease activity and injections are given every 12 or every 8 weeks. At the start of the loading treatment it is not possible to know which patients will be able to remain on Q12W dosing. There is a need to recognise baseline patient characteristics predicting Q8W treatment need. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who will be able to remain on Q12W dosing.
In the HAWK and HARRIER trials the treatment duration and follow-up time were only up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years. Because the data are limited to 2 years, the average duration of response to brolucizumab treatment is not known. From other anti-VEGF treatments we know that in some patients the treatment effect declines in the long run.
Comparators Aflibercept was the only comparator in the HAWK and HARRIER trials. The MAH provided an NMA that included ranibizumab as a comparator. In many European countries bevacizumab is one of the primary treatment options for nAMD. However, brolucizumab has not been compared with bevacizumab either directly or indirectly.
In clinical practice different anti-VEGF dosing schemes are often used, such as PRN and TREX. In the HAWK and HARRIER trials aflibercept was given as a fixed dose every 8 weeks, whereas the dosing frequency for brolucizumab was based on disease activity during the maintenance phase. According to the MAH, brolucizumab is expected to have long-lasting efficacy and a lower frequency of injections compared to other currently available anti-VEGF treatments. However, the trial design does not allow any conclusions to be drawn regarding the treatment burden (injection frequency) between brolucizumab and aflibercept.
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Outcomes Outcomes from the HAWK and HARRIER trials are reasonable. Regarding patient-reported outcomes, vision-related QoL is included (measured by NEI VFQ-25 tool). The only outcome that is missing in relation to the PICO for this assessment (Table 2.1) is HRQoL measured using a generic tool.
4.8 Direct evidence: results for clinical efficacy and safety
Only the 6 mg dose of brolucizumab was submitted for a marketing authorisation and received approval, so the intervention of interest in this REA is brolucizumab 6 mg. Therefore, study results for brolucizumab 3 mg are only presented in brief as supportive evidence in Section 4.9. The comparators of interest defined in PICO were aflibercept, ranibizumab and bevacizumab. The submission included two applicable studies for direct comparisons, HARRIER and HAWK. The OSPREY study has supportive evidence and is presented in Section 4.10. Thus, this section only presents direct comparisons between brolucizumab 6 mg and aflibercept 2 mg from the HAWK and HARRIER studies. The primary objective in HAWK and HARRIER was to demonstrate that the efficacy of brolucizumab 6 mg is not inferior to aflibercept 2 mg, one of the medications used for nAMD treatment.
This section presents results from the HAWK and HARRIER studies separately. The authoring team asked the MAH to provide pooled results for the HAWK and HARRIER studies. In response, the MAH stated that pooled results are not available. However, as part of the NMA, the MAH provided some pooled results for key outcomes. These included only mean differences for fixed- and random-effects models, which are presented in Appendix 8: Pooled results of HAWK and HARRIER studies.
The number of patients analysed is presented in Table 4.9. The full analysis (FAS) set includes all patients randomised to treatment who received at least one dose of the assigned treatment. The ITT population consists of all randomised subjects who received at least one dose of the study drug and underwent at least one follow-up visit, regardless of the dose actually received or the visits completed. The per-protocol (PP) population consists of all ITT subjects without any significant violation of the protocol, such as missing a critical number of planned treatments. More information on protocol deviations is available in Appendix 11: Protocol deviations in HAWK and HARRIER studies.
Table 4.9. Subject disposition in the HAWK and HARRIER studies HAWK study HARRIER study Brolucizumab 6 Aflibercept 2 Brolucizumab 6 Aflibercept 2 mg mg mg mg Number randomised 361 361 372 371 Full analysis set 360 (99.7%) 360 (99.7%) 370 (99.5%) 369 (99.5%) Per protocol set 328 (90.9%) 312 (86.4%) 351 (94.4%) 341 (91.9%) Completed week 48 333 (92.2%) 327 (90.6%) 354 (95.2%) 352 (94.9%) Completed week 96 304 (84.2%) 297 (82.3%) 342 (91.9%) 329 (88.7%) Subjects with at least 46 (12.7%) 52 (14.4%) 43 (11.6%) 43 (11.6%) one protocol deviation Source: European Medicines Agency public assessment report (27).
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4.8.1 Primary endpoint: change in BCVA from baseline to week 48 According to the primary analysis, HAWK and HARRIER demonstrated in both the FAS and PPS the noninferiority of brolucizumab 6 mg in comparison to aflibercept 2 mg. To demonstrate noninferiority, the lower bound of the 95% CI had to be greater than 4 letters in this outcome. Analyses in the FAS and PPS were consistent.
In the HAWK study, the LS mean change in BCVA from baseline to week 48 was 6.6 letters (95% CI 5.2–8.0) for brolucizumab 6 mg and 6.8 letters (95% CI 5.4–8.2) for aflibercept 2 mg for the FAS population. Pairwise ANOVA demonstrated the noninferiority (4-letter margin) of brolucizumab 6 mg compared to aflibercept 2 mg, with an LSMD of 0.2 (95% CI 2.1 to 1.8; p<0.0001). Results for the PPS population are presented in Table 4.10.
In the HARRIER study, the LS mean change in BCVA from baseline to week 48 was 6.9 letters (95% CI 5.7–8.1) for brolucizumab 6 mg and 7.6 letters (95% CI 6.4–8.8) for aflibercept 2 mg in the FAS population. Pairwise ANOVA demonstrated the noninferiority (4-letter margin) of brolucizumab 6 mg compared to aflibercept 2 mg, with an LSMD of 0.7 (95% CI 2.4 to 1.0; p=0.0001). Results for the PPS population are presented in Table 4.10.
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Table 4.10. Change in BCVA from baseline to week 48: summary statistics and ANOVA (FAS-LOCF, PPS-LOCF) HAWK trial HARRIER trial FAS population Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg (n=360) 2 mg (n=360) 6 mg (n=370) 2 mg (n=369) Change in BCVA from baseline to week 48 Mean (SD) 6.4 (14.40) 7.0 (13.16) 6.9 (11.47) 7.6 (12.47) Median (range) 7.5 (69, 52) 8.0 (57, 54) 8.0 (57, 38) 8.0 (37, 50) 95% CI for mean 4.9, 7.9 5.6, 8.3 5.8, 8.1 6.3, 8.9 Pairwise ANOVA (brolucizumab 6 mg vs. aflibercept 2 mg) LSM (SE) 6.6 (0.71) 6.8 (0.71) 6.9 (0.61) 7.6 (0.61) 95% CI for LSM 5.2, 8.0 5.4, 8.2 5.7, 8.1 6.4, 8.8 LSMD (SE) 0.2 (1.00) 0.7 (0.86) 95% CI for LSMD 2.1, 1.8 2.4, 1.0 p-value for treatment difference (2-sided) 0.8695 0.4199 p-value for noninferiority (4-letter margin; 1-sided) <0.0001 0.0001 PPS population Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg (n=328) 2 mg (n=312) 6 mg (n=351) 2 mg (n=341) Change in BCVA from baseline to week 48 Mean (SD) 6.6 (14.68) 7.4 (12.71) 7.0 (11.24) 7.8 (12.49) Median (range) 8.0 (69, 52) 8.0 (57, 51) 8.0 (57, 38) 8.0 (35, 50) 95% CI for mean 5.0, 8.2 6.0, 8.8 5.8, 8.2 6.5, 9.1 Pairwise ANOVA (brolucizumab 6 mg vs. aflibercept 2 mg) LSM (SE) 6.9 (0.74) 7.1 (0.76) 7.0 (0.62) 7.8 (0.63) 95% CI for LSM 5.4, 8.3 5.7, 8.6 5.8, 8.2 6.6, 9.0 LSMD (SE) 0.3 (1.06) 0.8 (0.88) 95% CI 2.4, 1.8 2.5, 1.0 p-value for treatment difference (2-sided) 0.7844 0.3771 p-value for noninferiority (4-letter margin; 1-sided) 0.0003 0.0001 Source: HAWK clinical study report, HARRIER clinical study report, Dugel et al. 2020 (28). Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; LSMD=least squares mean difference; PPS=per protocol set; SD=standard deviation; SE=standard error.
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4.8.2 Secondary endpoints Change in BCVA from baseline to week 96 Results for the change in BCVA from baseline to week 96, did not show difference between brolucizumab and aflibercept (Figure 4.5). The difference in mean change was 0.5 (95% CI 1.6 to 2.7) in the HAWK study and 0.4 (95% CI 2.5 to 1.6) in HARRIER.
Figure 4.5. LSM change in BCVA from baseline to week 96 (FAS-LOCF). Source: Submission dossier. Abbreviations: BCVA=best corrected visual acuity; ETDRS= Early Treatment Diabetic Retinopathy Study; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SE=standard error.
Selected secondary endpoints related to BCVA Selected secondary endpoints are presented in Table 4.11. A loss or gain of three lines (15 letters) is commonly used as an outcome in clinical trials in nAMD. The MAH was asked to present these outcomes as individual measures, but data for the outcome of a gain of at least 15 letters from baseline at week 48/week 96 were not available separately.
Table 4.11. Selected secondary endpoints related to BCVA (LS mean estimates; proportion of patients) at and up to week 48 and week 96 (FAS-LOCF) Trial HAWK HARRIER Secondary Brolucizumab Aflibercept LSMD Brolucizumab Aflibercept LSMD (95% BCVA 6 mg 2 mg (95% CI) 6 mg 2 mg CI) endpoint p-value p-value Analysis at week 48a ≥15 letters 33.6 25.4 8.2 29.3 29.9 0.6 gained from (2.2,15.0), (7.1,5.8), baseline/ p=0.0136 p=0.8600 BCVA of ≥84 letters at week 48 ≥15 letters 6.4 5.5 0.9 3.8 4.8 1.0 lost from (2.7,4.3), (3.9, 2.2), baseline at p=0.6198 p=0.5079 week 48 BCVA of ≥73 49.5 51.9 2.4 50.7 50.3 0.4 letters at (8.6, 3.6), (5.4,6.1), week 48 p=0.4442 p=0.8922
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Trial HAWK HARRIER Secondary Brolucizumab Aflibercept LSMD Brolucizumab Aflibercept LSMD (95% BCVA 6 mg 2 mg (95% CI) 6 mg 2 mg CI) endpoint p-value p-value Analysis at week 96a ≥15 letters 34.2 27.0 7.2 29.1 31.5 2.4 gained from (1.4,13.8), (8.8, 4.1), baseline/ p=0.0313 p=0.4765 BCVA of ≥84 letters at week 96 ≥15 letters 8.1 7.4 0.7 7.1 7.5 0.4 lost from (3.6,4.6), (3.8, 3.3), baseline at p=0.7210 p=0.8377 week 96 BCVA of ≥73 48.6 46.3 2.3 47.6 49.6 2.0 letters at (3.8,9.0), (8.1 to 4.1), week 96 p=0.4820 p=0.5295 Source: HAWK clinical study report, HARRIER clinical study report, Khanani et al. [52]. aAnalysis of variance (for continuous variables) and logistic regression (for categorical variables) models with baseline BCVA categories (55, 56–70, 71 letters), age categories (<75, 75 years) and treatment as fixed-effect factors were used. Abbreviations: BCVA=best-corrected visual acuity; CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; LSMD=least squares mean difference.
Additional secondary endpoints: anatomic outcomes CSFTns CSFTns was defined as the retina thickness measured from the apical outer segment tip to the inner limiting membrane (HARRIER CSR). The mean change in CSFTns from baseline to week 48 did not differ between brolucizumab 6 mg and aflibercept 2 mg (Table 4.12). Overall, the reduction in CSFTns observed at the end of the first year of treatment was maintained through to week 96 (Figure 4.6 and Figure 4.7) in both studies and for both treatments.
Table 4.12. Change in CSFTns (μm) from baseline to week 48 for the study eye in HAWK and HARRIER (FAS-LOCF) Trial HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept FAS populationa 6 mg (n=360) 2 mg (n=360) 6 mg (n=370) 2 mg (n=369) Mean change (SD) 66.6 (98.72) 64.5 (92.74) 56.2 (100.12) 42.9 (92.89) SE 5.20 4.89 5.20 4.84 Median change (range) 38.0 (681 to 33.5 (485 to 16.0 (434 to -21.5 (-552, 99) 159) 91) 344) 95% CI for mean (76.8 to 56.3) (74.1 to 54.9) (-66.4, -46.0) (52.4 to 33.3) Pairwise ANOVA (brolucizumab 6 mg vs. aflibercept 2 mg) LSM (SE) 65.8 (4.18) 65.3 (4.18) 53.0 (3.79) 46.0 (3.79) 95% CI for LSM (74.0 to 57.6) (73.5 to 57.1) (60.4 to 45.6) (53.5 to 38.6) LSM difference (SE) 0.5 (5.92) - 7.0 (5.36) - 95% CI for treatment (12.1 to 11.1) - (17.5 to 3.6) - difference p-value for treatment 0.9318 - 0.1945 - difference (2-sided) Source: HAWK clinical study report, HARRIER clinical study report. an is the number of subjects with data used in the model. The 95% CIs for the mean are based on a t-distribution. Analysed using an ANOVA model with baseline CSFTns categories (<250, ≥250 μm), age categories (<75, ≥75 years) and treatment as fixed-effect factors. CSFT assessments after the start of an alternative anti–vascular endothelial growth factor treatment in the study eye are censored and imputed using the last value before initiation of this alternative treatment. Abbreviations: ANOVA=analysis of variance; CI=confidence interval; CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SD=standard deviation; SE=standard error.
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Figure 4.6. LSM change in CSFTns (μm) from baseline by visit in HAWK (FAS-LOCF). LSM (±SE) estimates are based on an ANOVA model with baseline CSFTns categories (<250, ≥250 μm) age categories (<75, ≥75 years) and treatment as fixed-effect factors. Source: HAWK clinical study report. Abbreviations: CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.
Figure 4.7. LSM change in CSFTns (μm) from baseline by visit in HARRIER (FAS-LOCF). LSM (±SE) estimates are based on an ANOVA model with baseline CSFT-neurosensory retina categories (<250, ≥250 μm) age categories (<75, ≥75 years) and treatment as fixed effect factors. Source: HARRIER clinical study report. Abbreviations: CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.
CSFTtot In addition to CSFTns, CSFTtot was reported. At week 96, absolute changes in CSFTtot from baseline were 175 µm for brolucizumab 6 mg versus 149 µm for aflibercept 2 mg in HAWK, and 198 µm versus 155 µm in HARRIER, respectively. Absolute differences at the end of week 96 were 26 µm in HAWK and 43 µm in HARRIER. CSFTtot showed statistically significant difference between the groups at weeks 16, 48 and 96 (Table 4.13 and Figure 4.8).
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Table 4.13. LSMD in CSFTtot (μm) from baseline to weeks 48 and 96 for the study eye in HAWK and HARRIER (FAS-LOCF) Trial name HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept FAS population 6 mg (n=360) 2 mg (n=360) 6 mg (n=370) 2 mg (n=369) Week 48 LSM 172.8 143.7 193.8 143.9 LSM difference (95% CI) -29.0 (-47.6,-10.4)) 49.9 (68.9 to 30.9) p-value for treatment difference (2- 0.0023 <0.001 sided) week 96 LS Mean 174.8 148.7 197.7 155.1 LSM difference (95%CI) 26.0 (46.2 to 5.9) 42.6 (62.0 to 23.3) p-value for treatment difference (2- Not reported <0.0001 sided) Source: HAWK and HARRIER clinical study reports. aANOVA models with baseline CSFTns categories ( <400, ≥400 µm), age categories (<75, ≥75 years) and treatment as fixed-effect factors were used. CSFT assessments after the start of an alternative anti–vascular epithelial growth factor treatment in the study eye were censored and imputed using the last value before initiation of this alternative treatment. Abbreviations: ANOVA=analysis of variance; CI=confidence interval; CSFTns=central subfield thickness of the neurosensory retina; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.
Figure 4.8. LSM change in CSFTtot (µm) from baseline by visit through to week 96 (FAS-LOCF). The p-values are one-sided for HARRIER; two-sided p-values at week 96. The p-values are descriptive. Source: Submission dossier. Abbreviations: CSFTtot=total central subfield thickness; FAS=full analysis set; LOCF=last observation carried forward; LSM=least mean squares; SE=standard error.
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Proportion of patients with IRF The proportions of patients with IRF are presented in Figure 4.9 and Figure 4.10 and in Table 4.14. There was no difference in the proportion of subjects with IRF at week 16 and week 48 in either study.
Figure 4.9. Percentage of subjects with IRF by visit up to week 96 in HARRIER (FAS-LOCF). Source: HARRIER clinical study report. Abbreviations: FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward.
Figure 4.10. Percentage of subjects with IRF visit to week 96 in HAWK (FAS-LOCF). Source: HAWK clinical study report. Abbreviations: FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward
Table 4.14. Proportion of subjects with IRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression Trial name HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept
6 mg 2 mg 6 mg 2 mg Proportion with IRF at week 16 20.3 24.7 12.4 12.3 Difference (95% CI) 4.3 (10.0 to 1.9) 0.1 (4.5 to 4.4) p-value for treatment difference (2-sided) 0.1430 0.9670 Proportion with IRF at week 48 21,4 22.2 10.8 12.8 Difference (95% CI) 0.8 (6.4 to 5.5) 2.0 (6.2 to 2.2) p-value for treatment difference (2-sided) 0.7791 0.3820 Source: HAWK clinical study report, HARRIER clinical study report. Abbreviations: CI=confidence interval; FAS=full analysis set; IRF=intraretinal fluid; LOCF=last observation carried forward.
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Proportion of patients with SRF Figure 4.11 and Figure 4.12 show the proportion of patients with SRF from baseline to week 96. The proportions were higher in the aflibercept groups and the difference was statistically significant (Table 4.15).
Figure 4.11. Percentage of subjects with SRF by visit up to week 96 in HARRIER (FAS-LOCF). Source: HARRIER clinical study report. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.
Figure 4.12. Percentage of subjects with SRF by visit up to week 96 in HAWK (FAS-LOCF). Source: HAWK clinical study report. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.
Table 4.15. Proportion of subjects with SRF at week 16 and week 48 in HAWK and HARRIER (FAS-LOCF) according to logistic regression. Trial name HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept
6 mg 2 mg 6 mg 2 mg Proportion with SRF at week 16 17.0 36.6 21.2 35.4 Difference (95% CI) 19.7 (25.8 to 13.4) 14.2 (20.8 to 8.3) p-value for treatment difference (2-sided) <0.0001 <0.0001 Proportion with SRF at week 48 14.4 30.0 17.7 33.6 Difference (95% CI) 15.6 (21.2 to 9.7) 15.9 (22.4 to 10.4) p-value for treatment difference (2-sided) <0.0001 <0.0001 Source: HAWK clinical study report, HARRIER clinical study report. Abbreviations: CI=confidence interval; FAS=full analysis set; LOCF=last observation carried forward; SRF=subretinal fluid.
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Proportion of patients with sub-RPE fluid The proportion of participants with sub-RPE fluid at weeks 16, 48 and 96 is reported in Figure 4.13. These proportions were lower in the brolucizumab 6 mg group, and the difference was statistically significant for weeks 16 and 48 in HAWK and for weeks 16, 48 and 96 in HARRIER.
Figure 4.13. Proportion of patients with sub-RPE fluid at weeks 16, 48 and 96 in HAWK and HARRIER (FAS-LOCF). Source: Submission dossier. Abbreviations: FAS=full analysis set; LOCF=last observation carried forward; RPE=retinal pigment epithelium; SRF=subretinal fluid.
Change in CNV The mean change in CNV lesion size from baseline to week 48 was 4.0 mm2 versus 3.5 mm2 in HAWK, and 2.3 mm2 versus 2.5 mm2 in HARRIER. This difference between the brolucizumab 6 mg and aflibercept 2 mg arms had a p-value of 0.0344 for HAWK and 0.1207 for HARRIER. From baseline to week 96, the mean change in CNV lesion size was 4.1 mm2 versus 3.5 mm2 in HAWK, and 2.5 mm2 versus 2.7 mm2 in HARRIER. This difference between the brolucizumab 6 mg and aflibercept 2 mg arms had a p-value of 0.0022 in HAWK and 0.0366 in HARRIER.
Other additional secondary endpoints Proportion of patients maintained on Q12W dosing through week 48 The proportion of subjects maintained on the Q12W regimen up to the DAA at week 44 in the brolucizumab 6 mg arm was 55.6% (95% CI 50.1%–60.7%) in HAWK and 51.0% (95% CI 45.6%– 56.1%) in HARRIER (Figure 4.14 and Figure 4.15). Thus, only approximately half of the patients could remain on the Q12W regimen through the first year.
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Figure 4.14. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HAWK (FAS efficacy/safety approach). Source: HAWK clinical study report. Abbreviations: FAS=full analysis set; QxW=every x weeks.
Figure 4.15. Kaplan-Meier plot of time to first Q8W treatment needed for the brolucizumab group in HARRIER (FAS efficacy/safety approach). Source: HARRIER clinical study report. Abbreviations: FAS=full analysis set; QxW=every x weeks.
Treatment frequency (number of IVT injections) Over 96 weeks, the mean number of injections was 10.2 for brolucizumab versus 11.3 for aflibercept in HAWK, and 10.9 versus 12.1 in HARRIER, respectively. The difference in the mean number of active injections administered in the brolucizumab and aflibercept treatment arms of HAWK and HARRIER was 1.1 and 1.2, respectively.
Descriptive statistics for the number of active injections administered overall from baseline to week 96 are presented in Table 4.16. In HAWK, the majority of the brolucizumab 6 mg group (39.2%) received ten active injections and the majority of the aflibercept 2 mg group (67.5%) received 13 active injections during the study. In HARRIER, in the brolucizumab 6 mg arm approximately one-third of the subjects (34.1%) received 13 injections and one-third (34.3%) received ten active injections; the majority of the aflibercept 2 mg group (78.6%) received 13 active injections during the study. However, patients in the aflibercept group were not permitted to extend the interval between injections from fixed Q8W to Q12W.
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The differences in the number of active injections between the brolucizumab 6 mg and aflibercept 2 mg arms might be driven by differences in the dosing intervals (protocol difference).
Table 4.16. Number of injections from baseline to week 96 (SAF) Trial name HAWK HARRIER Brolucizumab 6 mg Aflibercept 2 mg Brolucizumab 6 mg Aflibercept 2 mg (N=360) (N=360) (N=370) (N=369) Mean (SD) 10.2 (2.74) 11.3 (3.21) 10.9 (2.38) 12.1 (2.32) Median 10.0 13.0 11.0 13.0 Range 1–13 1–13 1–13 1–14 Source: Submission dossier. Abbreviations: SAF=safety analysis set (including all patients who received at least 1 intravitreal injection); SD=standard deviation.
Patient-reported outcomes In the PICO, HRQoL was defined as a patient-relevant outcome in conjunction with vision-related QoL. Data on HRQoL were requested from MAH, but the response stated that HRQoL data measured using a generic tool were not available. Only vision-related QoL data using the NEI VFQ-25 instrument were presented. The mean changes in score are presented in Table 4.17. Separate presentations for the number of patients and vision-related QoL results for patients who received treatment for the first- affected eye and second-affected eye were requested, but the MAH did not provide these separately.
VFQ-25 is a patient-reported instrument widely used to measure vision-related QoL in nAMD. A positive change in VFQ-25 score indicates a benefit. Both HAWK and HARRIER showed a similar change in VFQ-25 score from baseline for both brolucizumab 6 mg and aflibercept 2 mg.
Table 4.17. Mean change in VFQ-25 composite scores from baseline in HAWK and HARRIER studies (FAS-observed) Trial HAWK HARRIER name Time Brolucizumab 6 mg Aflibercept 2 mg Brolucizumab 6 mg Aflibercept 2 mg point Week 24 4.0 (n=341) 3.5 (n=333) 3.9 (n=354) 3.5 (n=355) Week 48 4.1 (n=324) 4.5 (n=317) 4.8 (n=347) 3.6 (n=346) Week 72 3.9 (n=303) 4.0 (n=298) 5.0 (n=342) 3.2 (n=334) Week 96 3.8 (n=301) 2.8 (n=296) 3.8 (n=338) 2.6 (n=329) Source: Submission dossier. Abbreviations: FAS=full analysis set; VFQ-25=visual Function Questionnaire-25
4.8.3 Safety outcomes Safety outcomes of interest are listed in Table 2.1. Data were available for all of those outcomes except grade ≥3 AEs. Statistical comparisons between study arms were not available for any of the safety outcomes.
Frequencies of ocular AEs and serious ocular AEs in the study eye are presented in Table 4.18 and 4.19. At week 96, the number of patients with at least one AE in the study eye was similar across treatment arms and higher in HAWK (brolucizumab 6 mg: 220 [61.1%]; aflibercept 2 mg: 201 [55.8%]) than in HARRIER (brolucizumab 6 mg: 174 [47.0%]; aflibercept 2 mg: 176 [47.7%]; Table 4.18). Conjunctival haemorrhage and reduced VA were the most frequent ocular AEs across all treatment arms in both studies. These AEs are known effects of anti-VEGF drugs administered via the IVT route. The majority of ocular AEs were of mild or moderate severity in HAWK (96.1%) and HARRIER (94.9%).
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Table 4.18. Ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF) Event Patients experiencing an event, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Patients with at least one event 220 (61.1) 201 (55.8) 174 (47.0) 176 (47.7) Conjunctival haemorrhage 29 (8.1) 32 (8.9) 17 (4.6) 19 (5.1) VA reduced 22 (6.1) 29 (8.1) 32 (8.6) 26 (7.0) Vitreous floaters 22 (6.1) 16 (4.4) 15 (4.1) 5 (1.4) Retinal haemorrhage 21 (5.8) 20 (5.6) 12 (3.2) 4 (1.1) Cataract 20 (5.6) 13 (3.6) 11 (3.0) 43 (11.7) Vitreous detachment 19 (5.3) 19 (5.3) 10 (2.7) 8 (2.2) Dry eye 19 (5.3) 26 (7.2) 10 (2.7) 11 (3.0) Eye pain 18 (5.0) 21 (5.8) 13 (3.5) 19 (5.1) Posterior capsule opacification 14 (3.9) 11 (3.1) – – Intraocular pressure increased 13 (3.6) 15 (4.2) 14 (3.8) 15 (4.1) Blepharitis 13 (3.6) 12 (3.3) 13 (3.5) 5 (1.4) Retinal pigment epithelial tear 12 (3.3) 4 (1.1) 8 (2.2) 5 (1.4) Vision blurred 11 (3.1) 10 (2.8) – – Visual impairment 10 (2.8) 14 (3.9) – – Eye irritation 10 (2.8) 11 (3.1) – – Punctate keratitis 9 (2.5) 10 (2.8) – – Conjunctivitis 9 (2.5) 3 (0.8) 15 (4.1) 8 (2.2) Iritis 9 (2.5) 1 (0.3) 0 (0.0) 1 (0.3) Uveitis 8 (2.2) 1 (0.3) 3 (0.8) 0 (0.0) Visual field defect 7 (1.9) 5 (1.4) – – Corneal abrasion 7 (1.9) 10 (2.8) – – Macular fibrosis 5 (1.4) 4 (1.1) – – Dry AMD 5 (1.4) 3 (0.8) – – Foreign body sensation in eyes 4 (1.1) 9 (2.5) – – Lacrimation increased 4 (1.1) 5 (1.4) – – Lenticular opacities 1 (0.3) 4 (1.1) 13 (3.5) 12 (3.3) Source: Submission dossier. Abbreviations: AMD=age-related macular degeneration; SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).
Serious ocular AEs were rare. The number of patients with at least one serious ocular AEs was twelve (3.3%) in the brolucizumab 6 mg and five (1.4%) in the aflibercept 2 mg group in HAWK; the corresponding rates in HARRIER study were 13 (3.5%) and six (1.6%). Intraocular inflammation (endophthalmitis, uveitis, vitritis and anterior chamber inflammation) was more frequent in the brolucizumab 6 mg groups (6 [1.7%] in HAWK and 5 [1.4%] in HARRIER) than in the aflibercept 2 mg groups (0 [0%] and 1 [0.3%], respectively). Retinal arterial occlusive events (retinal artery thrombosis, retinal artery occlusion, retinal artery embolism) were more frequent in brolucizumab 6 mg (1 [0.3%] in HAWK and 3 [0.9%] in HARRIER) than in aflibercept 2 mg groups (0 [0%] in HAWK and 1 [0.3%] in HARRIER).
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Table 4.19. Serious ocular adverse events up to week 96 for the study eye (SAF) Event Patients experiencing an event, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Patients with at least one event 12 (3.3) 5 (1.4) 13 (3.5) 6 (1.6) Endophthalmitis 3 (0.8) 0 (0.0) 1 (0.3) 1 (0.3) Uveitis 2 (0.6) 0 (0.0) 3 (0.8) 0 (0.0) Retinal detachment 1 (0.3) 1 (0.3) 1 (0.3) 1 (0.3) VA reduced 1 (0.3) 2 (0.6) 1 (0.3) 1 (0.3) Macular hole 1 (0.3) 1 (0.3) – – Cataract 1 (0.3) 0 (0.0) – – Retinal artery thrombosis 1 (0.3) 0 (0.0) 1 (0.3) 0 (0.0) Retinal depigmentation 1 (0.3) 0 (0.0) – – Retinopathy proliferative 1 (0.3) 0 (0.0) – – Vitritis 1 (0.3) 0 (0.0) – – Retinal artery occlusion 0 (0.0) 0 (0.0) 1 (0.3) 1 (0.3) Glaucoma 0 (0.0) 0 (0.0) – – Cataract subscapular 0 (0.0) 1 (0.3) – – Retinal tear – – 2 (0.5) 1 (0.3) Retinal pigment epithelial tear – – 2 (0.5) 0 (0.0) Anterior chamber inflammation – – 1 (0.3) 0 (0.0) Blindness – – 1 (0.3) 0 (0.0) Cataract traumatic – – 1 (0.3) 0 (0.0) Dacryocystitis – – 1 (0.3) 0 (0.0) Retinal artery embolism – – 1 (0.3) 0 (0.0) Dry AMD – – 0 (0.0) 1 (0.3) Source: Submission dossier. Abbreviations: AMD=age-related macular degeneration; SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).
Table 4.20. Non-ocular adverse events up to week 96 (≥2% in any treatment group) for the study eye (SAF) Event Patients experiencing an event, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Patients with at least one event 289 (80.3) 303 (84.2) 282 (76.2) 272 (73.7) Nasopharyngitis 38 (10.6) 44 (12.2) 43 (11.6) 31 (8.4) Pneumonia 32(8.9) 20 (5.6) 7 (1.9) 13 (3.5) Urinary tract infection 27 (7.5) 41 (11.4) 16 (4.3) 19 (5.1) Hypertension 25 (6.9) 24 (6.7) 28 (7.6) 25 (6.8) Upper respiratory tract infection 18 (5.0) 16 (4.4) 6 (1.6) 14 (3.8) Influenza 17 (4.7) 20 (5.6) 24 (6.5) 27 (7.3) Arthralgia 15 (4.2) 21 (5.8) 14 (3.8) 13 (3.5) Pain in extremity 15 (4.2) 10 (2.8) 9 (2.4) 4 (1.1) Back pain 14 (3.9) 17 (4.7) 16 (4.3) 28 (7.6) Diarrhoea 14 (3.9) 13 (3.6) 10 (2.7) 6 (1.6) Cough 13 (3.6) 17 (4.7) 12 (3.2) 8 (2.2) Bronchitis 13 (3.6) 22 (6.1) 23 (6.2) 21 (5.7)
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Event Patients experiencing an event, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Constipation 13 (3.6) 13 (3.6) – – Nausea 12 (3.3) 12 (3.3) – – Headache 12 (3.3) 13 (3.6) 12 (3.2) 8 (2.2) Contusion 12 (3.3) 12 (3.3) – – Chronic obstructive pulmonary 12 (3.3) 12 (3.3) – – disease Arthritis 12 (3.3) 13 (3.6) – – Sinusitis 11 (3.1) 14 (3.9) – – Fall 10 (2.8) 7 (1.9) – – Musculoskeletal pain 10 (2.8) 4 (1.1) – – Seasonal allergy 10 (2.8) 9 (2.5) – – Osteoarthritis 9 (2.5) 11 (3.1) 19 (5.1) 7 (1.9) Blood pressure increased 9 (2.5) 9 (2.5) 2 (0.5) 11 (3.0) Cardiac failure congestive 9 (2.5) 6 (1.7) – – Atrial fibrillation 8 (2.2) 15 (4.2) 5 (1.4) 10 (2.7) Dizziness 8 (2.2) 6 (1.7) 5 (1.4) 9 (2.4) Gamma-glutamyltransferase 8 (2.2) 7 (1.9) – – increased Herpes zoster 8 (2.2) 8 (2.2) – – Dental caries 8 (2.2) 7 (1.9) – – Basal cell carcinoma 8 (2.2) 6 (1.7) – – Neck pain 8 (2.2) 3 (0.8) – – Anaemia 7 (1.9) 15 (4.2) 5 (1.4) 8 (2.2) Gastroesophageal reflux 7 (1.9) 3 (0.8) – – disease Oedema peripheral 7 (1.9) 8 (2.2) – – Dyspnoea 6 (1.7) 8 (2.2) – – Vomiting 6 (1.7) 5 (1.4) – – Anxiety 5 (1.4) 10 (2.8) – – Insomnia 5 (1.4) 10 (2.8) – – Laceration 5 (1.4) 6 (1.7) – – Cystitis 5 (1.4) 4 (1.1) 17 (4.6) 5 (1.4) Benign prostatic hyperplasia 5 (1.4) 5 (1.4) – – Depression 5 (1.4) 7 (1.9) – – Blood uric acid increased 4 (1.1) 4 (1.1) – – Dehydration 4 (1.1) 8 (2.2) – – Coronary artery disease 3 (0.8) 3 (0.8) – – Asthenia 3 (0.8) 2 (0.6) – – Blood urea increased 2 (0.6) 5 (1.4) – – Haematoma 2 (0.6) 4 (1.1) – – Muscle strain 1 (0.3) 10 (2.8) – – Hypercholesterolaemia – – 13 (3.5) 8 (2.2) Sciatica – – 9 (2.4) 8 (2.2) Pharyngitis – – 2 (0.5) 12 (3.3) Syncope – – 8 (2.2) 8 (2.2) Source: Submission dossier. Abbreviations: SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).
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Table 4.21. Serious non-ocular adverse events up to week 96 (≥3 patients in any treatment group) for the SAF Event Patients experiencing an event, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Patients with at least one event 85 (23.6) 110 (30.6) 69 (18.6) 85 (23.0) Pneumonia 10 (2.8) 9 (2.5) 2 (0.5) 8 (2.2) Cardiac failure congestive 6 (1.7) 4 (1.1) – – Chronic obstructive pulmonary 6 (1.7) 4 (1.1) 2 (0.5) 1 (0.3) disease Atrial fibrillation 4 (1.1) 2 (0.6) – – Cerebrovascular accident 4 (1.1) 3 (0.8) 0 (0.0) 4 (1.1) Sepsis 4 (1.1) 1 (0.3) – – Septic shock 3 (0.8) 0 (0.0) – – Urinary tract infection 2 (0.6) 2 (0.6) – – Hyponatraemia 2 (0.6) 1 (0.3) – – Syncope 2 (0.6) 3 (0.8) 3 (0.8) 2 (0.5) Myocardial infarction 2 (0.6) 3 (0.8) 2 (0.5) 0 (0.0) Femur fracture 2 (0.6) 4 (1.1) 2 (0.5) 0 (0.0) Coronary artery disease 1 (0.3) 3 (0.8) – – Cholelithiasis 1 (0.3) 2 (0.6) 2 (0.5) 0 (0.0) Transient ischaemic attack 1 (0.3) 2 (0.6) 1 (0.3) 2 (0.5) Noncardiac chest pain 1 (0.3) 3 (0.8) – – Subdural haematoma 1 (0.3) 3 (0.8) – – Influenza 0 (0.0) 1 (0.3) – – Intestinal obstruction 0 (0.0) 3 (0.8) – – Lower limb fracture – – 3 (0.8) 0 (0.0) Cardiac failure – – 2 (0.5) 2 (0.5) Ischaemic stroke – – 2 (0.5) 1 (0.3) Prostate cancer – – 2 (0.5) 1 (0.3) Rectal haemorrhage – – 2 (0.5) 1 (0.3) Benign prostatic hyperplasia – – 2 (0.5) 0 (0.0) Cholecystitis acute – – 2 (0.5) 0 (0.0) Gastroenteritis – – 2 (0.5) 0 (0.0) Inguinal hernia – – 2 (0.5) 0 (0.0) Joint dislocation – – 2 (0.5) 0 (0.0) Pulmonary oedema – – 2 (0.5) 0 (0.0) Bronchitis – – 1 (0.3) 2 (0.5) Femoral neck fracture – – 1 (0.3) 2 (0.5) Osteoarthritis – – 1 (0.3) 2 (0.5) Pulmonary embolism – – 1 (0.3) 2 (0.5) Death – – 0 (0.0) 3 (0.8) Arrhythmia – – 0 (0.0) 2 (0.5) Cerebrovascular disorder – – 0 (0.0) 2 (0.5) Fall – – 0 (0.0) 2 (0.5) Humerus fracture – – 0 (0.0) 2 (0.5) Source: Submission dossier. Abbreviations: SAF=safety analysis set (includes all subjects who received at least one injection of the study drug).
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Rates for study discontinuation due to death, SAEs or AEs are presented in Table 4.22. At week 96, 20 patients had died in HAWK (brolucizumab 6 mg: 8 patients [2.2%]; aflibercept 2 mg: 12 patients [3.3%]) and 11 in HARRIER (brolucizumab 6 mg: 4 patients [1.1%]; aflibercept 2 mg: 7 patients [1.9%]). Deaths were not suspected to be related to study treatment by the investigator in HAWK and HARRIER in brolucizumab 6 mg and aflibercept 2 mg arms. Discontinuations due to SAE were more frequently related to non-ocular SAE, while AEs leading to discontinuation were related to ocular AEs.
Table 4.22. Death, SAE or AE leading to permanent study treatment discontinuation up to week 96 (SAF) Event Patients with serious or significant AE, n (%) HAWK HARRIER Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Death 8 (2.2) 12 (3.3) 4 (1.1) 7 (1.9) SAEs 95 (26.4) 114 (31.7) 79 (21.4) 89 (24.1) Study eye 12 (3.3) 5 (1.4) 13 (3.5) 6 (1.6) Other eye 4 (1.1) 1 (0.3) 0 (0.0) 0 (0.0) Non-ocular 85 (23.6) 110 (30.6) 69 (18.6) 85 (23.0) AE leading to permanent study 16 (4.4) 22 (6.1) 20 (5.4) 9 (2.4) treatment discontinuation Study eye 11 (3.1) 12 (3.3) 13 (3.5) 6 (1.6) Other eye 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Non-ocular 5 (1.4) 10 (2.8) 8 (2.2) 3 (0.8) Source: Submission dossier. Abbreviations: AE=adverse event; SAE=serious AE; SAF=safety analysis set.
4.8.4 Subgroup analyses Change in BCVA from baseline to week 48 The results for subgroup analyses for the primary endpoint of change in BCVA from baseline to week 48 showed no difference between brolucizumab 6 mg and aflibercept 2 mg, irrespective of baseline disease characteristics or demographics (Figure 4.16). For the outcome of mean change in BCVA, the subgroups with poorer baseline VA (≤55 letters) showed a greater LSM change in BCVA (brolucizumab 6 mg 9.6 vs. aflibercept 2 mg 10.3) than those with better baseline VA (56–70 letters: 7.1 vs. 7.0; ≥71 letters: 2.4 vs. 2.4 respectively), but there was no difference between brolucizumab 6 mg and aflibercept 2 mg (Figure 4.16).
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Figure 4.16. Forest plot of summary statistics and ANOVA for change in BCVA from baseline to week 48 by subgroups of interest (FAS-LOCF) Source: Submission dossier. Abbreviations: ANOVA=analysis of variance; BCVA=best corrected visual acuity; CI=confidence interval; CNV=choroidal neovascularisation; CSFTtot=total central subfield thickness; FAS=full analysis set; LOCF=last observation carried forward; LSM=least squares mean; SRF=subretinal fluid.
Proportion of patients maintained on Q12W dosing until week 48 by baseline characteristics Subgroup analyses for Q12W treatment status at week 48 suggested that, irrespective of subgroup parameters, >40% of patients qualified for Q12W in all subgroups in the brolucizumab arms of both HAWK and HARRIER.
Baseline characteristics were not predictive for patients able to remain on a Q12W dosing interval until week 48. The most discriminative parameter in both trials influencing the potential to remain on the Q12W regimen was baseline CSFT status (Figure 4.17). Patients with CSFT <400 µm are potentially more likely to be able to remain on the Q12W dosing interval.
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Figure 4.17. Proportion of patients maintained on Q12W dosing interval until week 48 (FAS). Predefined subgroup analysis for the efficacy/safety population. The numbers are based on estimated percentages from Kaplan-Meier analysis. Source: Monés et al. 2018 (66). Abbreviations: BCVA=best corrected visual acuity; CST=central subfield thickness; Q12W=every 12 weeks; RPE=retinal pigment epithelium.
4.9 Direct supportive evidence: brolucizumab 3 mg
Following scientific advice from the EMA, the MAH included a brolucizumab 3 mg arm in the HAWK study. Nevertheless, the MAH only applied for a 6 mg dose, which is the dose finally approved for MA (27). In the HAWK study, treatment with brolucizumab 3 mg was noninferior to aflibercept in the primary outcome (change in BCVA from baseline to week 48), with an LS-mean estimate of 6.1 letters (in the aflibercept 2 mg arm 6.8 letters (95% CI 5.4–8.2)) giving a p-value of 0.0003 for noninferiority (4-letter margin, 1-sided) on ANOVA. The comparison between brolucizumab 3 mg and brolucizumab 6 mg was not presented. However, differences between the 3 mg and 6 mg doses across primary and secondary endpoints were numerically limited.
The brolucizumab 6 mg arm had a slightly higher proportion of patients maintained on a Q12W regimen compared to the brolucizumab 3 mg arm across all subgroups. The estimated proportion of patients remaining on the Q12W dosing interval up to week 48 was 49.4% in the brolucizumab 3 mg arm (HAWK), and 55.6% (HAWK) and 51.0% (HARRIER) in the brolucizumab 6 mg arms.
There was no significant difference in CSFT between brolucizumab 3 mg and aflibercept 2 mg; the mean difference on ANOVA (LSMD) was 1.3 (SE 5.75; 95% CI 10.0 to 12.6) with p-value of 0.8228.
According to EMA benefit-risk balance is positive for 3 mg dose as well. However, the 6 mg dose could be accepted by EMA based on limited numerical differences in efficacy and the similarity of the safety profile in unilateral administration between the doses of 3 mg and 6 mg (27).
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4.10 Direct supportive evidence: summary of the phase II OSPREY study
The phase II OSPREY study was a prospective multicentre RCT. It compared the efficacy and safety of brolucizumab 6 mg (n=44) with aflibercept 2 mg (n=45). Study subjects were followed for up to 56 weeks. The trial design is presented in Figure 4.18. In brief, the LP (weeks 0–8) and the period from 12 to 40 weeks were similar in both arms. In the LP, the study drugs were administered in weeks 0, 4 and 8. In the following period, both regimens were dosed in Q8W cycles (weeks 16, 24 and 32) up to week 40. Thereafter, the brolucizumab 6 mg group received one injection at week 44 (on Q12W cycle) and were followed up to week 56. The aflibercept group remained on the Q8W cycle up to week 56.
Figure 4.18. OSPREY trial design. Source: Submission dossier Abbreviations: q12w=every 12 weeks.
4.10.1 Clinical efficacy outcomes The primary outcome was the change in BCVA from baseline at week 12. The statistical hypothesis for the primary outcome was that brolucizumab is noninferior to aflibercept, using a margin of 5 letters and one-sided of 0.1 (27). The change in BCVA at week 16 and by visit were defined as secondary endpoints. Data for the outcomes of ≥15 letters gained or lost from baseline were not presented in the submission dossier. The change in CSFT from baseline by visit was a secondary outcome. Clinically relevant outcomes of change in VA (BCVA) and retinal thickness (CSFT) are presented in Table 4.23 and Table 4.24. Week 40 was chosen for presentation here because of the similar protocols in each arm.
Table 4.23. LSM estimates for the change in BCVA from baseline at weeks 12, 40 and 56 (FAS- LOFC) Time point Brolucizumab 6 mg (n=44) Aflibercept 2 mg (n=45) Week 12 LSM (SE) 5.75 (1.68) 6.89 (1.67) LSMD (80% CI) 1.13 (4.19 to 1.93) p-value 0.6335 Week 40 LSM (SE) 6.25 (2.14) 5.75 (2.12) LSMD (80% CI) 0.50 (3.39 to 4.39) p-value 0.8685 Week 56 LSM (SE) 4.84 (2.37) 7.33 (2.34) LSMD (80% CI) 2.49 (6.80 to 1.82) p-value 0.4579 Source: Submission dossier. Abbreviations: CI=confidence interval; FAS=full analysis set; LOCF=last observation carrier forward; LSM=least squares mean; LSMD=LSM difference; SE=standard error.
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Table 4.24. LSM estimates for the change in CSFT (µm) from baseline at weeks 12, 40 and 56 (FAS-LOFC) Time point Brolucizumab 6 mg (n=44) Aflibercept 2 mg (n=45) Week 12 LSM (SE) 196.57 (14.95) 189.00 (14.79) LSMD (80% CI) 7.57 (34.74, 19.60) p-value 0.7200 Week 40 LSM (SE) 197.46 (16.89) 178.29 (16.70) LSMD (80% CI) 19.17 (-49.86, 11.52) p-value 0.4221 Week 56 LSM (SE) 193.72 (16.04) 183.40 (15.86) LSMD (80% CI) 10.32 (39.47 to 18.82) p-value 0.6486 Source: OSPREY trial clinical study report. Abbreviations: CI=confidence interval; CSFT=central subfield thickness; FAS=full analysis set; LOCF=last observation carrier forward; LSM=least squares mean; LSMD=LSM difference; SE=standard error.
4.10.2 Safety outcomes The most common ocular AE for the study eye was conjunctival haemorrhage, which was reported by five patients (11.4%) in the brolucizumab 6 mg and seven (15.6%) in the aflibercept 2 mg arm. Other common ocular AEs in the study eye included vitreous floaters (11.4% vs. 8.9%), reduced VA (9.15% vs. 8.9%) and vitreous detachment (6.8% vs. 6.7%). Commonly reported non-ocular AEs were upper respiratory tract infection (11.4% vs. 6.7%) and urinary tract infection (4.5% vs. 8.9%). Serious AEs and deaths were rare. One 80-year-old subject in the brolucizumab 6 mg arm died of myocardial ischaemia. A total of 19 patients experienced nonfatal SAEs (10 in the brolucizumab 6 mg and 9 in the aflibercept 2 mg arm) with only one patient in the aflibercept 2 mg arm experiencing a treatment-related SAE. One patient discontinued because of an SAE of pancreatic carcinoma and another patient discontinued because of an SAE of retinal detachment in the study eye in the brolucizumab 6 mg and aflibercept 2 mg arms, respectively; neither event was considered to be treatment-related. No other nonfatal events led to study discontinuation.
More detailed information on clinical efficacy and safety outcomes in OSPREY is presented in Appendix 7.4 of the submission dossier.
4.11 Indirect evidence: NMA results
4.11.1 Quality assessment of the NMA The quality of the NMA provided by the MAH was evaluated using the tool developed by Ortega et al. [25]. The detailed evaluation is available in Appendix 9: Checklist for critical appraisal of indirect comparisons – Evaluation of the NMA provided by MAH. The quality assessment performed by the MAH of the trials included in the assessment is shown in Figure 4.19. The main limitation identified by the REA authors is related to the external validity and applicability of the results and the conclusions obtained, as one of the relevant comparators from the European perspective was not considered.
Additional limitations identified in the submission dossier include the assumption of time equivalence for 1-year and 2-year outcomes. In order to include all the available evidence for the treatments of interest, equivalence was assumed between 48 and 52 weeks for 1-year outcomes and between 96 and 104 weeks for 2-year outcomes. The MAH stated that no publication was found to validate this hypothesis, but the results from HAWK and HARRIER at week 52 were similar to those at week 48. The results from sensitivity analyses indicate that there was no impact on the results of the equivalence assumption used.
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In addition, the MAH stated that in order to connect the networks, an assumption was made for the VIEW 1&2 studies. While patients in VIEW 1&2 began a PRN treatment regimen at 52 weeks, these patients were still considered as remaining on continuous treatment arms (i.e. LP aflibercept 2 mg Q8W, aflibercept 2 mg Q4W and ranibizumab 0.5 mg Q4W) to connect to the brolucizumab treatments. To assess the impact of this assumption, heterogeneity for ranibizumab 0.5 mg Q4W was assessed for each endpoint at 2 years and was only found for injection frequency. Since only baseline pooling was conducted for injection frequency, this switch to a PRN regimen was considered in these analyses. Furthermore, CNV lesion size was considered as a treatment effect modifier in nAMD following feedback from a leading clinical expert who indicated that VIEW 1&2 seemed to be the biggest outlier. However, this trial was needed to connect the network and therefore this represents a limitation of the analysis.
Another limitation of the NMA was that ranibizumab 0.5 mg Q4W versus LP ranibizumab 0.5 mg TREX and LP brolucizumab 6 mg Q12/Q8W versus LP aflibercept 2 mg Q8W were the only comparisons for which multiple studies were included (as VIEW 1&2 were pooled in the analyses). The other comparisons were all connected by one trial only, making these arms of the network less robust.
Lastly, the NMA was performed by the MAH of brolucizumab, so we cannot exclude the possibility that conflicts of interest could have influenced the results. However, despite the above limitations, the methodological approach and conduct of the NMA can be considered as adequate.
Figure 4.19. Quality assessment performed by the MAH for trials included in the NMA. Source: Submission dossier. Abbreviations: MAH=marketing authorisation holder; NMA=network meta-analysis.
4.11.2 NMA results A brief summary of indirect comparisons is presented for the key outcomes in Table 4.25 and Table 4.26, followed by information on other outcomes such as injection frequency, treatment discontinuation and safety outcomes.
The network for the primary outcome (mean change in BCVA from baseline to 1 year) is presented in Figure 4.20. A total of 13 studies were included in the analysis. More detailed results are available in the submission dossier. Results are presented for cases with brolucizumab 6 mg (LP of three initial monthly injections and maintenance dosing either Q8W or Q12W) comparisons with each comparator (Table 4.25).
Sensitivity analyses and the results are presented in the submission dossier in detail. The sensitivity analyses performed showed that the results of the NMA were not significantly affected by the assumptions made.
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Mean change in BCVA (baseline to 1 year and baseline to 2 years) There was no difference between brolucizumab 6 mg and ranibizumab, aflibercept or brolucizumab 3 mg for the mean change in BCVA from baseline to 1 year or from baseline to 2 years. There was a difference observed between brolucizumab and sham for mean change in BCVA at both 1 and 2 years (MD 16.87, 95% credibility interval (CrI) 13.37–20.41 at 1 year, and 21.21, 95% CrI 17.46–24.99 at 2 years).
Figure 4.20. Network for mean change in BCVA from baseline to 1 year. Source: Submission dossier Abbreviations: BCVA=best corrected visual acuity; Afli=aflibercept; Bro=brolucizumab; IVT=intravitreal; LP=loading phase; Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re nata and extend dosing regimen; qXw=every X weeks; TREX= treat-and-extend dosing regimen.
Patients losing at least 15 letters (baseline to 1 year) There was no difference between brolucizumab 6 mg and aflibercept, brolucizumab 3 mg and most of the ranibizumab dosing schemes for loss of at least 15 letters from baseline to 1 year. Brolucizumab had lower odds for loss of at least 15 letters only compared to sham IVT (odds ratio [OR] 0.07, 95% CrI 0.03–0.18) and the ranibizumab dosing scheme LP 0.5 mg PRN (OR 0.29, 95% CrI 0.08–0.95).
Patients losing at least 15 letters (baseline to 2 years) There was no difference between brolucizumab 6 mg and aflibercept, ranibizumab or brolucizumab 3 mg for loss of at least 15 letters from baseline to 2 years. Brolucizumab had lower odds for loss of at least 15 letters only compared to sham IVT (OR 0.11, 95% CrI 0.05–0.23).
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Table 4.25. Summary of NMA results comparing MD in BCVA and OR of loss of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator. Comparator arm MD in BCVA (95% CrI)a OR for loss of ≥15 letters (95% CrI)b Baseline to 1 year Baseline to 2 Baseline to 1 Baseline to 2 years year years Rani 0.5 mg Q4W 0.72 0.29 0.79 0.90 (2.68, 1.23) (2.45, 1.88) (0.38, 1.62) (0.50, 1.60) LPAfli 2 mg Q8W 0.43 0.01 0.96 1.0 (1.72, 0.86) (1.48, 1.49) (0.60, 1.54) (0.68, 1.48) LPRani 0.5 mg PRN 1.18 0.91 0.29** 0.55 (1.77, 4.13) (2.39, 4.2) (0.08, 0.95) (0.23, 1.31) LPRani 0.5 mg 0.77 – 0.73 – Q12W (6.69, 8.29) (0.19, 2.98) LPRani 0.5 mg Q8W – – 0.11 – (0.2, 2.09) Afli 2 mg Q4W 1.33 0 0.96 0.97 (3.28, 0.62) (2.15, 2.16) (0.46, 2.0) (0.54, 1.72) LPRani 0.5 mg 0.89 3.4 0.70 0.08 TREX (3.29, 1.52) (4.57, 11.54) (0.28, 1.75) (0.0, 1.3) Rani 0.5 mg PRN 0.97 1.8 0.99 0.82 (1.99, 3.95) (2.03, 5.68) (0.35, 2.84) (0.29, 2.19) LPBro 6 mg Q8W 0.78 – – – Q12W (5.55, 7.08) LPBro 3 mg Q12/8W 0.38 0.01 1.01 0.89 (1.41, 2.17) (2.01, 2.04) (0.56, 1.85) (0.54, 1.48) Sham IVT 16.87* 21.21* 0.07** 0.11** (13.37, 20.41) (17.46, 24.99) (0.03, 0.18) (0.05, 0.23) LPRani 0.5 mg 3.29 – 0.28 – PRNX (12.13, 5.59) (0.04, 2.0) LPAfli 2 mg TREX 1.53 5.39 0.42 – (1.89, 4.9) (3.02, 14.09) (0.08, 2.11) Source: Modified from the submission dossier (Figures 27, 29, 31 and 33). aMD >1 favours brolucizumab. bOR <1 favours brolucizumab. *The lower bound of the 95% CrI interval is >0. **The upper bound of the 95% CrI is <1. Abbreviations: Afli=aflibercept; BCVA=best corrected visual acuity; Bro=brolucizumab; CrI=credibility interval; IVT=intravitreal; MD=mean difference; OR=odds ratio; LP=loading phase; Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re nata and extend dosing regimen; qXw=one injection every X weeks; TREX= treat-and-extend dosing regimen.
Patients gaining at least 15 letters (baseline to 1 year) There was no difference between brolucizumab and aflibercept and most of the ranibizumab dosing schemes for a gain of at least 15 letters from baseline to 1 year. However, compared to the following treatment options, brolucizumab had greater odds of gaining at least 15 letters:
Sham IVT (odds ratio 10.99, 95% CrI 5.47–23.43); Ranibizumab: dosing scheme LP 0,5 mg Q12W (OR 7.57, 95 % CrI 1.89–30.06); Ranibizumab: dosing scheme 0,5 mg PRN (OR 1.74, 95% CrI 1.07–2.84); Brolucizumab LP 3 mg Q12W/Q8W (OR 1.37, 95% CrI 1.01–1.86).
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Patients gaining at least 15 letters (baseline to two years) There was no difference between brolucizumab 6 mg and aflibercept, ranibizumab or brolucizumab 3 mg for gain of at least 15 letters from baseline to 2 years. Brolucizumab had greater odds for a gain of at least 15 letters only compared to sham IVT (OR 16.06, 95% CrI 7.47–37.99).
Mean change in CRT (baseline to 1 year) There was a difference observed between brolucizumab 6 mg and aflibercept as well as brolucizumab 6 mg and ranibizumab for mean change in retinal thickness at one year (Table 4.26). No differences were observed in comparisons to brolucizumab 3 mg and brolucizumab 6 mg dosing scheme LP Q8W Q12W (Table 4.26).
Mean change in CRT (baseline to 2 years) There was a difference observed between brolucizumab 6 mg and nearly all comparators for mean change in CRT at 2 years. No difference was observed for the following comparator arms: ranibizumab dosing scheme LP 0.5 mg TREX, aflibercept dosing scheme LP 2 mg TREX and brolucizumab 3 mg (Table 4.26).
Table 4.26. Summary of NMA results comparing the MD in CRT and OR in gain of at least 15 letters (fixed effects). Results are presented as brolucizumab 6 mg Q8W/Q12W vs. each comparator. Comparator arm OR for gain of ≥15 letters (95% CrI)a MD in CRT (95% CrI)b Baseline to 1 year Baseline to 2 years Baseline to 1 year Baseline to 2 years Rani 0.5 mg Q4W 1.11 1.21 50.49* 49.57* (0.8, 1.54) (0.87, 1.70) (71.63, 29.7) (70.22,-29.29) LPAfli 2 mg Q8W 1.19 1.11 39.66* 35.01* (0.95, 1.49) (0.89, 1.39) (53.02, 26.44) (48.94,-21.23) LPRani 0.5 mg PRN 1.36 1.29 59.79* 58.98* (0.84, 2.2) (0.80, 2.11) (91.68, 28.13) (89.59,-28.75) LPRani 0.5 mg Q12W 7.57** – – – (1.89, 30.06) LPRani 0.5 mg Q8W 2.18 – – – (0.52, 9.32) Afli 2 mg Q4W 1.06 1.24 40.26* 39.78* (0.77, 1.48) (0.9, 1.72) (61.45, 19.66) (60.22, 19.23) LPRani 0.5 mg TREX 0.95 0.67 57.86* 16.81 (0.62, 1.45) (0.15, 2.47) (89.88, 25.87) (83.06, 53.94) Rani 0.5 mg PRN 1.74** 1.34 75.79* 68.53* (1.07, 2.84) (0.77, 2.35) (111.7, 39.55) (110.54, 27.11) LPBro 6 mg Q8W – – 22.68 – Q12W (77.62, 31.8) LPBro 3 mg Q12/8W 1.37** 0.96 10.42 0.44 (1.01, 1.86) (0.72, 1.30) (28.26, 7.18) (18.05, 18,72) Sham IVT 10.99** 16.06** – – (5.47, 23.43) (7.47, 37.99) LPRani 0.5 mg PRNX 0.77 – – – (0.24, 2.38)
LPAfli 2 mg TREX 1.03 – – 4.77 (0.49, 2.17) (72.68, 68,31) Rani 0.5 mg TREX – – – – Source: Modified from the submission dossier (Figures 35, 37, 40 and 42). aOR >1 favours brolucizumab. bMD <1 favours brolucizumab. *The upper bound of the 95% CrI is <0. **The lower bound of the 95% CrI is >1. Abbreviations: Afli=aflibercept; Bro=brolucizumab; CrI=credibility interval; CRT=central retinal thickness; IVT=intravitreal; MD=mean difference; OR=odds ratio; LP=loading phase; Rani=ranibizumab; PRN= pro re nata dosing regimen; PRNX=pro re nata and extend dosing regimen; qXw=one injection every X weeks; TREX= treat-and-extend dosing regimen.
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Injection frequency The MAH presented arm-based pooling of the injection frequency for each comparator from baseline to 1 year and baseline to 2 years (Tables 48 and 49 in the submission dossier). However, different dosing schemes cannot be compared with each other in terms of injection frequency.
Overall rate of treatment discontinuation (baseline to 1 year and baseline to 2 years) There was no difference between brolucizumab 6 mg and ranibizumab, aflibercept or brolucizumab 3 mg for the odds of discontinuation from baseline to 1 year and baseline to 2 years.
AEs The MAH presented molecule-based pooling and regimen-based pooling for SAEs (Tables 54–61 and 63–69 in the submission dossier). Indirect comparisons of AEs were not presented.
4.12 Literature review: evidence of bevacizumab as a treatment option in nAMD
4.12.1 Quality assessment of the SRs included in the assessment The systematic literature search (see Sections 3.1, 4.1 and 4.2) performed to identify relevant SRs and/or NMAs in which bevacizumab was evaluated as a treatment for nAMD resulted in selection of two SRs by Solomon et al. (30) and Pham et al. (29). The results from the screening of the searches, information on the studies that met eligibility criteria, and excluded articles are available in Appendiced 4-6.
The SR by Solomon et al. (30) only included RCTs. The inclusion and exclusion criteria, and the RCTs included are available in Appendix 6: Excluded articles from bevacizumab literature review. The trials included patients with nAMD as defined by the study investigators, and compared anti-VEGF treatment to another treatment, sham treatment or no treatment. In the SR, 16 RCTs that had enrolled a total of 6347 participants with nAMD were selected and one potentially relevant ongoing trial was identified. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab or bevacizumab) to a control, and 10 trials compared bevacizumab versus ranibizumab; a total of 3657 participants were included in direct comparisons between bevacizumab and ranibizumab in those trials.
The RoB summary for the ten trials that compared bevacizumab and ranibizumab is presented in Figure 4.21. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centres across five continents (North and South America, Europe, Asia and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low RoB. All but one trial had been registered prospectively.
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Figure 4.21. RoB summary: judgements for each RoB item for each study comparing bevacizumab versus ranibizumab included by Solomon et al.
Legend: low risk of bias; unclear risk of bias; high risk of bias. Source: Solomon et al. (30). Abbreviations: RoB=risk of bias.
The SR by Pham et al. (29) included RCTs evaluating treatment for several retinal conditions. A total of twelve trials evaluating treatment of nAMD were included. The judgment of the SR authors on the RoB of the studies is detailed in Figure 4.22.
Figure 4.22. Cochrane RoB results for individual studies on nAMD included by Pham et al.
Legend: low risk of bias; unclear risk of bias; high risk of bias. Source: Pham et al. (29). Abbreviations: RoB=risk of bias; nAMD=neovascular age-related neovascularisation.
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The REA authors applied the AMSTAR-2 tool to both SRs. Details of the evaluation are available in Appendix 10: Critical appraisal for the systematic reviews selected from the SLR of bevacizumab. According to the tool, the SR by Solomon et al. is a low-quality review. The main limitations of the SR are related to the level of detail of some aspects of the study selection methodology, such as the reasons for selecting RCTs only and not describing the meta-analysis techniques in sufficient detail. Despite these limitations, the REA authors consider that the results of the SR by Solomon et al. are robust enough to derive some conclusions on effectiveness of bevacizumab compared to other nAMD treatments.
Using the AMSTAR-2 tool, the REA authors considered the SR by Pham et al. a critically low-quality review. The main limitations are related to the lack of detailed information in the SR protocol, failure to explain the reasons for selecting only RCTs and detailed information on some aspects of the study selection, such as detailed justification of the trials excluded and the predetermined follow-up timeframe in the search strategy. Moreover, even if RoB and heterogeneity were assessed as detailed in the method section of the SR by Pham et al., the impact on the results is not thoroughly detailed in their discussion section. Even with the limitations described, the REA authors consider that the review provides some useful data for indirect comparisons of aflibercept not included in the SR by Solomon et al.
4.12.2 Results from the SRs In both SRs, meta-analysis was used to gather evidence from different studies. In the SR by Solomon et al. the authors concluded that bevacizumab and ranibizumab were similar in terms of vision-related outcomes among participants followed for at least 1 year (30). More detailed meta-analysis results for the mean change in BCVA (number of letters) are presented in Table 4.27; there was no difference between the groups (MD 0.52, 95% CI 1.49 to 0.45). For the outcome of gain of ≥15 letters in VA, comparison of bevacizumab to ranibizumab revealed RR of 0.95 (95% CI 0.81–1.12) at 1 year and 0.84 (95% CI 0.64–1.11) at 2 years. Nine of ten trials reported the mean change in CRT at 1 year; the MD was 11.6 (95% CI 21.55 to 1.66). There were no differences between bevacizumab and ranibizumab in ocular or non-ocular AEs (Table 4.28).
Table 4.27. Treatment effect estimates: bevacizumab versus ranibizumab Outcomea Number of participants Results of evidence synthesis Bevacizumab Ranibizumab Mean VA change in 1 year 1562 1628 MD, random: 0.52 (95% CI 1.49 to 0,45) (letters) Gain of ≥15 letters in VA 1542 1602 RR 0.95 (95% CI 0.81–1.21) Gain of ≥15 letters in VA at 751 796 RR 0.84 (95% CI 0.64–1.11] 2 years Reduction in central retinal 1317 1376 MD, random: 11.61 (95% CI 21.55 to thickness at 1 year 1.66) Reduction in central retinal 592 607 MD, random: 12.4 (95% CI 33.83 to 9.04) thickness at 2 years Source: Modified from Solomon et al.(30) (studies included: CATT 2011; IVAN 201; BISWAS 2011; GEFAL 2013; MANTA 2013; SUBRAMANIAN 2010; BRAMD 2016; LUCAS 2015; SCHOLLER 2014). aOutcomes are for bevacizumab versus ranibizumab. There were no direct comparisons for bevacizumab versus pegaptanib. Abbreviations: AE=adverse event; CI=confidence interval; MD=mean difference; RR=relative risk for bevacizumab vs. ranibizumab; VA=visual acuity.
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Table 4.28. AEs up to 1 year: bevacizumab versus ranibizumab Patients, n (%) RR (95% CI) Studies reporting AEs Bevacizumab Ranibizumab With AE Total With AE Total Serious ocular AEs Endophthalmitis 5 (<1%) 1052 3 (< 1%) 1059 1.68 (0.40 to 7.00) CATT 2011; GEFAL 2013; LUCAS 2015 Retinal detachment 3 (<1%) 832 0 838 7.05 (0.36–136.28) CATT 2011; GEFAL 2013 Retinal pigment epithelial tear 4 (<1%) 1102 3 (< 1%) 1134 1.37 (0.31–6.12) CATT 2011; IVAN 2013; LUCAS 2015 Traumatic cataract 1 (<1%) 1128 2 (< 1%) 1152 0.51 (0.05–5.62) CATT 2011; GEFAL 2013; IVAN 2013 Severe uveitis 4 (<1%) 882 1 (< 1%) 913 4.14 (0.46–36.97) CATT 2011; IVAN 2013 Non-ocular SAEs At least 1 SAE 298 (18%) 1663 265 (16%) 1702 1.15 (0.99–1.34) BRAMD 2016; CATT 2011;GEFAL 2013; IVAN 2013; LU-CAS 2015; MANTA 2013 Death 30 (2%) 1663 28 (2%) 1702 1.10 (0.66–1.83) BRAMD 2016; CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013 Myocardial infarction 8 (<1%) 1502 16 (1%) 1536 0.51 (0.22–1.19) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013 Stroke or cerebral infarction 7 (<1%) 1502 11 (< 1%) 1536 0.65 (0.25–1.67) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013 Transient ischaemic attack 6 (<1%) 1348 4 (< 1%) 1373 1.53 (0.43–5.40) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015 Cardiac disorders 46 (3%) 1663 56 (3%) 1702 0.84 (0.57–1.23) BRAMD 2016; CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015; MANTA 2013 Venous thrombotic event 8 (<1%) 1348 4 (< 1%) 1373 2.04 (0.61–6.75) CATT 2011; GEFAL 2013; IVAN 2013; LUCAS 2015 Source: Modified from Solomon et al. (30). Abbreviations: AE=adverse event; CI=confidence interval; RR=relative risk for bevacizumab vs. ranibizumab.
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The SR by Pham et al. only included RCTs. There were twelve RCTs for which the population matched our PICO, namely nAMD (Appendix 5: Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review). The SR included studies in which the interventions were anti-VEGF drugs in use in Canada (ranibizumab, IVT bevacizumab and aflibercept) and the comparators were placebo, ranibizumab, IVT bevacizumab or aflibercept. In this SR, meta-analysis was used to perform evidence synthesis from direct comparisons performed in different studies.
The evidence synthesis results show no difference between bevacizumab and ranibizumab in terms of vision-related outcomes or numbers of AEs among participants followed for at least 1 year (Table 4.29 and Table 4.30). Meta-analysis results for the mean change in BCVA (number of letters) are presented in Table 4.29. The average change in the number of letters read was seven versus six, with no difference between the groups (Table 4.29). Comparison of bevacizumab to ranibizumab for the outcome of gain of ≥15 letters in VA at 1 year also revealed no difference.
Two studies comparing ranibizumab and aflibercept directly were found in the SR by Pham et al. In terms of the gain and mean change in VA, no differences were found between ranibizumab and aflibercept. Other outcomes are presented in Table 4.29. Vision-related function was evaluated using the NEI VFQ-25 questionnaire in both studies comparing ranibizumab and aflibercept, with similar changes in NEI VFQ-25 scores observed.
RCTs with direct comparisons between bevacizumab and aflibercept were not found in the SR by Pham et al. While the MD in BCVA change was 0.03 (95% CI 1.08 to 1.02) between bevacizumab and ranibizumab and 0.05 (95% CI 2.5 to 2.4) between aflibercept and ranibizumab, the MD estimate between bevacizumab and aflibercept was 0.02 (95% CI 2.60 to 2.64). Moreover, for vision gain, the RR estimate was 0.96 (95% CI 0.75–1.22) for bevacizumab versus aflibercept, 0.95 (95% CI 0.84– 1.07) for bevacizumab versus ranibizumab and 0.99 (95% CI 0.81–1.22) for aflibercept versus ranibizumab (29).
The mean change in CRT was not reported for bevacizumab versus ranibizumab or ranibizumab versus aflibercept. There were no differences between bevacizumab and ranibizumab or between ranibizumab and aflibercept in ocular or non-ocular AEs (Table 4.30).
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Table 4.29. Treatment effect estimates Direct Participants Mean estimated effect (range) RR (95% CI) RD (95% CI) I2 comparisons Treatment Comparator (%) Bevacizumab versus ranibizumab Vision gain in BCVA of ≥15 ETDRS letters 9 3245 0.22 (0.12–0.33) 0.23 (0.14–0.29) 0.95 (0.84–1.08) 1.62 (4.86 to 1.62) 0 Vision loss in BCVA of ≥15 ETDRS letters 10 3302 0.06 (0–0.11) 0.07 (0.04–0.14) 1.1 (0.84–1.43) 0.39 (1.46 to 2.23) 4 Mean change in BCVA (MD in letters) 8 3064 7.24 (4.1–15.2) 5.85 (0.6–11.43) NA 0.03 (1.02 to 1.08) 0 Vision-related function NR NR NR NR NR NR NR Aflibercept versus ranibizumab Vision gain in BCVA of ≥15 ETDRS letters 2 1815 0.32 (0.3–0.34) 0.32 (0.31–0.34) 0.99 (0.81–1.22) 0.21 (6.82 to 6.4) 52 Vision loss in BCVA of ≥15 ETDRS letters 2 1815 0.05 (0.05–0.05) 0.06 (0.05–0.06) 0.9 (0.6–1.35) 0.51 (2.75 to 1.72) 0 Mean change in BCVA (MD in letters) 2 1793 8.83 (8.25–9.41) 8.75 (8.1–9.4) NA 0.05 (2.36 to 2.46) 66 Vision related function 2 1632 5.32±14.46 5.60±14.40 NA 2.23 (5.07 to 0.61) 73 Bevacizumab versus aflibercept None Source: Modified from Pham et al. (29) (studies included: BRAMD 2016; LUCAS 2015; Scholler 2014; IVAN 2013; GEFAL 2013; MANTA 2013; Biswas 2011 a & b; CATT 2011; Subramanian 2010, VIEW1 2012; VIEW2 2012). Abbreviations: AE=adverse event; BCVA=best corrected visual acuity; ETDRS=Early Treatment Diabetic Retinopathy Study; MD=mean difference; NA=not applicable; NR=not reported; RD=risk difference; RR=relative risk.
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Table 4.30. Adverse events: treatment versus comparator Direct Participants Mean estimated effect (range) RR (95% CI) RD (95% CI) comparisons Treatment Comparator Bevacizumab versus ranibizumab Blindness 3 1823 0.04 (0–0.12) 0.02 (0–0.06) 2.04 (0.32–12.5) 0.11 (0.25 to 0.47) Mortality 6 2941 0.04 (0.01–0.12) 0.03 (0.01–0.06) 1.14 (0.72–1.79) 0.31 (0.74 to 0.36) Serious AEs 5 3026 0.19 (0.12–0.28) 0.18 (0.09–0.28) 1.09 (0.93–1.27) 0.02 (0.01 to 0.05) Arterial thromboembolic events 4 2033 0.03 (0–0.05) 0.04 (0–0.08) 0.86 (0.51–1.47) 0.03 (0.97 to 0.9) Venous thromboembolic events 3 2135 0 (0–0.01) 0 (0–0.01) 1.59 (0.42–5.88) 0.18 (0.43 to 0.79) Bacterial endophthalmitis 3 2011 0 (0–0.01) 0 (0–0) 1.75 (0.44–6.67) 0.18 (0.40 to 0.77) Retinal detachment 2 1526 0.01 (0.01–0.01) 0 (0–0.01) 2.33 (0.31–16.67) 0.38 (0.2 to 0.96) Aflibercept versus ranibizumab Blindness NR NR NR NR NR NR Mortality NR NR NR NR NR NR Serious AEs NR NR NR NR NR NR Arterial thromboembolic events 2 1818 0.02 (0.01–0.02) 0.02 (0.02–0.02) 0.96 (0.45–2.04) 0.07 (1.32 to 1.18) Venous thromboembolic events 1 913 0.0033 0 00.25 (0.01–7.69) 0.25 (0.93 to 0.44) Bacterial endophthalmitis NR NR NR NR NR NR Retinal detachment NR NR NR NR NR NR Bevacizumab versus aflibercept None Source: Modified from Pham et al. (29). Abbreviations: AE=adverse event; NR=not reported; RD=risk difference; RR=relative risk.
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5 PATIENT INVOLVEMENT
A summary of patient involvement is presented in Table 5.1. The key message is that reduced VA means that patients with AMD often lose their autonomy and mobility. They have difficulties in daily life such as reading, driving and recognising people’s faces. Some patients experience depression, anxiety and other mental health issues.
With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. They would also appreciate other modes of administration (e.g., drops or tablets).
Table 5.1. Summary of patient involvement Question Summary of the responses How does AMD affect AMD has a significant impact on quality of life. As their visual acuity declines, patients’ quality of life? patients often lose their autonomy and mobility. They are unable to read, drive, watch TV or recognise faces. They also feel social exclusion. How does AMD affect Family members often have to take responsibility for duties previously carried out carers/unpaid care- by the person with AMD, such as household duties and driving. Caregivers may givers? also have financial or time pressures (time away from work, time away from the rest of the family). They often feel guilty that they are not taking enough care of the patient. They also feel sadness observing the patient decline over time. How well are adult Anti-VEGF injections cause feelings of fear and anxiety for some patients. Some patients managing patients also feel pain or disturbed vision after injection. For patients who live far neovascular (wet) AMD away from urban centres, a lot of effort is required to travel for injections with currently available (transportation time and cost, caregiver’s time). However, the majority of patients therapies? receiving anti-VEGF injections feel that they are very beneficial. Benefits include retaining the ability to read and drive, employment and the ability to take care of him/herself and of family members when needed. Some answers also indicated that for many patients current treatment is not effective or if it is effective, at some point patient become refractory to the treatment and the disease continues to progress. What are the Possibility to maintain current vision and even restore vision that has already expectations and been lost requirements for a new Lower frequency of injections or no need for regular injections medicine for adult No side effects or fewer side effects patients with neovascular Improvement in quality of life (wet) AMD? Other methods of administration, such as drops or tablets Please include any The number of AMD patients is increasing. New treatment options are needed additional information you that are more effective and less expensive for the patient. European protocols for believe would be helpful AMD treatment were also suggested. AMD impacts elderly people who often to the EUnetHTA Joint have other significant health problems. If AMD is effectively treated, it may have Assessment Team (e.g., positive effects on many other areas of the health service and society. For ethical or social issues) example, effective AMD treatment could reduce the risk of falls, depression and the need to move to a nursing home. In addition to medical treatment, more attention should be paid to rehabilitation such as better lighting conditions and the possibility of using a white cane. Abbreviations: AMD=age-related macular degeneration; VEGF=vascular endothelial growth factor.
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6 DISCUSSION
The aim of this assessment was to compare the clinical effectiveness and safety of brolucizumab in the treatment of nAMD with relevant comparators. The EUnetHTA PICO survey identified aflibercept, ranibizumab and bevacizumab as relevant comparators. Ranibizumab and aflibercept are licensed drugs for the treatment of nAMD and for which the patents are ceasing in the USA in 2020 and in Europe in 2022 (ranibizumab) and in 2025 (aflibercept) (67). Bevacizumab does not have an approved indication for nAMD. However, bevacizumab has shown similar efficacy and safety compared to ranibizumab in clinical trials (20, 68, 69) and its use as a treatment for nAMD is widespread in Europe1.
6.1 Direct comparisons
The efficacy and safety of brolucizumab have been directly compared only with aflibercept in two phase III RCTs. The studies demonstrated noninferiority of brolucizumab in comparison to aflibercept for the primary efficacy endpoint, mean change in BCVA.
Study level risk of bias was assessed to be low in both HAWK and HARRIER studies. On outcome level, the risk of bias was low for most of the outcomes and unclear for some of the outcomes such as visual function related QoL (measured by NEI VFQ-25) and part of the safety outcomes.
In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events was higher for brolucizumab. These safety concerns were also raised in the European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.
Moreover, in real life most patients need treatment for longer than 2 years and some patients will need to be treated simultaneously for both eyes, so the safety of long-term use and systemic exposure needs to be monitored. Moreover, in real life patients might be previously treated with other anti-VEGF treatments and efficacy and safety of treatment in these patients is unclear. However, after the launch of brolucizumab in USA, safety signals of retinal vasculitis events has raised concerns and updated information on use and safety of brolucizumab (70).
Brolucizumab has not been directly compared to ranibizumab or bevacizumab in an RCT setting.
6.1.1 Key notes on the outcomes assessed In all trials (HAWK, HARRIER, OSPREY) the ETDRS chart was used to measure VA. ETDRS charts can reliably identify changes in VA of two lines (10 letters) or more, but not changes of one line (5 letters) or less (71). A loss or gain of three lines (15 letters) is considered a moderate degree of change and is commonly used as an outcome in clinical trials (72). From this perspective, the rationale for choosing a noninferiority margin of four letters (in HAWK and HARRIER) or five letters (in OSPREY) seems justified. In addition, noninferiority compared to aflibercept in terms of the mean change in BCVA can be fairly reliably concluded from the clinical perspective.
However, it should be noted that VA is only one component contributing to overall visual function and the ability to perform everyday visual tasks (e.g., reading, recognising faces, driving and using the telephone). Overall visual function also depends on variables such as contrast sensitivity, near vision, colour vision and sensitivity to glare. The use of distance acuity to measure the effectiveness of drug treatments in AMD is established practice but is not optimal. Difficulty in reading is a common complaint among persons with nAMD and distance VA is usually two ETDRS lines better than reading vision (72). Contrast sensitivity is an important contributor to reading performance (72).
1 At the time of publication of the Joint Assessment (March 2020), bevacizumab did not have an EU marketing authorisation for the indication under assessment. Bevacizumab is included as a comparator because of its importance identified in the EUnetHTA PICO survey; however its inclusion in the Joint Assessment should not be understood or quoted as a recommendation for its unlicensed use.
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In the HAWK and HARRIER trials, optical coherence tomography was used to measure retinal thickness. The change in retinal thickness is an intermediate outcome measure that is modestly correlated with changes in vision and cannot be interpreted separately from VA change or used as a substitute for VA or other patient-reported outcomes (73). The correlation between change in retinal thickness and VA is one-way: a gain in VA is related to a decrease in retinal thickness, but a reduction in retinal thickness is not always related to a gain in VA, especially in late stages of nAMD. In the HAWK and HARRIER studies, statistically significant difference in the change in CSFTtot was observed between brolucizumab and aflibercept. CSFTtot is an intermediate outcome and therefore the clinical relevance of this difference cannot and should not be evaluated separately from changes in VA. The clinical relevance of possible differences observed for other anatomic outcomes such as IRF, SRF, sub- RPE fluid and CNV cannot be evaluated either.
Vision-related QoL was measured using the NEI VFQ-25 instrument, which includes 25 items relevant to 11 vision-related constructs, in addition to a single-item general health component. Determination of a clinically meaningful change in NEI VFQ-25 appears to be linked to its correlation with VA. A three- line (15 letters) change in VA has been used as the outcome of interest in clinical trials, and corresponding changes in NEI VFQ-25 are suggested as clinically meaningful endpoints (73). For patients with nAMD and specifically for the study eye, which is typically the worse-seeing eye, a 15- letter change in VA corresponds to a 4-point change in overall NEI VFQ-25 score. For the better-seeing eye, the clinically relevant difference for NEI VFQ-25, based on a three-line change in VA, is 7–8 points in the overall score (74, 75). For the worse-seeing eye in patients with AMD, the NEI VFQ-25 instrument showed weaker correlation or was not responsive to changes in VA (76). This may have implications when evaluating patients with unilateral disease. In the HAWK and HARRIER studies there were no data on whether the treated eye was the first (worse seeing) or second (better seeing) affected eye. In addition, the analysis of visual function–related QoL (NEI VFQ-25) was not performed separately for the first and second affected eye, although the assessment team asked the MAH to provide this information. The mean changes in NEI VFQ-25 scores from baseline to week 96 (3.8 for brolucizumab 6 mg vs. 2.8 for aflibercept 2 mg in HAWK and 3.8 vs. 2.6, respectively, in HARRIER) suggest that the change in vision-related QoL is not clinically meaningful.
6.1.2 Brolucizumab 3 mg The marketing authorisation is for brolucizumab 6 mg in nAMD. It should be emphasised that the benefit–risk balance is also positive for brolucizumab 3 mg. The European public assessment report states that no strong evidence was provided by the MAH to clearly support the choice of 6 mg instead of 3 mg. However, the 6 mg dose could be accepted on the basis of limited numerical differences in efficacy and the similarity of the safety profile in unilateral administration between the two doses.(27)
6.1.3 Regarding the direct evidence, the following key limitations were identified during the assessment: In both the HAWK and HARRIER trials, the study eye in each patient had to be treatment-naïve for any anti-VEGF agents. The efficacy and safety of brolucizumab have not been studied as a second- or third-line treatment. However, the therapeutic indication for brolucizumab does not include any limitations in terms of prior anti-VEGF treatments; The first three loading doses of brolucizumab are given Q4W. In maintenance treatment the dosing interval is based on disease activity and injections are given Q12W or Q8W. At treatment initiation, it is not possible to know which patients will be able to remain on Q12W dosing. It would be beneficial for both patients and hospitals if brolucizumab treatment could be targeted to patients who are able to remain on Q12W dosing; In the HAWK and HARRIER trials the treatment duration and follow-up time were only up to 96 weeks. Therefore, the long-term efficacy and safety of brolucizumab are not known. In clinical practice the treatment duration is often longer than 2 years; Brolucizumab has only been compared to aflibercept 2 mg with fixed Q8W dosing and not to other dosing schemes commonly used in clinical practice (e.g., PRN or TREX). Because dosing schemes differed for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn regarding treatment burden (injection frequency) between these two regimens. Further investigations involving comparable treatment regimens would be needed;
March 2020 EUnetHTA Joint Action 3 WP4 76 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Data on general HRQoL (e.g., EQ-5D) are not available. However, vision-related QoL (measured using NEI VFQ-25) was included.
6.2 Indirect comparisons
Direct comparisons to ranibizumab and bevacizumab were not performed. The MAH provided an NMA of RCTs in which the main focus was comparison of brolucizumab 6 mg and different dosing schemes for aflibercept 2 mg and ranibizumab 0.5 mg. No differences were observed for the main outcome (mean change in BCVA) or for most of the other outcomes.
The quality of the NMA provided by the MAH was evaluated by the assessment team using the tool developed by Ortega et al. Quality assessment of the individual trials was perfomed by the MAH. The main limitation of the NMA is related to the external validity and applicability of the results and conclusions obtained, because one of the relevant comparators from the European perspective has not been considered.
Overall, the credibility and validity of the NMA rely on a few key assumptions (homogeneity, transitivity and consistency assumptions) and have well-known limitations that should be taken into account in drawing conclusions from these results. In this NMA, some simplifying assumptions were made for practical reasons. These include assuming equivalence between the dosing regimens at year one and year two for the treatments in VIEW 1&2 studies. The other key assumptions were: (1) CRT, CFT, CSFT and CMT were considered as the same measure; and (2) equivalence was assumed for assessment times between 48 and 52 weeks for 12-month outcomes, and between 96 and 104 weeks for 24-month outcomes. Furthermore, the NMA results are reported as mean differences only and not as absolute values or absolute changes. Therefore, it is difficult to evaluate the clinical relevance of the NMA results. However, despite the above limitations the methodological approach and conduct of the NMA can be considered adequate.
6.3 Literature review of bevacizumab
Two systematic reviews (29, 30) that included bevacizumab as a comparator in the treatment of nAMD were identified in the literature search. According to the AMSTAR-2 tool, the SR by Solomon et al. is a low quality review and the SR by Pham et al a critically low quality review. However, the main limitations of the SRs are related to the level of details included in the methodology description of the SRs, and the authors of this REA consider that the results are robust enough to derive some conclusions on the effectiveness of bevacizumab in this setting.
On the basis of two SRs, bevacizumab and ranibizumab were similar in terms of vision-related outcomes and numbers of AEs among participants followed for at least 1 year (29, 30). Similarly, the SR by Pham et al. (29) found no difference in vision-related outcomes between ranibizumab and aflibercept. The authors estimated that the mean difference between bevacizumab and aflibercept in terms of the change in BCVA suggests no difference between these regimens, but the planned NMA performed by the same authors has not been published.
Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparison between these two treatments was not formally conducted.
6.4 Patient perspective
The key message from the EUnetHTA patient survey is that patients with AMD often lose their autonomy and mobility and experience many difficulties in daily life. With current anti-VEGF treatments, regular hospital visits are a significant burden in terms of time, travel arrangements, financial issues, fear of injections and injection-related AEs. Patients expect new treatments to have long-lasting efficacy and less frequent injections. Unfortunately, the HAWK and HARRIER trial designs do not allow any conclusions regarding injection frequency between brolucizumab and aflibercept. The same limitation applies to other treatment options included in the NMA: the different dosing schemes cannot be compared with each other in terms of injection frequency.
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7 CONCLUSIONS
Two pivotal phase III RCTs showed the noninferiority of brolucizumab in comparison to aflibercept in terms of visual function measured as BCVA in the treatment of patients with nAMD. Brolucizumab 6 mg Q8W or Q12W has only been compared to aflibercept 2 mg dosed at fixed intervals of Q8W and not to other dosing schemes commonly used in clinical practice. Because the dosing schemes were different for brolucizumab and aflibercept in the HAWK and HARRIER trials, the trial design does not allow any conclusions to be drawn about treatment burden (injection frequency) between these two drugs. Consequently, it is unknown how brolucizumab compares with existing flexible dose regimens, so no advantages related to treatment burden can be anticipated with available data. Further investigations involving comparable treatment regimens would be needed.
In comparison to aflibercept, the incidence of intraocular inflammation and retinal artery occlusive events were higher for brolucizumab. These safety concerns were raised also in European public assessment report and a close monitoring is requested in post-marketing setting to further investigate these events (27). The clinical trial data presented for brolucizumab did not raise previously undetected safety concerns for anti-VEGF treatments, at least up to 2 years of use. There are no safety data for brolucizumab beyond 2 years of treatment or in bilateral use.
Evidence of the efficacy and safety of brolucizumab is based only on data for anti-VEGF treatment– naïve patients. There is no evidence regarding the efficacy and safety of brolucizumab in patients with nAMD previously treated with an anti-VEGF agent.
Direct comparisons to ranibizumab and bevacizumab are not available. Indirect comparisons based on NMA between brolucizumab and ranibizumab showed no differences in the main outcome (mean change in BCVA) or most of the other outcomes. Differences between brolucizumab and bevacizumab remain unknown since direct comparisons are not available and indirect comparisons between these two treatments were not formally conducted.
March 2020 EUnetHTA Joint Action 3 WP4 78 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
8 REFERENCES
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82. Arnold JJ. Age-related macular degeneration: anti-vascular endothelial growth factor treatment. BMJ Clin Evid. 2016;2016. 83. Solomon SD, Lindsley KB, Krzystolik MG, Vedula SS, Hawkins BS. Intravitreal Bevacizumab Versus Ranibizumab for Treatment of Neovascular Age-Related Macular Degeneration: Findings from a Cochrane Systematic Review. Ophthalmology. 2016;123(1):70-7.e1. 84. Chen G, Li W, Tzekov R, Jiang F, Mao S, Tong Y. Bevacizumab versus ranibizumab for neovascular age-related macular degeneration: a meta-analysis of randomized controlled trials. Retina. 2015;35(2):187-93. 85. Schmid MK, Bachmann LM, Fas L, Kessels AG, Job OM, Thiel MA. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol. 2015;99(2):141-6. 86. Barbosa BRD, Barbosa SF, Tavares GD, Chacra NAB, Pinto TdJA. Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration. Brazilian Journal of Pharmaceutical Sciences. 2014;50:63- 72. 87. Jiang S, Park C, Barner JC. Ranibizumab for age-related macular degeneration: a meta- analysis of dose effects and comparison with no anti-VEGF treatment and bevacizumab. J Clin Pharm Ther. 2014;39(3):234-9. 88. Kodjikian L, Decullier E, Souied EH, Girmens JF, Durand EE, Chapuis FR, et al. Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials. Graefes Arch Clin Exp Ophthalmol. 2014;252(10):1529-37. 89. Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. The Cochrane database of systematic reviews. 2014(8):Cd005139. 90. Thulliez M, Angoulvant D, Le Lez ML, Jonville-Bera AP, Pisella PJ, Gueyffier F, et al. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132(11):1317-26. 91. Wang W, Zhang X. Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: a meta-analysis. PLoS One. 2014;9(10):e109744. 92. Wu B, Wu H, Liu X, Lin H, Li J. Ranibizumab versus bevacizumab for ophthalmic diseases related to neovascularisation: a meta-analysis of randomised controlled trials. PLoS One. 2014;9(7):e101253. 93. Zhang XY, Guo XF, Zhang SD, He JN, Sun CY, Zou Y, et al. Comparison of bevacizumab and ranibizumab in age-related macular degeneration: a systematic review and meta-analysis. Int J Ophthalmol. 2014;7(2):355-64. 94. Anothaisintawee T, Leelahavarong P, Ratanapakorn T, Teerawattananon Y. The use of comparative effectiveness research to inform policy decisions on the inclusion of bevacizumab for the treatment of macular diseases in Thailand's pharmaceutical benefit package. Clinicoecon Outcomes Res. 2012;4:361-74. 95. Pitlick JM, Vecera KF, Barnes KN, Reski JW, Forinash AB. Bevacizumab for the treatment of neovascular age-related macular degeneration. Ann Pharmacother. 2012;46(2):290-6. 96. Schmucker C, Ehlken C, Agostini HT, Antes G, Ruecker G, Lelgemann M, et al. A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard. PLoS One. 2012;7(8):e42701. 97. C. W. Avastin® bei Altersbedingter Makuladegeneration. [Avastin® for age-related macular degeneration] Vienna: Ludwig Boltzmann Institut fuer Health Technology Assessment (LBIHTA). Rapid Assessment Nr 5. 2012. 98. Mitchell P. A systematic review of the efficacy and safety outcomes of anti-VEGF agents used for treating neovascular age-related macular degeneration: comparison of ranibizumab and bevacizumab. Curr Med Res Opin. 2011;27(7):1465-75. 99. Schmucker C, Loke YK, Ehlken C, Agostini HT, Hansen LL, Antes G, et al. Intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a safety review. Br J Ophthalmol. 2011;95(3):308-17. 100. Jyothi S, Chowdhury H, Elagouz M, Sivaprasad S. Intravitreal bevacizumab (Avastin) for age- related macular degeneration: a critical analysis of literature. Eye (Lond). 2010;24(5):816-24. 101. Schmucker C, Ehlken C, Hansen LL, Antes G, Agostini HT, Lelgemann M. Intravitreal bevacizumab (Avastin) vs. ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a systematic review. Curr Opin Ophthalmol. 2010;21(3):218-26.
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102. Andriolo RB, Puga ME, Belfort Junior R, Atallah AN. Bevacizumab for ocular neovascular diseases: a systematic review. Sao Paulo Med J. 2009;127(2):84-91. 103. Schouten JS, La Heij EC, Webers CA, Lundqvist IJ, Hendrikse F. A systematic review on the effect of bevacizumab in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2009;247(1):1-11. 104. Ziemssen F, Grisanti S, Bartz-Schmidt KU, Spitzer MS. Off-label use of bevacizumab for the treatment of age-related macular degeneration: what is the evidence? Drugs Aging. 2009;26(4):295-320. 105. Brown A, Hodge W, Cruess A, Blackhouse G, Hopkins R, McGahan L, et al. Management of neovascular age-related macular degeneration: systematic drug class review and economic evaluation. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH). Technology Report No 110. 2008. 106. Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, et al. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(10):1837-46. 107. Escassi Pérez C, Márquez Calderón S. Eficacia y seguridad de las nuevas terapias para la degeneración macular asociada a la edad [Disponible en: https://www.aetsa.org/publicacion/eficacia-y-seguridad-de-las-nuevas-terapias-para-la- degeneracion-macular-asociada-a-la-edad/]. Sevilla: Agencia de Evaluación de Tecnologías Sanitarias. Informe 10/2007. 2007. 108. Iu LP, Kwok AK. An update of treatment options for neovascular age-related macular degeneration. Hong Kong Med J. 2007;13(6):460-70. 109. Wild C, Adlbrecht C. Avastin for age-related macular degeneration. Vienna: Ludwig Boltzmann Institut fuer Health Technology Assessment (LBI-HTA). Rapid Assessment LBI-HTA 02. 2007. 110. Bashshur ZF, Schakal A, Hamam RN, El Haibi CP, Jaafar RF, Noureddin BN. Intravitreal bevacizumab vs verteporfin photodynamic therapy for neovascular age-related macular degeneration. Arch Ophthalmol. 2007;125(10):1357-61. 111. Costagliola C, Romano MR, Rinaldi M, dell'Omo R, Chiosi F, Menzione M, et al. Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Br J Ophthalmol. 2010;94(2):180-4. 112. Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve- month results of the DENALI study. Ophthalmology. 2012;119(5):1001-10. 113. Schmidt-Erfurth U, Eldem B, Guymer R, Korobelnik JF, Schlingemann RO, Axer-Siegel R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age- related macular degeneration: the EXCITE study. Ophthalmology. 2011;118(5):831-9. 114. Tano Y, Ohji M, Group E-IS. EXTEND-I: safety and efficacy of ranibizumab in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Acta Ophthalmol. 2010;88(3):309-16. 115. Heier JS, Boyer DS, Ciulla TA, Ferrone PJ, Jumper JM, Gentile RC, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol. 2006;124(11):1532-42. 116. Hahn R, Sacu S, Michels S, Varga A, Weigert G, Geitzenauer W, et al. [Intravitreal bevacizumab versus verteporfin and intravitreal triamcinolone acetonide in patients with neovascular age-related macula degeneration]. Ophthalmologe. 2007;104(7):588-93. 117. Ho AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age- related macular degeneration. Ophthalmology. 2014;121(11):2181-92. 118. Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: a phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006;113(4):633.e1-4. 119. Lazic R, Gabric N. Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration. Ophthalmology. 2007;114(6):1179-85. 120. Larsen M, Schmidt-Erfurth U, Lanzetta P, Wolf S, Simader C, Tokaji E, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve- month MONT BLANC study results. Ophthalmology. 2012;119(5):992-1000. 121. Potter MJ, Claudio CC, Szabo SM. A randomised trial of bevacizumab and reduced light dose photodynamic therapy in age-related macular degeneration: the VIA study. Br J Ophthalmol. 2010;94(2):174-9.
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122. Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology. 2009;116(9):1731-9. 123. Weigert G, Michels S, Sacu S, Varga A, Prager F, Geitzenauer W, et al. Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular age-related macular degeneration: 6-month results of a prospective, randomised, controlled clinical study. Br J Ophthalmol. 2008;92(3):356-60. 124. Li J, Xu J, Chen Y, Zhang J, Cao Y, Lu P. Efficacy Comparison of Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. J Ophthalmol. 2018;2018:1425707. 125. Zhang Y, Chioreso C, Schweizer ML, Abramoff MD. Effects of Aflibercept for Neovascular Age- Related Macular Degeneration: A Systematic Review and Meta-Analysis of Observational Comparative Studies. Invest Ophthalmol Vis Sci. 2017;58(13):5616-27. 126. Hussain RM, Hariprasad SM, Ciulla TA. Treatment Burden in Neovascular AMD:Visual Acuity Outcomes are Associated With Anti-VEGF Injection Frequency. Ophthalmic Surg Lasers Imaging Retina. 2017;48(10):780-4. 127. Gemenetzi M, Patel PJ. A Systematic Review of the Treat and Extend Treatment Regimen with Anti-VEGF Agents for Neovascular Age-Related Macular Degeneration. Ophthalmol Ther. 2017;6(1):79-92. 128. Gerding H. Long-term Results of Intravitreal Anti-VEGF Injections in Wet AMD: A Meta- Analysis. Klin Monbl Augenheilkd. 2016;233(4):471-4. 129. Mikacic I, Bosnar D. Intravitreal Bevacizumab and Cardiovascular Risk in Patients with Age- Related Macular Degeneration: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies. Drug Saf. 2016;39(6):517-41. 130. New Zealand National Health Committee (NHC). Age-related macular degeneration. Wellington: New Zealand National Health Committee (NHC). 2015. 131. CADTH. Long-term use of bevacizumab for the treatment of age-related macular degeneration: safety. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH). Rapid Response. 2014. 132. Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of aflibercept for the treatment of patients with neovascular age-related macular degeneration. Clin Ophthalmol. 2013;7:495- 501. 133. Fadda V, Maratea D, Trippoli S, Messori A. Treatments for macular degeneration: summarising evidence using network meta-analysis. Br J Ophthalmol. 2011;95(10):1476-7. 134. van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ, Hendrikse F, Schouten JS. A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. Retina. 2011;31(8):1449-69. 135. Micieli JA, Micieli A, Smith AF. Identifying systemic safety signals following intravitreal bevacizumab: systematic review of the literature and the Canadian Adverse Drug Reaction Database. Can J Ophthalmol. 2010;45(3):231-8. 136. Kymes S, Vollman D, Spry C. Supplement to “The Role of Pharmacologic Management in Neovascular Age-Related Macular Degeneration: Clinical and Cost-Effectiveness”. Ottawa: Canadian Agency for Drugs and Technologies in Health. 2009. 137. Mengarelli C, Augustovski, Pichon-Riviere A, García Martí S, Alcaraz A, Bardach A, et al. Ranibizumab, bevacizumab ya para degeneración macular asociada a la edad. [Ranibizumab, bevacizumab y aflibercept for age-related macular degeneration] Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rapida No. 398. 2015. 138. Ma N, He XG. [Efficacy and safety in treatment of ocular neovascularization by Bevacizumab versus Ranibizumab: a meta-analysis]. Zhonghua Yan Ke Za Zhi. 2010;46(3):263-7.
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APPENDIX 1: GUIDELINES FOR MANAGEMENT OF AMD
Table A1. Overview of guidelines used for this assessment Name of society/organisation Date of issue Country/ies Summary of recommendation issuing guidance to which applicable Agencia de Evaluación de 2011 Spain Efficacy: bevacizumab and ranibizumab provide similar gains in visual acuity and in Tecnologías Sanitarias de reduction of visual acuity loss at 1 year follow-up. Andalucía (50) Safety: systemic adverse effects are rare for both bevacizumab and ranibizumab. (No level of evidence/strength of recommendation provided) American Academy of 2020 United States of America With the introduction of the VEGF inhibitors pegaptanib sodium, off-label Ophthalmology (51) bevacizumab, ranibizumab, and aflibercept, more effective treatments for neovascular AMD exist. The VEGF inhibitors have demonstrated improved visual and anatomic outcomes compared with other therapies. Anti-VEGF therapies have become first-line therapy for treating and stabilizing most cases of nAMD and a Cochrane systematic review demonstrates the effectiveness of these agents to maintain visual acuity. (I+, Good quality, Strong recommendation) Presently, there does not appear to be a significant difference in efficacy between ranibizumab and bevacizumab. SRs and NMAs have concluded that bevacizumab and ranibizumab have equivalent efficacy for BCVA, whereas ranibizumab has greater reduction in central macular thickness. Aflibercept and ranibizumab have comparable efficacy for BCVA and central macular thickness. If a difference in safety between these anti-VEGF drugs exists, it is minimal. (I+, Good quality, Strong recommendation) Belgian Retina Society (9) 2019 Belgium Three different intravitreal anti-VEGF agents (bevacizumab, ranibizumab, and aflibercept) are currently available for treating nAMD. Until now, no clinically significant differences in the efficacy and safety between the different anti-VEGF drugs have been shown in the treatment of nAMD during the first few years of follow- up. In case of recent cardiovascular event (within 3 months), anti-VEGF treatment can be considered after careful evaluation of the possible treatment related benefits and adverse effects. (No level of evidence/strength of recommendation provided) Consejería de Sanidad, 2012 Spain Taking into account the efficacy and safety evidence on the use ranibizumab and Servicio Madrileño de Salud bevacizumab, and the wide accumulated experience of use, it is considered that both (77) drugs have a similar benefit/risk profile for the treatment of patients with nAMD. (No level of evidence/strength of recommendation provided)
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Name of society/organisation Date of issue Country/ies Summary of recommendation issuing guidance to which applicable European Society of Retina 2014 Europe Ranibizumab continuously for 2 years on a PRN regimen with strict monthly Specialists (EURETINA) (2) monitoring and retreatment, whenever any evidence of fluid is noted by retinal imaging has been found to be the regimen that secures the optimum results in vision outcome. The recommendations are based on the ANCHOR, MARINA, PIER, EXCITE, HARBOR and CATT study data (evidence level I) and as well as the SECURE and HORIZON study data (evidence level II). The CATT and IVAN studies results indicate that ranibizumab and bevacizumab both confer solid visual function benefits. Non-inferiority was proven with monhtly use of both drugs, and among as-needed treatments. Bevacizumab used in a PRN regimen failed to demonstrate non-inferiority to monthly ranibizumab. Therefore, the choice of fixed month regimen is relevant when off-label bevacizumab is used. How much reduction in ocular efficacy one would be willing to sacrifice for reducing the number of injections and/or costs might depend on individual circumstances. No major safety issues have emerged, but conclusive data are lacking, and none of the trials were powered for safety. Nevertheless, bevacizumab’s impact on plasma concentrations of VEGF and its prolonged half-life in the circulation are proven. Therefore, the individual physical condition of each patient should be considered in the choice of therapy. Informed consent after discussing the optimal benefit, comfort and risks and the off-label status of the drug is mandatory. (Evidence level I). The EU label for Eylea (aflibercept) recommends three initial injections at monthly intervals, followed by eight weekly injections without any subsequent monitoring. However, based on VIEW 1 study data, monthly aflibercept provided statistically superior visual gains compared with aflibercept dosed every 8 weeks. Many interventional studies suggest a superior anatomic efficacy of aflibercept compared with ranibizumab and bevacizumab. The bimonthly fluctuations in BCVA and CRT values are small when averaged but are more impressive individually. This suggests patients with more intensive disease activity who can benefit from a monthly regimen should be identified. Beyond the first year, increased dosing with continued monthly/bimonthly injections may be needed in eyes with morphologic signals which are likely associated with aggressive progression of CNV disease. (Evidence level I) Finnish Ophthalmological 2017 Finland Bevacizumab and ranibizumab seem to have the same efficacy in maintaining visual Society (11) acuity in the treatment of nAMD during 1-2 years of follow-up. (Evidence level B). Monthly or less frequent intravitreal injections of aflibercept seem to be as effective as monthly injected ranibizumab in maintaining visual acuity. (Evidence level B). There seem to be no clinically significant short-term safety differences between ranibizumab and bevacizumab in the treatment of nAMD. (Evidence level B). Monthly or less frequent intravitreal injections of aflibercept may be as safe as monthly injected ranibizumab in the treatment of nAMD. (Evidence level C).
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Name of society/organisation Date of issue Country/ies Summary of recommendation issuing guidance to which applicable Fondazione G.B. Bietti per lo 2008 Italy Taking into account only clinical evidence, anti-VEGF drugs administered at a high Studio e la Ricerca in frequency (pegaptanib every 6 weeks or ranibizumab every 4 weeks) should be given Oftalmologia (12) to patients with nAMD. (Strong recommendation of pegaptanib and ranibizumab; high quality of evidence for ranibizumab; moderate quality evidence for pegaptanib). Anti-VEGF therapy must consist of a loading phase of three doses, followed by individualized regimens. (Strong recommendation based on very low quality evidence for pegaptanib and low quality evidence for ranibizumab). Haute Autorité de Santé (13) 2017 France Be aware that no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials considered by the guideline committee. Given the guideline committee’s view that there is equivalent clinical effectiveness and safety of different anti-VEGF agents (aflibercept, bevacizumab, and ranibizumab), comparable regimens will be more cost effective if the agent has lower net acquisition, administration and monitoring costs. (No level of evidence/strength of recommendation provided). Sociedad Española de Retina y 2014 Spain Based on CATT and IVAN study data, bevacizumab and ranibizumab have equivalent Vítreo (15) effects on BCVA when administered in equivalent regimens, while anatomical outcomes favour ranibizumab. No significant differences in safety have been identified after 2 years of treatment. Monthly treatment regimens have better visual outcomes than PRN regimens, although the difference is not clinically relevant. The risk of geographic atrophy is higher with monthly regimens (Evidence level I, strength of recommendation A) Aflibercept every eight weeks has demonstrated equivalent efficacy and safety to monthly ranibizumab (Evidence level I, strength of recommendation A) Abbreviations: AMD=age-related macular degeneration; BCVA=best corrected visual acuity; CNV=choroidal neovascularisation; CRT=central retinal thickness; nAMD=neovascular age-related macular degeneration; PRN=pro re nata, VEGF=vascular endothelial growth factor.
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APPENDIX 2: SEARCHES STRATEGIES FOR BEVACIZUMAB LITERATURE REVIEW
Strategies to select NMAs and SRs
Database: Ovid MEDLINE to October 24, 2019
1 exp Macular degeneration/ 2 exp retinal degeneration/ 3 exp retinal neovascularization/ 4 exp choroidal neovascularization/ 5 exp macula lutea/ 6 maculopath$.tw. 7 ((macul$ or retina$ or choroid$) adj3 degener$).tw. 8 ((macul$ or retina$ or choroid$) adj3 neovasc$).tw. 9 (macula$ adj2 lutea).tw. 10 (AMD or ARMD or CNV).tw. 11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 12 angiogenesis inhibitors/ 13 angiogenesis inducing agents/ 14 endothelial growth factors/ 15 vascular endothelial growth factors/ 16 (anti adj2 VEGF$).tw. 17 (endothelial adj2 growth adj2 factor$).tw. 18 (anti adj1 angiogen$).tw. 19 *Antibodies, Monoclonal/ad, tu [Administration & Dosage, Therapeutic Use] 20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF).ti,ab. 21 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 22 11 and 21 23 (letter or "case report*" or "historical article*" or (commentor editorial or in vitro or news)).pt. 24 22 not 23 25 animals/ not (animals/ and humans/) 26 24 not 25 27 limit 26 to "reviews (maximizes specificity)" 25 animals/ not (animals/ and humans/) 26 24 not 25 27 limit 26 to "reviews (maximizes specificity)"
Database: Embase to October 24, 2019
#1 'macular degeneration'/exp #2 'retina degeneration'/exp #3 'retina neovascularization'/exp #4 'subretinal neovascularization'/exp #5 'retina macula lutea'/exp #6 maculopath$:ti,ab #7 ((macul* OR retina* OR choroid$) NEAR/3 degener*):ti,ab #8 ((macul* OR retina* OR choroid*) NEAR/3 neovasc*):ti,ab #9 (macula* NEAR/2 lutea):ti,ab #10 amd:ti,ab OR armd:ti,ab OR cnv:ti,ab
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#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 #12 'angiogenesis inhibitor'/exp #13 'angiogenic factor'/exp #14 'endothelial cell growth factor'/exp #15 'vasculotropin'/exp #16 (anti NEAR/2 vegf*):ti,ab #17 (endothelial NEAR/2 growth NEAR/2 factor*):ti,ab #18 (anti NEAR/1 angiogen*):ti,ab #19 'monoclonal antibody'/mj #20 #19 AND ('drug administration'/lnk OR 'drug dose'/lnk OR 'drug therapy'/lnk) #21 bevacizumab:ti,ab OR avastin:ti,ab OR r435:ti,ab OR rg435:ti,ab OR rhumabvegf:ti,ab #22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #20 OR #21 #23 #11 AND #22 #24 'conference abstract'/it OR 'conference paper'/it OR 'note'/it OR 'short survey'/it OR 'abstract report'/exp OR 'abstract report' OR 'letter'/exp OR 'letter' #25 #23 NOT #24 #26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND [systematic review]/lim AND ([systematic review]/lim OR [meta analysis]/lim)
Database: CRD to October 24, 2019
1 (MeSH DESCRIPTOR Macular Degeneration EXPLODE ALL TREES) 2 (MeSH DESCRIPTOR retinal degeneration EXPLODE ALL TREES) 3 (MeSH DESCRIPTOR retinal neovascularization EXPLODE ALL TREES) 4 (MeSH DESCRIPTOR choroidal neovascularization EXPLODE ALL TREES) 5 MeSH DESCRIPTOR macula lutea EXPLODE ALL TREES 6 (maculopath*) 7 (((macul* or retina* or choroid*) NEAR3 degener*)) 8 ((macula* NEAR2 lutea)) 9 ((AMD or ARMD or CNV)) 10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 11 MeSH DESCRIPTOR angiogenesis inhibitors EXPLODE ALL TREES 12 MeSH DESCRIPTOR angiogenesis inducing agents EXPLODE ALL TREES 13 MeSH DESCRIPTOR endothelial growth factors EXPLODE ALL TREES 14 MeSH DESCRIPTOR Vascular Endothelial Growth Factors EXPLODE ALL TREES 15 ((anti NEAR2 VEGF*)) 16 ((endothelial NEAR2 growth NEAR2 factor*)) 17 ((anti NEAR1 angiogen*)) 18 MeSH DESCRIPTOR Antibodies, Monoclonal WITH QUALIFIERS AD, TU 19 ((bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF)) 20 #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 21 #10 AND #20
Database: Cochrane to October 24, 2019
#1 [mh "Macular Degeneration"] #2 [mh "retinal degeneration"] #3 [mh "retinal neovascularization"] #4 [mh "choroidal neovascularization"] #5 [mh "macula lutea"]
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#6 maculopath*:ti,ab #7 ((macul* or retina$ or choroid*) NEAR/3 degener*):ti,ab #8 ((macul* or retina* or choroid*) NEAR/3 neovasc*):ti,ab #9 (macula* NEAR/2 lutea):ti,ab #10 (AMD or ARMD or CNV):ti,ab #11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 #12 [mh "angiogenesis inhibitors"] #13 [mh "angiogenesis inducing agents"] #14 [mh "endothelial growth factors"] #15 [mh "vascular endothelial growth factors"] #16 (anti NEAR/2 VEGF*):ti,ab #17 (endothelial NEAR/2 growth NEAR/2 factor*):ti,ab #18 (anti NEAR/1 angiogen*):ti,ab #19 [mh ^"Antibodies, Monoclonal"/AD,TU] #20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF):ti,ab #21 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 #22 #11 AND #21 in Cochrane Reviews
Strategies to update the included NMAs and SRs
Database: Ovid MEDLINE January 1, 2018 to November 19, 2019
1 exp Macular degeneration/ 2 exp retinal degeneration/ 3 exp retinal neovascularization/ 4 exp choroidal neovascularization/ 5 exp macula lutea/ 6 maculopath$.tw. 7 ((macul$ or retina$ or choroid$) adj3 degener$).tw. 8 ((macul$ or retina$ or choroid$) adj3 neovasc$).tw. 9 (macula$ adj2 lutea).tw. 10 (AMD or ARMD or CNV).tw. 11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 12 angiogenesis inhibitors/ 13 angiogenesis inducing agents/ 14 endothelial growth factors/ 15 vascular endothelial growth factors/ 16 (anti adj2 VEGF$).tw. 17 (endothelial adj2 growth adj2 factor$).tw. 18 (anti adj1 angiogen$).tw. 19 *Antibodies, Monoclonal/ad, tu [Administration & Dosage, Therapeutic Use] 20 (bevacizumab or avastin or R435 or RG435 or rhuMAbVEGF).ti,ab. 21 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 22 11 and 21 23 (letter or "case report*" or "historical article*" or (commentor editorial or in vitro or news)).pt. 24 22 not 23 25 animals/ not (animals/ and humans/) 26 24 not 25 27 limit 26 to randomized controlled trial 28 limit 27 to yr="2018 -Current"
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Database: Embase January 1, 2018 to November 19, 2019
#1 'macular degeneration'/exp #2 'retina degeneration'/exp #3 'retina neovascularization'/exp #4 'subretinal neovascularization'/exp #5 'retina macula lutea'/exp #6 maculopath$:ti,ab #7 ((macul* OR retina* OR choroid$) NEAR/3 degener*):ti,ab #8 ((macul* OR retina* OR choroid*) NEAR/3 neovasc*):ti,ab #9 (macula* NEAR/2 lutea):ti,ab #10 amd:ti,ab OR armd:ti,ab OR cnv:ti,ab #11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 #12 'angiogenesis inhibitor'/exp #13 'angiogenic factor'/exp #14 'endothelial cell growth factor'/exp #15 'vasculotropin'/exp #16 (anti NEAR/2 vegf*):ti,ab #17 (endothelial NEAR/2 growth NEAR/2 factor*):ti,ab #18 (anti NEAR/1 angiogen*):ti,ab #19 'monoclonal antibody'/mj #20 #19 AND ('drug administration'/lnk OR 'drug dose'/lnk OR 'drug therapy'/lnk) #21 bevacizumab:ti,ab OR avastin:ti,ab OR r435:ti,ab OR rg435:ti,ab OR rhumabvegf:ti,ab OR lucentis*:ti,ab OR rhufab*:ti,ab OR '347396 82 1':ti,ab #22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #20 OR #21 #23 #11 AND #22 #24 'conference abstract'/it OR 'conference paper'/it OR 'note'/it OR 'short survey'/it OR 'abstract report'/exp OR 'abstract report' OR 'letter'/exp OR 'letter' #25 #23 NOT #24 #26 #25 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) AND [2018-2019]/py AND [randomized controlled trial]/lim
March 2020 EUnetHTA Joint Action 3 WP4 92 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
APPENDIX 3: SEARCHES PERFORMED BY THE INFORMATION SPECIALIST TO THE COMPLETENESS OF THE STUDY POOL
Search 1: Search in study registries for Brolucizumab
1. ClinicalTrials.gov Provider: U.S. National Institutes of Health
URL: http://www.clinicaltrials.gov Input interface: Advanced Search Search strategy Condition of disease Age Related Macular Degeneration Other terms brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258
2. EU Clinical Trials Register Provider: European Medicines Agency
URL: https://www.clinicaltrialsregister.eu/ctr-search/search Input interface: Basic Search Search strategy age related macular degeneration AND (brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258)
3. International Clinical Trials Registry Platform Search Portal Provider: World Health Organization
URL:http://apps.who.int/trialsearch/ Input interface: Standard Search Search strategy age related macular degeneration AND brolucizumab OR esba1008 OR esba 2008 OR dlx1008 OR dlx 1008 OR rth258 OR rth 258
March 2020 EUnetHTA Joint Action 3 WP4 93 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Search 2: Search in study registries for ranibizumab, bevacizumab and aflibercept
1. ClinicalTrials.gov Provider: U.S. National Institutes of Health
URL: http://www.clinicaltrials.gov Input Interface: Advance Search Search strategy (ranibizumab OR lucentis OR rg3645 OR rhuFab) OR (aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap) OR (bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435) | Age Related Macular Degeneration
2. EU Clinical Trials Register Provider: European Medicines Agency
URL: https://www.clinicaltrialsregister.eu/ctr-search/search Input interface: Basic Search Search strategy age related macular degeneration AND ((ranibizumab OR lucentis OR rg3645 OR rhuFab) OR (aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap) OR (bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435) )
3. International Clinical Trials Registry Platform Search Portal Provider: World Health Organization
URL:http://apps.who.int/trialsearch/ Input interface: Standard Search Search strategy age related macular degeneration AND ranibizumab OR lucentis OR rg3645 OR rhuFab OR aflibercept OR eylea OR AVE 0005 OR AVE0005 OR AVE005 OR AVE 005 OR Zaltrap OR VEGF trap OR bevacizumab OR avastin OR rhumbab-vegf OR R435 or RG435
March 2020 EUnetHTA Joint Action 3 WP4 94 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Search 3: Search focused in Pubmed
Provider: National Library of Medicine
Search Query Items found #1 Search neovascular age related macular degeneration 4747 #2 Search BROLUCIZUMAB 21 #3 Search (neovascular age related macular degeneration) AND 9 BROLUCIZUMAB #4 Search 30986442[uid] 1 #5 Similar articles for PubMed (Select 30986442) 111 #6 Select 20 document(s) 20 #7 Search 28551167[uid] 1 #8 Similar articles for PubMed (Select 28551167) 315 #9 Select 20 document(s) 20 #10 #3 OR #6 OR #9 40
March 2020 EUnetHTA Joint Action 3 WP4 95 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
APPENDIX 4: RESULTS FROM THE SCREENING OF THE SEARCHES OF BEVACIZUMAB
Table A2. Information about the screening of the records from the searches of bevacizumab to include SRs and NMAs. MEDLINE Embase CRD Cochrane TOTAL Total number of records retrieved 212 22 125 12 371 Duplicated records 5 9 45 12 71 Excluded based on title or abstract 167 10 67 - 244 Different population 90 5 31 - 126 Different interventions 37 4 17 - 58 Different comparators (combination 3 - - - 3 therapy) Different outcomes 4 - 12 - 16 Different objectives 32 - 5 - 37 Different designs 1 1 2 - 4 Number of records to be reviewed by 40 3 13 - 56 full text Full text not available, excluded based 2 - 5 - 7 on abstract Excluded based on full text 9 1 4 - 14 Included in the assessment report 29 2 4 - 35
Table A3. Information about the screening of the records from the searches to update included SRs and NMAs. MEDLINE Embase TOTAL Number records retrieved from databases 87 23 110 Duplicated 2 - 2 Excluded based on title or abstract 85 23 108 Different population 60 14 74 Different interventions 13 6 19 Different comparators (combination therapy) 1 - 1 Different outcomes - - - Different objectives 11 3 14 Excluded based on full text 0 0 0 Included 0 0 0
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APPENDIX 5: STUDIES (SR OR NMA) THAT MET THE ELIGIBILITY CRITERIA FOR THE BEVACIZUMAB LITERATURE REVIEW
Table A4. Studies (SR or NMA) that met the eligibility criteria for the bevacizumab literature review Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Solomon SD. Inclusion criteria: Cochrane Central Register of The review included a total of 6347 2019 (30) - Population: patients with nAMD; Controlled Trials participants from 16 RCTs: - Interventions and comparators: anti-VEGF treatment versus another treatment, (CENTRAL), which contains ABC 2010 sham treatment, or no treatment; the Cochrane Eyes and ANCHOR 2006 - Primary outcome: BCVA at one-year follow-up; Vision Trials Register; BISWAS 2011 - Study design: Only RCTs; MEDLINE Ovid; Embase BRAMD 2016 - Follow up time of the included studies: at least one year and outcomes at two- Ovid; the Latin American and CATT 2011 year follow-up, when these data were available. Caribbean Health Sciences GEFAL 2013 Literature Database IVAN 2013 Exclusion criteria: Interventions: (LILACS); the International LUCAS 2015 - No control or comparator group; Standard Randomized MANTA 2013 - Comparison of different doses of one anti-VEGF treatment against another; Controlled Trials Number MARINA 2006 - Anti-VEGF agents in combination with other treatments; (ISRCTN) Registry; PIER 2008 - Studies of aflibercept (not considered because other Cochrane reviews have ClinicalTrials.gov; and the SACU 2009 evaluated it); World Health Organization SAVE-AMD 2017 - Comparison of different treatment schedules (e.g. monthly vs. as needed dosing) (WHO) International Clinical SCHOLLER 2014 (not considered because other Cochrane reviews have evaluated those Trials Registry Platform SUBRAMANIAN 2010 interventions). (ICTRP). VISION 2004 The search included no language or publication year restrictions. The date of the most recent search was January 31, 2018.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Pham B. 2019 Inclusion criteria: MEDLINE, Embase and Twelve RCTs were included for (29) - Population: patients ≥ 18 years of age and with retinal conditions including wet Cochrane Central Register of patients with nAMD: AMD, diabetic macular edema, macular edema due to retinal vein occlusion and Controlled Trials were BRAMD 2016 myopic choroidal neovascularisation. searched from inception to LUCAS 2015 - Interventions: anti-VEGF drugs in use in Canada, namely ranibizumab, 17 August 2017 Scholler 2014 intravitreal bevacizumab and aflibercept. IVAN 2013 - Comparators: placebo, ranibizumab, intravitreal bevacizumab or aflibercept. GEFAL 2013 - Outcomes: 14 outcomes (including five efficacy and nine safety outcomes) were MANTA 2013 selected a priori at the protocol stage according to feedback from the research VIEW1 2012 team, clinical experts, patient advocacy groups, industry stakeholders and CADTH. VIEW2 2012 - Study design: parallel- and cluster-RCTs. Biswas 2011 a y b - Follow-up: all reports pertaining to an RCT were located to obtain data at the CATT 2011 longest follow-up duration. Subramanian 2010
Exclusion criteria: - Population: RCTs reporting only results for paediatric patients - Interventions: studies evaluating the anti-VEGF drug pegaptanib, or studies that compared an anti-VEGF drug with other comparators (such as photodynamic therapy, intravitreal corticosteroids, grid laser photocoagulation or cataract removal surgery). Low A. 2019 - Population: adults with nAMD, diabetic macular edema, or branch or central Ovid MEDLINE, PubMed, Eleven studies in nAMD: (78) retinal vein occlusion; Elsevier EMBASE, Ovid EMB Biswas 2011 - Intervention: aflibercept, bevacizumab or ranibizumab; Reviews, trial registries and BRAMD (Schauwvlieghe 2016) -Comparators: One anti-VEGF intervention versus another anti-VEGF intervention regulatory agency websites CATT (Martin 2012) (head-to-head). were searched from GEFAL (Kodjikian 2013) - Outcomes of interest: Short- and long-term outcomes; Visual acuity, functional database inception to 6 IVAN (Chakravarthy 20139 status, quality of life, systemic adverse events, ocular harms or cost-effectiveness; February 2017 LUCAS (Berg 2015) - Study design: controlled clinical trials (randomized or non-randomized); and MANTA (Krebs 2013) cohort and modelling studies that reported cost outcomes in the USA; Scholler 2014 - Follow-up: There was no minimum length of follow-up specified. Subramanian 2010 VIEW 1; Heier 2012 VIEW 2; Heier 2012
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Nguyen CL. Inclusion criteria: CENTRAL, Ovid MEDLINE, VISION 2004 2018 (79) - Population: nAMD; EMBASE, the metaRegister ANCHOR 2006 - Interventions and comparators: anti-VEGF treatment (pegaptanib, ranibizumab, of Controlled Trials (mRCT) MARINA 2006 bevacizumab, aflibercept or conbercept) compared to another treatment or each ClinicalTrials.gov and the PIER 2008 other. WHO International Clinical ABC 2010 -Outcomes: Efficacy: mean change in BCVA and in central macular thickness; Trials Registry Platform SACU 2009 Safety: death, arteriothrombotic and venous thrombotic events, and serious (ICTRP). CATT 2011 systemic adverse events. The final search was IVAN 2013 - Study design: RCTs; performed on June 2016. GEFAL 2013 - Follow up: at least one year, and outcomes at two-year follow-up, when these MANTA 2013 data were available. Subramanian Biswas 2011 Exclusion criteria: Interventions: LUCAS 2015 - No control or comparator group; BRAMD 2016 - Anti-VEGF agents used in combination with other treatments; VIEW 1 - Studies in which different doses of one anti-VEGF agent were compared with VIEW 2 each other.
Thulliez M. 2018 - Population: AMD, diabetic macular edema, or retinal vein occlusion diseases; PubMed and the Cochrane The article is an overview of (80) - Interventions: all anti-VEGF available treatments were considered (pegaptanib, Central Register of Systematic Reviews and Meta- bevacizumab, ranibizumab, and aflibercept); Controlled Trials databases analyses. The individual trials in - Comparators: All comparators were considered (treatments with comparison anti- Systematic reviews each of the ten SRs that were VEGF medication, sham procedures, absence of anti-VEGF treatments, and published between January included related to patient with absence of treatments of any kind); 1, 2011, and June 30, 2016 AMD were not reported in the - Outcomes: focused only on safety: serious adverse events; were included. overview of SRs. - Study design: meta-analyses or systematic reviews of clinical trials or observational studies; - Follow-up: There was no minimum length of follow-up specified. Wang X. 2018 To be considered eligible for inclusion in the meta-analysis, the studies had to PubMed, Embase, the 5 RCTs (81) meet the following criteria: Cochrane Library, and CATT 2011; - Population: previously untreated nAMD; clinicaltrials.gov from LUCAS 2015; - Intervention: bevacizumab versus ranibizumab; inception of the study until IVAN 2012; - Primary outcome: BCVA; August 2017. GEFAL 2013, - Study design: non-inferiority RCT; and BRAMD 2016. - Follow-up: one year.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Arnold JJ. 2016 - Population: exudative AMD; Medline, Embase, and the Two SRs (Mitchell 2011 and (82) - Interventions: bevacizumab, ranibizumab and aflibercept. Cochrane Database of Schmucker 2012), 10 RCTs - Outcomes: Visual acuity; quality of life; adverse effects (thrombotic events Systematic Reviews up to [MARINA (Rosenfeld 2006 and [myocardial infarction, stroke], infection, bleeding), and death; January 2014. Chang 2007), PIER, CATT, - Study design: systematic reviews and RCTs at least single blinded, and MANTA, GEFAL, HARBOR Study, containing 20 or more patients (10 in each arm), of whom more than 80% were EXCITE Study, IVAN, View 1 and followed up; View 2] and four further reports - Follow-up: Authors indicated that there was no minimum length of follow-up to (Subgroups analysis from MARINA include studies. and ANCHOR) were included.
Solomon SD. - Population: patients with nAMD; CENTRAL (Cochrane Eyes Six RCTs: 2016 (83) - Interventions and comparators: direct comparisons among intravitreal injections and Vision Group Trials Biswas 2011; of bevacizumab and ranibizumab, in comparable dosages and regimens; Register), Ovid MEDLINE, CATT 2011; - Outcomes: The primary outcome was 1-year gain in best-corrected visual acuity Ovid MEDLINE In-Process GEFAL 2013; (BCVA) of 15 or more logMAR letters; and Other Non-indexed IVAN 2013; - Study design: RCTs; Citations, Ovid MEDLINE MANTA 2013; - Follow-up: Trials in which participants were followed for at least one year. When Daily, Ovid OLDMEDLINE, Subramanian 2010. data were available, two years of follow up. EMBASE and LILACS. The metaRegister of Controlled Exclusion criteria: Interventions and comparators: Trials of aflibercept and trials Trials, clinicaltrials.gov, and that used bevacizumab or ranibizumab in combination with other treatments. the WHO International Clinical Trials Registry Platform (ICTRP). Databases were searched last on 27 March 2014. Chen G. 2015 - Population: patients with nAMD with minimum age of 50 years; PubMed, EMBASE, and the A total of six studies were included (84) - Intervention: bevacizumab versus ranibizumab; Cochrane Library. in the meta-analysis: CATT, IVAN, - Outcomes: mean change in BCVA from baseline, mean change in central The final search was MANTA, GEFAL Biswas, 2011 macular thickness from baseline, and safety (death, arteriothrombotic events, performed on December and Subramanian 2010. venous thrombotic events, and serious systemic adverse event); 2013. - Study design: RCTs; - Follow-up: There was no minimum length of follow-up specified.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Schmid MK. - Population: AMD; Medline, Premedline, Eleven trials assessing five active 2015 (85) - Interventions and comparators: aflibercept, bevacizumab or ranibizumab against EMBASE, SCOPUS and the treatments (ranibizumab 0.3mg, placebo or in a head-to-head fashion; Cochrane Library ranibizumab 0.5mg, bevacizumab - Outcomes: visual acuity and serious side effects; The search was last updated 1.25mg, aflibercept 0.5mg and - Study design: RCTs; in June 2013. aflibercept 2mg): ANCHOR 2006; - Follow-up: Studies had to include 1-year follow-up data. CATT 2011; IVAN 2013; MARINA 2006; VIEW1, VIEWS2; SAILOR 2009; FOCUS 2006; EXCITE 2011; MONT BLANC 2012 and DENALI 2012.
Barbosa BRD. Although in the abstract it is stated that the record is a systematic review, in the full The databases for the CATT; IVAN; Marina and 2014 (86) text, the methodology is not detailed. literature search are not ANCHOR (Brown et al., 2006; The inclusion and exclusion criteria are not described. specified. Rosenfeld et al., 2006). The study aimed at reviewing the literature related to the off-label indication and A systematic survey of the risks associated with the use of multi-dose vials in AMD treatment. scientific works and of electronic database relevant information up to November 2012 was carried out. Jiang S. 2014 - Population: AMD; A systematic literature Eight studies met the inclusion (87) - Interventions and comparators: ranibizumab or bevacizumab, treatment regimen search was conducted using criteria: ANCHOR 2006; MARINA clearly stated as monthly or as-needed/ quarterly; PubMed, Web of Science 2006; FOCUS 2007; PIER 2010; - Outcomes: efficacy: visual acuity outcomes (letters gained or number of patients and Google Scholar from CATT 2011; Subramanian 2010, ≥15 visual acuity letters); Jan 2004 to March 2013. SAILOR 2009 and EXCITE 2011. - Study design: Randomized- controlled clinical phase III or IV trials; - Follow-up: at least one-year follow-up. Kodjikian L. - Population: only patients with AMD; Medline, Embase, and the Five studies were included: 2014 (88) - Interventions and comparators: ranibizumab or bevacizumab; Cochrane Library and Trial Subramanian et al.; the CATT - Outcomes: efficacy (Functional and anatomical endpoints) and/or safety: adverse registers up to October study; the IVAN study; MANTA; events; 2013. Trial registers were and GEFAL. - Study design: RCTs; also checked for unpublished - Follow-up: at least one-year follow-up (whatever the injection regimen). studies.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Moja L. 2014 - Population: nAMD; CENTRAL, MEDLINE, Nine RCTs met eligibility criteria. (20) - Interventions and comparators: bevacizumab and ranibizumab irrespective of the EMBASE and other online Of these, six RCTs were dosage, whether treatment is continuous or discontinuous; databases were searched up completed and published (Biswas - Outcomes: Primary outcomes: death and all serious systemic adverse events. to 27 March 2014. 2011; CATT; GEFAL; IVAN; Secondary outcomes: specific serious systemic adverse events such as fatal and MANTA; Subramanian 2010),. non-fatal myocardial infarctions, strokes, arteriothrombotic events, serious Three RCTs were unpublished: infections; two were completed (BRAMD; - Study design: Head-to-head RCTs; LUCAS), and one was still - Follow-up: Trials were included irrespective of the duration of follow-up. ongoing (VIBERA) at the time of the report.
Solomon SD. - Population: Participants had nAMD as defined by study investigators; CENTRAL (Cochrane Eyes ANCHOR 2006; VISION 2004; 2014 (89) - Interventions and comparators: anti-VEGF treatment (pegaptanib, ranibizumab, and Vision Group Trials CATT 2011; MARINA 2006; PIER or bevacizumab) versus each other or a control treatment (e.g., sham treatment or Register), Ovid MEDLINE, 2008; Subramanian 2010; photodynamic therapy) or no treatment; Ovid MEDLINE In-Process MANTA 2013; Sacu 2009; ABC - Outcomes: Primary outcomes: BCVA at one year of follow up; and Other Non-indexed 2010; IVAN 2013; GEFAL 2013 - Study design: RCTs only Citations, Ovid MEDLINE and Biswas 2011. - Follow-up: Trials in which participants were followed for at least one year. When Daily, Ovid OLDMEDLINE, data were available, two years of follow up. EMBASE and LILACS. The metaRegister of Controlled Exclusion criteria: Interventions: Trials, clinicaltrials.gov, and - Different doses of one anti-VEGF treatment compared with each other, the WHO International - No control or comparator group. Clinical Trials Registry - Aflibercept Platform (ICTRP). - Anti-VEGF agents in combination with other treatments. Databases were searched last on 27 March 2014. Thulliez M. 2014 - Population: patients with wet AMD, diabetic macular edema, or retinal vein MEDLINE and Cochrane 21 studies were included in (90) occlusion. Central Register of quantitative synthesis. 12 in - Interventions and comparators: intravitreal ranibizumab or bevacizumab with no Controlled Trials databases patients with AMD: MARINA, treatment (sham) or a non-antiangiogenic treatment. Trials that compared different from inception until June 30, ANCHOR, FOCUS, PIER, treatment regimens were also included for a dose-response analysis; 2013. SAILOR, EXTEND-I, EXCITE, - Outcomes: Clinically relevant cardiovascular outcomes as well as mortality; ABC, Subramanian, CATT, IVAN, - Study design: parallel RCTs; MANTA. – Follow-up: studies with a minimum 3-month follow-up period.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Wang W. 2014 - Population: patients with wet AMD; Pubmed, Embase, the CATT, (91) - Interventions: intravitreal bevacizumab and intravitreal ranibizumab, which were Chinese Biomedicine IVAN, directly compared in head-to-head design; Database, and the Cochrane GEFAL, - Outcomes: incidence of systemic adverse events; library from inception up to and MANTA. - Study design: RCTs with at least ten patients in each arm; December 2013. - Follow-up: at least one year.
Exclusion criteria: Population: patients with other indications than wet AMD, patients previously treated with VEGF inhibitors, or patients receiving systemic anti-VEGF therapy. Wu B. 2014 - Population: patients with ophthalmic diseases related to neovascularization; Four electronic databases, Nine articles were incorporated in (92) - Interventions and comparators: ranibizumab and bevacizumab. including PubMed and the meta-analysis. Five of those - Outcomes: BCVA as primary outcome. Secondary outcomes: any EMBASE until August 2013. included patients with AMD: ocular/systemic adverse events (death from any cause, arteriothrombotic event, or GEFAL; CATT; IVAN; MANTA serious ocular event). 2013, and Subramanian 2010. - Study design: comparative RCTs and head-to-head comparison -Follow- up: at least six months.
Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy; - Study design: non-RCT and studies without data from a comparison group; RCTs that enrolled less than 20 patients. Zhang XY. 2014 - Population: patients with AMD; PubMed (1966-October Four RCTs (IVAN, CATT, Biswas (93) - Interventions and comparators: bevacizumab and ranibizumab; 2012) and the Cochrane and Subramanian). - Outcomes: at least one of the primary outcomes (BCVA, foveal thickness, retina Library (1988-October In addition of the RCTs, ten thickness and central macular thickness) or secondary outcomes (serious adverse 2012). retrospective chart series met the effects, such as ocular inflammation, deaths and thromboembolic events); inclusion criteria. - Study design: RCTs, non-RCTs, case control and cohort studies that enrolled a minimum of 10 eyes. - Follow-up: There was no minimum length of follow-up specified. Anothaisintawee - Population: at least one participant with AMD, diabetic macular edema, or retinal Medline and Scopus were Six studies eligible for review for T. 2012 (94) vein occlusion; searched until December AMD: Sacu 2009; Martin 2011 - Interventions and comparators: any pairs of the following interventions – 2011. (CATT); Biswas 2011; bevacizumab, ranibizumab, photocoagulation, and sham; Subramanian 2010; Bashshur - Outcomes: visual acuity or central macular thickness; 2007 and Lazic&Gabric 2007. - Study design: RCTs with sufficient data for pooling treatment-effect sizes. - Follow-up: There was no minimum length of follow-up specified.
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Pitlick JM. 2012 There is no methods section. Literature was searched It is not clear which RCTs were (95) The inclusion and exclusion criteria are not clearly stated. Interventions and using MEDLINE and included (nor the number of trials, comparators are not detailed. It is only indicated that search terms included EMBASE until September neither which trials). The authors bevacizumab, Avastin, neovascular macular degeneration, age-related macular 2011. remarked upon ABC study, CATT degeneration, VEGF, intravitreal, and safety; and that only RCTs were described in and Subramanian. On the other detail in the article while safety data from observational trials were summarized. hand, Biswas and MANTA studies appear among the references. Schmucker C. - Population: nAMD; Medline, Premedline, The inclusion criteria were met by 2012 (96) - Interventions and comparators: bevacizumab or ranibizumab in direct Embase and the Cochrane 11 RCTs: CATT, ANCHOR, comparisons (head-to-head studies) or against any other control group (for library from inception until MARINA, PIER, SAILOR, potential indirect comparison). RCTs which compared different treatment regimens May 2011. EXCITE, SACU, ABC, Biswas, of ranibizumab or bevacizumab were also included; Subramanian, and Costagliola - Outcomes: long-term harm, such as myocardial infarction or stroke; 2010. - Study design: randomised phase III/IV trials; - Follow-up: one year follow-up data had to be available.
Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy; - Study design: RCTs that enrolled less than 20 patients. Wild C. 2012 Not found. The full text is in German. Not found. The full text is in The rapid assessment report (97) German. There is no English includes CATT, IVAN and MANTA language summary available. trials (those RCTs were completed at the time of the assessment). It also includes 4 more RCTs which were ongoing at the time of the assessment (VIBERA, LUCAS, GEFAL and SAFETY). Observational studies were included to report safety outcomes.
Mitchell P. - Population: wet AMD; PubMed.gov in June 2010. MARINA, ANCHOR, FOCUS, 2011 (98) - Interventions and comparators: ranibizumab and bevacizumab; PIER, Rosenfeld et al., SAILOR, - Outcomes: ocular and systemic safety and efficacy (BCVA; central macular EXTEND-I, ABC, Bashur et al. thickness; central retina thickness; central foveal thickness); 2007, Lazic et al. 2007, Potter et al. (VIA); and Sacu et al. 2009.
March 2020 EUnetHTA Joint Action 3 WP4 104 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year - Study design: Clinical studies that met Level I or Level II criteria (as assessed by the author) Level I criteria indicates strong evidence (e.g., well-designed, randomized, controlled clinical trials that address the issue in question); Level II criteria indicates substantial evidence that lacks some qualities (e.g., derived from randomized trials but with flaws, such as a lack of clearly defined primary outcomes, inclusion and exclusion criteria, or sufficiently long follow-up); - Follow-up: There was no minimum length of follow-up specified. Schmucker C. - Population: nAMD. Medline (Ovid), Embase and Four RCTs (ANCHOR, MARINA, 2011 (99) - Interventions and comparators: intravitreal bevacizumab or ranibizumab as the Cochrane Library from PIER and Heier; 11 publications) monotherapy compared with any other treatment; inception until March 2008. evaluating ranibizumab vs. PDT, - Outcomes: focused only on safety: adverse effects and the reporting of harm An update search focusing sham or usual care; and four - Study design: RCTs and non-RCTs. Case series were included if they enrolled a on RCTs was carried out in RCTs (SACU, Bashshur, minimum of 10 patients and met predefined quality standards (the publication had August 2009. Lazic&Gabric, and Hahn; five to provide adequate information regarding patient selection criteria or the selection publications) evaluating of patients had to be consecutive). bevacizumab vs. PDT with or - Follow-up: There was no minimum length of follow-up specified. without triamcinolone. In addition, 17 case series Exclusion criteria: examining bevacizumab (11 - Population: patients previously treated with VEGF inhibitors or patients receiving prospective and 6 retrospective systemic anti-VEGF therapy. series). Jyothi S. 2010 - Population: detailed as terms or combinations used in the search strategy: CNV; MEDLINE (2005 to January 55 reports met the inclusion (100) choroidal neovascularisation;; age-related macular degeneration; age-related 2009) and the National criteria. These included 5 RCTs maculopathy. Institutes of Health clinical that compared bevacizumab to - Interventions and comparators: detailed as terms or combinations used in the trial databases (up to other treatment options (Bashshur search strategy: anti-VEGF; bevacizumab; avastin; pegaptanib; macugen; January 2009). 2007, Hahn 2007,Lazic 2007, ranibizumab; lucentis Sacu 2009 and Wiegert 2008) and - Outcomes: mean change in visual acuity and central retinal thickness. 50 STROBE-qualified studies, of - Study design and follow-up: RCTs and observational case series with at least 3- which 12 studies evaluated the month follow-up, both prospective and retrospective, which met the STROBE combination of bevacizumab with criteria. another treatment modality. Schmucker C. - Population: exudative AMD; Medline (Ovid), Embase and The RCTs included in this paper 2010 (101) - Interventions and comparators: intravitreal bevacizumab or ranibizumab as the Cochrane Library without are the same ones as the RCTs monotherapy against any other treatment; date limit [main search for included in the previous article - Outcomes: efficacy and safety (not detailed in eligibility criteria) randomized clinical trials (same final date of search). - Study design: RCTs and case series which were included if they enrolled a (RCTs): August 09]. However, the number of case minimum of 10 patients and met predefined quality standards (the publication had series included differed between to provide adequate information regarding patient selection criteria or the selection both records. of patients had to be consecutive).
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Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year - Follow-up: There was no minimum length of follow-up specified.
Exclusion criteria: - Population: patients previously treated with VEGF inhibitors or patients receiving systemic anti-VEGF therapy. Andriolo RB. - Population: diagnosis of ocular diseases with the same underlying Medline, Controlled Trials Nine studies satisfied the pre- 2009 (102) pathophysiological mechanism of increased local levels of VEGF, according to the Register of the Cochrane established inclusion criteria. Of criteria established by the authors of the primary studies, such as age-related Collaboration (2008, issue 2) those, three studies included macular disease, corneal neovascularization, retinal angiomatous proliferation or and Lilacs to June 2008. patients diagnosed with AMD and angiogenic retinal diseases, among others; one study tested bevacizumab on - Interventions and comparators: bevacizumab alone or in association with other patients with subfoveal choroidal strategies available; neovascularization associated with - Outcomes: primary outcome of interest was visual acuity. Adverse events, e.g. AMD (Bashshur 2007, Hahn 2007, ocular or systematic hypertension, ocular toxicity, local inflammation, retinal Lazic 2007 and Wiegert 2008) detachment, vitreous hemorrhage, corneal abrasions, lens injury and thromboembolic events; - Study design: Only randomized or quasi-randomized clinical trials; - Follow-up: There was no minimum length of follow-up specified.
Exclusion criteria: - Studies in which the analysis unit was based on the eyes were not included, since there is evidence demonstrating an adverse event (vitritis) associated with bevacizumab in the contralateral eye. - Outcomes: Surrogate outcomes, such as central foveal thickness, and fluorescein angiography. Schouten JS. - Population: exudative AMD; MEDLINE, EMBASE, and the 26 studies with different design 2009 (103) - Interventions and comparators: Bevacizumab systemic or intravitreal therapy; Cochrane database. met the criteria. Three randomised - Outcomes: visual acuity, central retinal thickness and adverse events; All years were included up to controlled trials (Bashshur 2007, - Study design: RCTs, nonrandomized controlled studies, or before-and-after March 2008. Hahn 2007 and Lazic 2007) were studies in more than one patient; identified. The authors combined - Follow-up: There was no minimum length of follow-up specified. the data of the patients of these 3 RCTs who had received only Exclusion criteria: Studies that did not have visual acuity as the primary outcome or intravitreal bevacizumab, and the that had as the primary objective to study differences between subgroups. data of patients of 23 before-and- after studies (prospective and retrospective studies).
March 2020 EUnetHTA Joint Action 3 WP4 106 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year Ziemssen F. - Population: subfoveal CNV secondary to neovascular AMD; MEDLINE between June 1, Thirty-three studies and case 2009 (104) - Intervention: bevacizumab monotherapy; 2005 and July 31, 2008. series were found to meet the - Comparator: PDT with verteporfin for the subgroup of patients with a confirmed inclusion and exclusion criteria; of diagnosis of classic with no occult subfoveal wet AMD; these, 13 studies declared a - Outcomes: BCVA as primary outcome measure; prospective study design. The - Study design: not specified; highest grade studies were one - Follow-up: There was no minimum length of follow-up specified. non-randomized controlled trial and three RCTs (Lazic 2007, Bashshur 2007 and Wiegert 2008). CATT, VIBERA, IVAN and MANTA studies are mentioned as ongoing trials. Brown A. 2008 - Population: adults 40 years of age or more with nAMD. MEDLINE, EMBASE, BIOSIS Twelve reports of RCTs and 6 of (105) - Interventions and comparators: comparison of V-PDT with pegaptanib, Previews, CINAHL, PubMed, non-RCTS (one controlled trial, bevacizumab, ranibizumab, anecortave acetate, placebo, or clinically relevant and The Cochrane Library. and five case series) were combinations (intravitreal triamcinolone in combination with one or more of the All relevant articles were identified. The RCTs compared V- others was acceptable.). searched until November 2, PDT vs placebo; anecortave - Outcomes: Primary outcome: a measure of visual acuity convertible to utility 2007. acetate vs V-PDT; different values. Secondary outcomes: quality of life indicators, size of the lesion regimens of V-PDT; ranibizumab + before/after (measured by fluorescein angiography or ocular coherence vs V-PDT; ranibizumab + V-PDT topography); as well as adverse events and other harm information. vs verteporfin; bevacizumab vs V- - Study design: RCTs (though later non-RCTs were included to search for PDT; and bevacizumab + V-PDT information on combination therapies). vs V-PDT. - Follow-up: There was no minimum length of follow-up specified. Ip MS. 2008 - Population: nAMD; PubMed and Cochrane The RCTs included were (106) - Interventions and comparators: anti-VEGF pharmacotherapies (bevacizumab, Central Register of ANCHOR, MARINA, PIER and ranibizumab and pegaptanib); Controlled Trials VISION. - Outcomes: efficacy and safety; The literature search was - Study design: not specified; conducted on January 25, - Follow-up: There was no minimum length of follow-up specified. 2007. An update search was conducted on October 11, 2007. Escassi C. 2007 - Population: adults 45 years of age or more diagnosed with nAMD with any type of MEDLINE, Embase, 26 articles (out of 25 studies) were (107) choroideal neovascular lesions; Cochrane Library and other selected. Four were RCTs (5 - Intervention: pegaptanib, ranibizumab or bevacizumab; Internet resources (INAHTA, articles) MARINA (Rosenfeld - Comparison: the before mentioned treatments compared with each other, with ECRI and Centre for 2006), ANCHOR (Brown 2006), placebo or with other treatments, such as: photodynamic therapy with verteporfin; Gragoudas (2004), Mills (2006).
March 2020 EUnetHTA Joint Action 3 WP4 107 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Author and Eligibility criteria Date of search strategies Studies included in the SR publication and searched databases and/or NMA * year - Outcomes: efficacy and/or safety; Reviews and Dissemination The trials were ranibizumab vs - Study design: phase II and III RCTs, observational studies with or without control of University of York). placebo, ranibizumab vs group (case series with at least two patients). The search strategy covered verteporfin, pegaptanib vs placebo - Follow-up: There was no minimum length of follow-up specified. until May 2007. and pegaptanib continued Exclusion criteria: Full text in Spanish. treatment vs pegaptanib with - Population: patients previously treated. treatment discontinuation. The remaining 21 articles were 2 trials in phase I / II trial and one case series of ranibizumab; 5 case series of pegaptanib; and 13 case series of bevacizumab. Iu LP There is no methodology section with the inclusion and exclusion criteria. Medline till March 2007. This The phase III clinical trials 2007 (108) Key words/terms ‘treatment’ and ‘age-related macular degeneration were used to information only appears in MARINA and ANCHOR are briefly retrieve relevant original papers and review articles. This information only appears the abstract. described in ranibizumab section, in the abstract. and the study of Bashshur 2007 is succinctly described in bevacizumab section. Wild C. 2007 - Population: AMD; This report is based on a 21 published prospective and (109) - Intervention: bevacizumab intravenous /systemic and intraocular; simple literature review, retrospective clinical trials on - Outcomes: safety risks; using Medline and Embase safety and side effects of - Study design: prospective and retrospective clinical trials with more than 5 Dates of search strategies bevacizumab and 56 partially patients; not found. unpublished references - Follow-up: There was no minimum length of follow-up specified. Full is in text in German, it concerning the topic were has English abstract and evaluated. appendices. The follow-up of the 10 prospective trials on the safety of intravitreal bevacizumab therapy was between 4 weeks and 26 weeks. The follow-up of the 11 retrospective trials was between 4 weeks and 4.5 months. IVAN was included as an ongoing trial at the time of the assessment. * All the RCTs highlighted in bold are included in the SR by Solomon SD. 2019(30).
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The RCTs that are not highlighted in bold in the last column of Table A4 were not included in the most up-to-date systematic review (Solomon 2019) mainly due to one of the following reasons: follow-up less than one year; administration of combination therapy; or different drug doses or regimens compared with each other within a trial.
These criteria (combination therapy; or comparison of different doses of the same drug in a trial) are also considered for exclusion in the JA report. Therefore, from the 35 previous included articles, 33 are not further described in detail in this systematic review of the relative efficacy and safety of bevacizumab in patients with nAMD as the RCTs considered in those reviews are included in the most up-to-date and complete systematic review by Solomon 2019.
Table A5. RCTs not included in the SR by Solomon 2019 which are considered in the other references and reasons for exclusion in Solomon SR. Bashshur 2007 (110) RCT with a follow-up less than 1 year. Costagliola 2010 (111) This RCT assessed combination therapy: intravitreal bevacizumab alone vs intravitreal bevacizumab plus low-fluence PDT DENALI 2012 (112) Compared ranibizumab vs. combination therapy (ranibizumab+PDT) EXCITE (113) Different regimens of ranibizumab were assessed (monthly versus quarterly ranibizumab treatment) EXTEND-I 2008 (114) Dosing study. Different doses/regimens of ranibizumab were compared. FOCUS 2006 (115) The study compared intravitreal ranibizumab alone vs. combination therapy with intravitreal ranibizumab plus verteporfin PDT. Hahn 2007 (116) RCT with a follow-up less than 1 year. HARBOR (117) Comparison of 2 doses of ranibizumab administered monthly or on a PRN basis after 3 monthly loading doses. Heier 2006 (118) RCT with a follow-up less than 1 year. Lazic&Gabric 2007 RCT with a follow-up less than 1 year (119) MONT BLANC 2012 Compared ranibizumab vs. combination therapy (ranibizumab+PDT) (120) Potter et al (VIA) (121) Combination therapy
Rosenfeld 2006 (54) Dosing study. Different doses/regimens of ranibizumab were compared.
SAILOR 2009 (122) Tolerability and efficacy of multiple escalating doses of ranibizumab were compared.
VIEW 1; Heier 2012 RCTs that evaluated aflibercept, drug not considered in Solomon. (53) VIEW 2; Heier 2012 RCTs that evaluated aflibercept, drug not considered in Solomon (53) Weigert 2008 (123) RCT with a follow-up less than 1 year.
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APPENDIX 6: EXCLUDED ARTICLES FROM BEVACIZUMAB LITERATURE REVIEW
Table A6. Excluded articles, based on the full text, from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD. Study reference Reason for non-consideration of the study Li J, Xu J, Chen Y, Zhang J, Cao Y, Lu P. Efficacy Comparison of The report was excluded because of its objective. The study aimed to compare the efficacy among Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular different subtypes of neovascular AMD. Age-Related Macular Degeneration: A Systematic Review and Meta- A systematic review and meta-analysis were carried out in order to determine the relationship Analysis. J Ophthalmol. 2018;2018:1425707.(124) between treatment efficacy and lesion subtype. Zhang Y, Chioreso C, Schweizer ML, Abràmoff MD. Effects of The report was excluded because of its design. RCTs were not included. The review and meta- Aflibercept for Neovascular Age-Related Macular Degeneration: A analysis were based on evidence from observational studies. Systematic Review and Meta-Analysis of Observational Comparative Available studies from January 2011 through July 2017 were examined. Articles were considered Studies. Invest Ophthalmol Vis Sci. 2017;58(13):5616-5627.(125). only if they compared the functional or anatomic outcomes between aflibercept monotherapy and other anti- VEGF agents (ranibizumab or/and bevacizumab) among nAMD patients with no previous therapy. All included studies were retrospective observational cohort studies. Hussain RM, Hariprasad SM, Ciulla TA. Treatment Burden in No abstract, it is a five-page article. Neovascular AMD: Visual Acuity Outcomes are Associated With The report was excluded because of its objective. The meta-analysis reviewed RCTs employing the Anti-VEGF Injection Frequency. Ophthalmic Surg Lasers Imaging treat and extend regimen for nAMD through a PubMed search (in January 2016) of “bevacizumab Retina. 2017;48(10):780-784(126). treat and extend” and “ranibizumab treat and extend.” Gemenetzi M, Patel PJ. A Systematic Review of the Treat and The report was excluded because of its objective. Extend Treatment Regimen with Anti-VEGF Agents for Neovascular Clinical trials, prospective and retrospective studies, systematic reviews and meta-analyses to Age-Related Macular Degeneration. Ophthalmol Ther. 2017;6(1):79– February 2017 linked to the treat and extend treatment regimen with anti-VEGF agents in 92(127). neovascular AMD were considered. The article includes six prospective studies (RCTs and non-controlled non-randomised studies) and eleven real-world studies (one prospective and 10 retrospective studies). Gerding H. Long-term Results of Intravitreal Anti-VEGF Injections in The report was excluded because of its design. The study does not include RCTs. Wet AMD: A Meta-Analysis. Langzeitergebnisse der intravitrealen The selection of the studies was performed by analysis of available abstracts in order to identify anti-VEGF-Injektionstherapie bei feuchter altersabhangiger those publications reporting original data of long-term case series. 13 publications, including 14 case Makuladegeneration Eine Meta-Analyse. 2016;233(4):471–4(128). series, remained for definite analysis. 9 of 13 studies (69%) represent retrospective single centre case series, the remaining (n = 4, 31%) either extension- or follow-up studies of previously randomized controlled or prospective multicentre studies, prospective single centre evaluations (n = 1, or retrospective multicentre analysis n = 1).
March 2020 EUnetHTA Joint Action 3 WP4 110 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Study reference Reason for non-consideration of the study Mikacic I, Bosnar D. Intravitreal Bevacizumab and Cardiovascular The report was excluded because of its design. The article includes studies pertained to intravitreal Risk in Patients with Age-Related Macular Degeneration: Systematic administration of bevacizumab in humans with AMD. RCTs, case–control studies, stratified cohort Review and Meta-Analysis of Randomized Controlled Trials and studies, or clinical non-randomized controlled or uncontrolled studies (prospective or retrospective) Observational Studies. Drug Saf. 2016;39(6):517–41(129). were eligible. A total of 15 studies (ten RCTs in 12 publications; one non-randomized controlled clinical study; two population-based stratified cohort studies, and two uncontrolled clinical cohorts) met the inclusion criteria. Meta-analysis of randomized controlled trials of more versus less frequent bevacizumab dosing in patients with age-related macular degeneration in respect to cardio-/cerebrovascular adverse events were reported. Ba J, Peng R-S, Xu D, Li Y-H, Shi H, Wang Q, et al. Intravitreal anti- The report was excluded because it considered combination therapy as comparator. VEGF injections for treating wet age-related macular degeneration: a RCTs that compared ranibizumab vs. bevacizumab; ranibizumab vs. aflibercept; and ranibizumab systematic review and meta-analysis. Drug Des Devel Ther. monotherapy to the combination of ranibizumab with PDT in patients undergoing intravitreal anti- 2015;9:5397–405(19). VEGF injection for wet AMD PubMed, Embase, the Cochrane Library, and CNKI from inception until May 2014 were searched Twelve RCTs were eligible based on the inclusion criteria and were selected for the meta-analysis. Five of those 12 studies compared ranibizumab monotherapy vs ranibizumab plus PDT. New Zealand National Health Committee (NHC). Age-related The report was excluded because of its objective. Its purpose was to explore the model of care for macular degeneration. Wellington: New Zealand National Health patients with AMD and identify interventions where the New Zealand Health Committee could Committee (NHC). 2015(130). conduct further assessment in order to improve health outcomes and efficiency. CADTH. Long-term use of bevacizumab for the treatment of age- The report is a summary of findings which was prepared from the abstracts of the relevant related macular degeneration: safety. Ottawa: Canadian Agency for information. The aim of this rapid response report was to assess the clinical evidence regarding the Drugs and Technologies in Health (CADTH). Rapid Response. long-term safety (at least 2 years) of bevacizumab for the treatment of AMD. One systematic review 2014(131). and two randomized controlled trials (IVAN and CATT) were identified. Thomas M, Mousa SS, Mousa SA. Comparative effectiveness of In the full text, it is indicated that “Using databases such as PubMed, Medline, and ClinicalTrials.gov, aflibercept for the treatment of patients with neovascular age-related data were collected to compare the efficacy of aflibercept versus other therapies in the treatment of macular degeneration. Clin Ophthalmol. 2013;7:495-501(132). wet AMD”. However, in the methodology section, the authors did not state the "other therapies" that had been considered nor the date of the search strategies. No RCTs related to the use of bevacizumab were included in the results section. Fadda V, Maratea D, Trippoli S, Messori A. Treatments for macular No abstract, it is a two-page article. Publication date 2011. degeneration: summarising evidence using network meta-analysis. A simplified NMA was conducted to examine all controlled trials evaluating treatments for AMD. A Br J Ophthalmol. 2011;95(10):1476-7(133). PubMed search (on 20 April 2011) identified five controlled studies (ANCHOR, FOCUS, MARINA, VISION, ABC). The preliminary results of the CATT trial were also available at the time of the search. van der Reis MI, La Heij EC, De Jong-Hesse Y, Ringens PJ, The report was excluded because its design. Hendrikse F, Schouten JSAG. A systematic review of the adverse The article is focus on safety. It included randomized trials, and observational studies including more events of intravitreal anti-vascular endothelial growth factor than 5 patients and case reports describing adverse events after anti-VEGF injections. Based on the injections. Retina. 2011;31(8):1449–69(134). mentioned inclusion and exclusion criteria, 278 articles were included and these were published from 2002 to 2009.
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Study reference Reason for non-consideration of the study Micieli JA, Micieli A, Smith AF. Identifying systemic safety signals Studies that evaluated systemic adverse events following intravitreal injection of bevacizumab alone following intravitreal bevacizumab: systematic review of the literature or in combination for any ocular condition (age-related macular degeneration, diabetic retinopathy, and the Canadian Adverse Drug Reaction Database. Can J retinal vascular occlusion, central retinal vascular occlusion, and diabetic macular oedema) were Ophthalmol. 2010;45(3):231-8(135). eligible for inclusion. Kymes S, Vollman D, Spry C. Supplement to “The Role of The report was excluded because its objective. Pharmacologic Management in Neovascular Age-Related Macular It is a supplement to “The Role of Pharmacologic Management in Neovascular Age-Related Macular Degeneration: Clinical and Cost-Effectiveness”. Ottawa: Canadian Degeneration: Clinical and Cost-Effectiveness” from Brown et al. The publication is only focused on Agency for Drugs and Technologies in Health; 2009(136). cost-effectiveness. The research questions were about the impact on the incremental cost- effectiveness ratio (ICER) of the economic evaluation taking into account different scenarios.
Table A7. Articles excluded, by title and abstract (full text not available), from the literature search regarding the relative efficacy and safety of bevacizumab for nAMD. Study reference Reason for non-consideration of the study Mengarelli C, Augustovski, Pichon-Riviere A, García Martí S, Alcaraz This record is a brief technical report in Spanish. Full text is not available and was not requested A, Bardach A, Ciapponi A, López A, Rey-Ares L. Ranibizumab, to IECS. This record was excluded because due to its publication date, 2015, there are more up-to- bevacizumab ya para degeneración macular asociada a la edad. date SRs. [Ranibizumab, bevacizumab y aflibercept for age-related macular degeneration] Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rápida No. 398. 2015(137). Ma N, He X-G. [Efficacy and safety in treatment of ocular Date of search strategy unknown as the full text article in Chinese was not requested. This neovascularization by Bevacizumab versus Ranibizumab: a meta- record was excluded because due to its publication date, 2010, there are more up-to-date SRs. analysis]. Chinese Journal of Ophthalmology. 2010;46(3):263– The article considers clinical controlled trials comparing bevacizumab and ranibizumab in treatment 7(138). of ocular neovascularization. Medline, EMbase, the Cochrane Library and CBM were searched. Only 7 literatures came into meta-analysis (1620 eyes). Bevacizumab (Avastin) for age-related macular degeneration. Full text is not available and was not purchased from Hayes due to its publication date as the Lansdale: HAYES, Inc.. Directory Publication. 2008. report is now outdated. Augustovski F, Colantonio L, Pichon Riviere A. Vascular endothelial This record is a brief technical report in Spanish. The objective of the report was to assess the growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) usefulness of VEGF inhibitors in the treatment of AMD. Full text is not available and was not in age-related macular degeneration treatment. Buenos Aires: requested to IECS. Nevertheless, this record was excluded because due to the publication date, Institute for Clinical Effectiveness and Health Policy (IECS). Informe 2007, there are more up-to-date SRs. Técnico Breve No.33. 2007. Bock F, Konig Y, Dietrich T, Zimmermann P, Baier M, Cursiefen C. The authors only searched in one database, Pubmed. Date of search strategy unknown as the full [Inhibition of angiogenesis in the anterior chamber of the eye]. text article in German was not requested. This record was excluded because due to its Antiangiogene Ther am Vor Augenabschnitt. 2007;104(4):336–44. publication date, 2007, there are more up-to-date.
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Study reference Reason for non-consideration of the study Pichon-Riviere A, Augustovski F, Colantonio L. Vascular endothelial This record is a brief technical report in Spanish. Full text is not available and was not requested growth factor inhibitors (pegaptanib, ranibizumab and bevacizumab) to IECS. Nevertheless, this record was excluded because due to the publication date, 2007, as in age-related macular degeneration treatment. Buenos Aires: there are more recent SRs. Institute for Clinical Effectiveness and Health Policy (IECS). Informe Técnico Breve No.33. 2007. BlueCross BlueShield Association. Special report: current and This report aims to provide an understanding of emerging therapies in the context of the treatment evolving strategies in the treatment of age-related macular options available around 2005 and the underpinnings on which age-related macular degeneration degeneration. Chicago: BlueCross BlueShield Association (BCBS). treatments are based. TEC Assessment 20(11). 2005. Full text is not available and was not requested to BSBS. The BlueCross BlueShield Association Technology Evaluation Center website includes the most recent 3 years of TEC Assessments. Older reports have to be requested. Nevertheless, this record was excluded because due to the publication date not all the interventions which we want to compare in this assessment report were available to be used in clinical practice.
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APPENDIX 7: BASELINE CHARACTERISTICS OF HAWK AND HARRIER STUDY POPULATIONS
Table A8. Baseline characteristics of the study populations (FAS, excluding brolucizumab 3 mg group in HAWK study) Characteristics HAWK study (NCT02307682) HARRIER study (NCT02434328) Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) Age (years) Mean (SD) 76.7 (8.95) 76.2 (8.80) 74.8 (8.58) 75.5 (7.87) Median (range) 78.0 (51–97) 77.0 (51–96) 75.0 (50–94) 76.0 (52–95) Age category (years) – n (%) <50 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 50-64 35 (9.7) 37 (10.3) 44 (11.9) 28 (7.6) 65-74 103 (28.6) 112 (31.1) 124 (33.5) 126 (34.1) 75-84 155 (43.1) 148 (41.1) 150 (40.5) 167 (45.3) ≥85 67 (18.6) 63 (17.5) 52 (14.1) 48 (13.0) Sex – n (%) Male 155 (43.1) 166 (46.1) 160 (43.2) 157 (42.5) Female 205 (56.9) 194 (53.9) 210 (56.8) 212 (57.5) Race – n (%) White 285 (79.2) 287 (79.7) 340 (91.9) 341 (92.4) Asian 61 (16.9) 53 (14.7) 22 (5.9) 23 (6.2) Other 9 (2.5) 17 (4.7) 5 (1.4) 4 (1.1) Multiple 3 (0.8) 1 (0.3) 2 (0.5) 1 (0.3) Black or African American 1 (0.3) 1 (0.3) 1 (0.3) 0 (0.0) American Indian or Alaska 1 (0.3) 1 (0.3) 0 (0.0) 0 (0.0) Native Native Hawaiian or other 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Pacific Islander Ethnicity – n (%) Not Hispanic or Latino 329 (91.4) 319 (88.6) 321 (86.8) 322 (87.3) Hispanic/Latino 29 (8.1) 40 (11.1) 23 (6.2) 25 (6.8) Unknown 1 (0.3) 1 (0.3) 18 (4.9) 17 (4.6) Not reported 1 (0.3) 0 (0.0) 8 (2.2) 5 (1.4) Japanese ancestry – n (%) Japanese 60 (16.7) 53 (14.7) NR NR Non-Japanese 300 (83.3) 307 (85.3) NR NR Time since diagnosis of nAMD (months) – n (%) <1 159 (44.2) 154 (42.8) 136 (36.9) 139 (37.7) 1–3 184 (51.1) 190 (52.8) 191 (51.8) 197 (53.4) >3 17 (4.7) 16 (4.4) 42 (11.4) 33 (8.9) Unilateral versus bilateral nAMD – n (%) Unilateral 271 (75.3) 268 (74.4) 268 (72.4) 255 (69.1) Bilateral 89 (24.7) 92 (25.6) 102 (27.6) 114 (30.9) BCVA (letters read) Mean (SD) 60.8 (13.66) 60.0 (13.92) 61.5 (12.59) 60.8 (12.93) Median (range) 64.0 (23–85) 63.0 (16–83) 64.0 (22–78) 64.0 (23–79)
March 2020 EUnetHTA Joint Action 3 WP4 114 PTJA09 - Brolucizumab for patients with neovascular (wet) AMD
Characteristics HAWK study (NCT02307682) HARRIER study (NCT02434328) Brolucizumab Aflibercept Brolucizumab Aflibercept 6 mg 2 mg 6 mg 2 mg (N=360) (N=360) (N=370) (N=369) BCVA (letters read) – n (%) ≤55 101 (28.1) 116 (32.2) 102 (27.6) 107 (29.0) 56-70 157 (43.6) 153 (42.5) 171 (46.2) 170 (46.1) ≥71 102 (28.3) 91 (25.3) 97 (26.2) 92 (24.9) CSFT total (μm) Mean (SD) 463.1 (166.62) 457.9 (146.37) 473.6 (171.39) 465.3 (151.21) Median (range) 417 (217–1204) 425 (215– 434 (200–1192) 442 (206– 1082) 1319) CSFT total (μm) – n (%) ˂400 157 (43.6) 146 (40.6) 148 (40.0) 130 (35.2) ≥400 203 (56.4) 214 (59.4) 222 (60.0) 239 (64.8) Type of CNV – n (%) Predominantly classic 113 (31.4) 116 (32.3) 154 (41.6) 144 (39.5) Minimally classic 39 (10.8) 34 (9.5) 33 (8.9) 34 (9.3) Occult 208 (57.8) 209 (58.2) 183 (49.5) 187 (51.2) Area of lesion associated with CNV (mm2) Mean (SD) 4.6 (4.1) 4.4 (3.7) 2.6 (2.8) 2.9 (4.0) Median (range) 3.4 (0–20) 3.7 (0–19) 1.5 (0–14) 1.6 (0–34) Presence of fluid – n (%) SRF 250 (69.4) 245 (68.1) 251 (67.8) 268 (72.6) IRF/cyst 194 (53.9) 194 (53.9) 149 (40.3) 139 (37.7) SRF and/or IRF 334 (92.8) 336 (93.3) 330 (89.2) 332 (90.0) Sub-RPE fluid 168 (46.7) 158 (43.9) 125 (33.8) 127 (34.4) PCV (Japanese patients 39 (66.1) 30 (56.6) NR NR only) Source: Submission dossier, European Medicines Agency public assessment report. Abbreviations: FAS=full analysis set; nAMD=Neovascular (Wet) Age-Related Macular Degeneration; BCVA=best-corrected visual acuity; CSFT=central subfield thickness; CNV=choroidal neovascularisation; IRF=intraretinal fluid; PCV=polypoidal choroidal vasculopathy; RPE=retinal pigment epithelium; SD=standard deviation; SRF=subretinal fluid.
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APPENDIX 8: POOLED RESULTS OF HAWK AND HARRIER STUDIES
As part of the network meta-analysis, MAH presented direct comparison results of HAWK and HARRIER studies. Results of the key outcomes are presented here. More detailed analysis, including also safety results, are available in the submission dossier.
Table A9. Summary of direct comparison results (pooled results) for HAWK and HARRIER studies Outcome Mean Difference [95% CI] I-square p-value of the and Trials Fixed-effects Random-effects Cochran test comparison model model Mean change in BCVA from baseline to one year Afli 2 mg HARRIER 0.43 0.43 0.00% 0.763 vs Bro 6 mg HAWK [-0.85; 1.71] [-0.85; 1.71] Mean change in BCVA from baseline to two years Bro 6 mg HARRIER 0.01 0.01 0.00% 0.467 vs Afli 2 mg HAWK [-1.46;1.49] [-1.46;1.49] Odds of losing at least 15 letters from baseline to one year Bro 6 mg HARRIER 0.97 0.97 0.0% 0.390 vs Afli 2 mg HAWK [0.61; 1.55] [0.61; 1.55] Odds of losing at least 15 letters from baseline to two years Bro 6 mg HARRIER 1.00 1.00 0.0% 0.686 vs Afli 2 mg HAWK [0.68; 1.47] [0.68; 1.47] Odds of gaining at least 15 letters from baseline to one year Bro 6 mg HARRIER 1.19 1.19 69.7% 0.069 vs Afli 2 mg HAWK [0.95; 1.49] [0.79; 1.80] Odds of gaining at least 15 letters from baseline to two years Bro 6 mg HARRIER 1.11 1.12 72.4% 0.057 vs Afli 2 mg HAWK [0.89; 1.39] [0.73; 1.71] Mean change in central retinal thickness from baseline to one year Afli 2 mg HARRIER 39.28 39.41 57.6% 0.125 vs Bro 6 mg HAWK [26.02; 52.55] [19.03; 59.79] Mean change in central retinal thickness from baseline to two years Bro 6 mg HARRIER -34.69 -34.60 25.4% 0.247 vs Afli 2 mg HAWK [-48.64; -20.74] [-50.77; -18.44] Source: modified from Submission dossier. Abbreviations: Afli=aflibercept; BCVA=best corrected visual acuity; Bro=brolucizumab; CI=confidence interval.
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APPENDIX 9: CHECKLIST FOR CRITICAL APPRAISAL OF INDIRECT COMPARISONS – EVALUATION OF THE NMA PROVIDED BY MAH
Table A10. Evaluation of the NMA provided by MAH (A) Are indirect comparison results valid? 1. Is it justified to conduct an indirect comparison (IC)? Yes. There are no direct comparisons between Some criteria must be fulfilled to conduct an IC: brolucizumab and ranibizumab which is one of the drug considered in the NMA, in Are the objective(s), inclusion criteria, methods (assumptions addition to aflibercept which is the control included) and results clear? drug in the pivotal trials. Are the studies clinically comparable? (patients, general conditions, co-interventions, drug dosing, treatment duration, variables, etc, that act as effect modifiers? Are outcomes comparable in definition and presentation? Are outcomes clinically relevant? 2. Is the IC methodology appropriate? Yes. NMA has been used for the IC. In addition, several sensitivity analyses were conducted to assess the robustness of the base case results. 3. Was the search strategy for study selection Yes adequate? Was the search question correctly established? Are all relevant studies included? Is the comparator relevant?
After answering the previous questions, do you consider Yes that you should continue analysing the study/paper? (B) Detailed questions: checklist for an indirect comparison evaluation 1. Common comparator Yes, thus reliability high Are comparator and studies represented graphically? How many intermediate comparators are there between the two alternatives (A and B) we are most interested in comparing? 2. Search strategy Multiple databases were searched for. Are systematic methods used to find all relevant studies? Were Strategy was reported. References were not the different databases as well as the search strategy checked and publication bias was not included? Were references checked? Were strict limits used? evaluated. Thus. reliability is low Was publication bias evaluated? 3. Criteria for selection of studies Reliability acceptable Are they stated? Are they reasonable? Are they systematically A flowchart was presented and the reasons applied? to exclude studies were stated. However, the rationale for the selection criteria does not match the European PICO and a relevant comparator has not been considered. 4. Common outcome measure Yes, thus reliability high Do studies share the same outcome measure (defined in the same manner, including same time horizon and reported in the same way)? 5. Outcome relevance Yes, thus reliability high Is outcome measure clinically relevant? Is the main outcome included in the studies? 6. Clinical similarity, patient similarity Are inclusion/exclusion criteria similiar between studies? Were Reliability acceptable randomised patients within each study similar?
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7. Common comparator Regarding the duration of the treatment, the Is the common comparator or control drug used at the same MAH stated as a limitation of the NMA that dose and for the same duration? time equivalence was assumed for one-year and two-year outcomes. In order to include And are the same concomitant treatments that can act as all available evidence for treatments of effect modifiers permitted? interest, equivalence was assumed between 48 and 52 weeks for one-year outcomes and between 96 and 104 weeks for two-year outcomes. No publication was found to validate this hypothesis, but the results for HAWK and HARRIER at Week 52 were similar to those at Week 48. In addition, the results from sensitivity analyses that extrapolated endpoints that were published at 48 weeks and 104 weeks were similar to the base case. This demonstrated that there was no impact on the results with the equivalence assumption used. Uncertain. Combination intravitreal therapy was not allowed in the trials. 8. Outcome result in the control group (or common Reliability acceptable compartor group) Is this similar in the studies being compared? 9. Study quality Reliability high What is the quality of the studies being combined? The MAH has assessed the RoB of the Are results within each study reported? RCTs included in the NMA. They stated that overall evidence was of moderate to high quality. The greatest risk of bias was due to insufficient information identified in the publication during the quality assessment. The majority of studies did not have unexpected imbalances in drop-outs between groups. The RoB of each trial, as reported by the MAH, is shown in Figure 4.19.
10. Missing patient/data Reliability low. In studies being combined: are missing patient/data similar? This information was not avaible in the NMA Were they handled in the same way? Is data analysis similar from the MAH (pP, ITT)?
11. Reliability of studies data Reliability high Are data obtained from the studies? Or was there a previous extrapolation or any manipulation of data? 12. Adjusting by control group Yes, thus reliability high Was an adjusted IC (Bucher method, NMA, etc) conducted? Are reltive effects to common comparator group of each study compared? 13. Data/statistical analysis conducted in the IC or NMA Yes, thus reliability high Is it adequate? Are assumptions acceptable? When a sensitivity analysis is necessary, was it done correctly? 14. Study similarity No, thus reliability high Is there anything more that makes studies not comparable? 15. Answer this question only if there is a published direct Not applicable comparison of the treatments being compared: Is there inconsistency? Are results from direct and indirect comparisons different? 16. External validity and applicability No The main limitation of the NMA is regarding the external validity and applicability of the
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Were conclusions obtained from the results? Can the results results and conclusions obtained because be extrapolated to our patients? Has the relevant alternative one of the relevant comparators form the for our practice been analysed? European perspective has not been considered. 17. Conflict of interest NMA performed by the MAH Is there any conflict stated? Is the study independent? Abbreviations: MAH=marketing authorisation holder; NMA=network meta-analyis; RoB=risk of bias.
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APPENDIX 10: CRITICAL APPRAISAL FOR THE SYSTEMATIC REVIEWS SELECTED FROM THE SLR OF BEVACIZUMAB
Table A11. Critical appraisal for the SRs selected from the SLR of bevacizumab AMSTAR-2 items Solomon et al Pham et al 1. Did the research questions and inclusion criteria Yes Yes for the review include the components of PICO? For Yes: Population Intervention Comparator group Outcome Optional (recommended): Timeframe for follow-up 2. Did the report of the review contain an explicit Yes No statement that the review methods were established In the Cochrane website, In the appendix of the prior to the conduct of the review and did the report the protocol with all the SR, the authors referred justify any significant deviations from the protocol? detailed information to the published protocol, required is available. In which answered to 5 out For Partial Yes: addition, the differences of the 7 requested items The authors state that they had a written protocol or between the protocol and by AMSTAR-2. The guide that included ALL the following: the review have been search strategies were - review question(s) indicated. not provided in the - a search strategy published protocol. - inclusion/exclusion criteria There is no information in - a risk of bias assessment the SR about existence For Yes: or not of deviations. As for partial yes, plus the protocol should be registered and should also have specified: - a meta-analysis/synthesis plan, if appropriate, and - a plan for investigating causes of heterogeneity - justification for any deviations from the protocol 3. Did the review authors explain their selection of the No No study designs for inclusion in the review? The study design The authors specified the considered was stated. study design (parallel- For Yes, the review should satisfy ONE of the However, there is no and cluster-RCTs) following: explanation regarding the However, they did not - Explanation for including only RCTs inclusion of only RCTs explain the reasons for - OR Explanation for including only NRSI including only RCTs - OR Explanation for including both RCTs and NRSI 4. Did the review authors use a comprehensive Yes Yes literature search strategy? For Partial Yes (all the following): - searched at least 2 databases (relevant to research question) - provided key word and/or search strategy - justified publication restrictions (e.g. language)
For Yes, should also have (all the following): - searched the reference lists / bibliographies of included studies - searched trial/study registries - included/consulted content experts in the field - where relevant, searched for grey literature - conducted search within 24 months of completion of the review 5. Did the review authors perform study selection in Yes Yes duplicate? Two review authors All titles/abstracts and For Yes, either ONE of the following: independently evaluated potentially relevant full- - at least two reviewers independently agreed on the titles and abstracts text articles were selection of eligible studies and achieved consensus obtained through screened by two on which studies to include electronic searches. A reviewers, independently.
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- OR two reviewers selected a sample of eligible third review author Discrepancies were studies and achieved good agreement (at least 80 resolved discrepancies discussed and if percent), with the remainder selected by one necessary, resolved with reviewer. input from a third reviewer. 6. Did the review authors perform data extraction in Yes Yes duplicate? Two review authors Data extraction was For Yes, either ONE of the following: independently extracted conducted by two - at least two reviewers achieved consensus on study characteristics. reviewers, independently. which data to extract from included studies One review author Discrepancies were - OR two reviewers extracted data from a sample of entered discussed and if eligible studies and achieved good agreement (at data into Review necessary, resolved with least 80 percent), with the remainder extracted by Manager and a second input from a third one reviewer. review author verified the reviewer data entered 7. Did the review authors provide a list of excluded Yes Partial yes studies and justify the exclusions? For Partial Yes: - provided a list of all potentially relevant studies that were read in full-text form but excluded from the review For Yes, must also have: - Justified the exclusion from the review of each potentially relevant study 8. Did the review authors describe the included Yes Partial yes studies in adequate detail? Detailed information is provided in the For Partial Yes (ALL the following): supplementary online - described populations content. However, the - described interventions timeframe for follow-up - described comparators for each study was not - described outcomes detailed. - described research designs For Yes, should also have ALL the following: - described population in detail - described intervention in detail (including doses where relevant) - described comparator in detail (including doses where relevant) - described study’s setting - timeframe for follow-up 9. Did the review authors use a satisfactory technique Yes Yes for assessing the risk of bias (RoB) in individual Two review authors Quality assessment was studies that were included in the review? assessed potential done by two reviewers, For Partial Yes, must have assessed RoB from sources of bias in trials independently, using the unconcealed allocation, and lack of blinding of according Cochrane risk of bias tool patients and assessors when assessing outcomes to methods set out in the for RCTs (unnecessary for objective outcomes such as all- Cochrane Handbook for cause mortality) Systematic Reviews of Interventions For Yes, must also have assessed RoB from: allocation sequence that was not truly random, and selection of the reported result from among multiple measurements or analyses of a specified outcome 10. Did the review authors report on the sources of Yes Yes funding for the studies included in the review? Funding sources and The authors reported that Must have reported on the sources of funding for Declarations of interest 2 of the 19 RCTs (10.5%) individual studies included in the review. Note: are reported for each were industry funded. Reporting that the reviewers looked for this RCT included in the SR. information but it was not reported by study authors also qualifies. 11. If meta-analysis was performed did the review No No. authors use appropriate methods for statistical The weighted technique Authors performed a combination of results? used is not detailed to meta-analysis, although judge its appropriateness the justification for
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RCTs For Yes: combining the data and The authors justified combining the data in a meta- the weighted technique analysis AND they used an appropriate weighted to combine study results technique to combine study results and adjusted for was not described. heterogeneity if present AND investigated the causes Causes of heterogeneity of any heterogeneity. were investigated. A publication of the NMA is pending. 12. If meta-analysis was performed, did the review Yes Yes authors assess the potential impact of RoB in Authors indicated that The authors performed a individual studies on the results of the meta-analysis they planned to conduct sensitivity analysis by or other evidence synthesis? sensitivity analyses to restricting results to trials For Yes: assess the impact of determined to be at low included only low risk of bias RCTs OR, if the pooled studies graded as having risk of selection bias. estimate was based on RCTs and/or NRSI at variable high risk of bias on any RoB, the authors performed analyses to investigate parameter, unpublished possible impact of RoB on summary estimates of data only, or industry effect. funding. After assessing the studies included and the data collected, authors of the SR determined that these analyses were not needed because studies within each meta- analysis did not differ on the basis of these factors. 13. Did the review authors account for RoB in Yes No individual studies when interpreting/ discussing the The authors provided in RoB methodology was results of the review? the discussion section described in methods, For Yes: the impact of RoB of the but how this assessment - included only low risk of bias RCTs selected RCTs. impacted the results is - OR, if RCTs with moderate or high RoB, or NRSI not included in the were included the review provided a discussion of the discussion likely impact of RoB on the results 14. Did the review authors provide a satisfactory Yes No explanation for, and discussion of, any heterogeneity When heterogeneity was Assessment of observed in the results of the review? present Solomon et al heterogeneity is For Yes: commented on the described in methods, There was no significant heterogeneity in the results impact of it on the SR. but the impact on results OR if heterogeneity was present the authors is not detailed in the performed an investigation of sources of any discussion heterogeneity in the results and discussed the impact of this on the results of the review 15. If they performed quantitative synthesis did the No No review authors carry out an adequate investigation of The authors stated that in publication bias (small study bias) and discuss its future updates of the SR, likely impact on the results of the review? when outcome data from For Yes: 10 or more studies are performed graphical or statistical tests for publication included in a meta- bias and discussed the likelihood and magnitude of analysis, they will use a impact of publication bias funnel plot to judge potential publication bias. 16. Did the review authors report any potential Yes Yes sources of conflict of interest, including any funding The authors stated the The authors stated the they received for conducting the review? internal and external funding and declared no For Yes: sources of support conflicts of interest. The authors reported no competing interests OR The received. authors described their funding sources and how they The authors of the SR managed potential conflicts of interest declared that there were no interests known. Abbreviations: RCT=randomised clinical trial; RoB=risk of bias SR=systematic review.
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APPENDIX 11: PROTOCOL DEVIATIONS IN HAWK AND HARRIER STUDIES
Table A12. Protocol deviations by deviation category (RAN) in HAWK study - week 48 analysis Brolucizumab Aflibercept Overall 6 mg 2 mg (N = 1082) (N = 361) (N = 361) n (%) n (%) n (%) Number of subjects 46 (12.7)) 52 (14.4) 156 (14.4 with at least 1 protocol deviation Inclusion / exclusion 12 (3.3) 13 (3.6) 41 (3.8) criteria not met Withdrawal criteria met 0 (0.0) 0 (0.0) 0 (0.0) but subject not withdrawn Deviation related to 26 (7.2) 30 (8.3) 92 (8.5) active treatment* Prohibited concomitant 7 (1.9) 4 (1.1) 17 (1.6) medication administered Other 4 (1.1) 7 (1.9) 17 (1.6) Source: HAWK CSR. A subject with multiple occurrences of a protocol deviation category is counted only once in the protocol deviation category. A subject may have protocol deviations in more than one protocol deviation category. Percentages (%) are calculated based on N. *Deviations related to active treatment include subjects who were randomized but not treated, received wrong treatment, missed active treatment due to reason other than lack of efficacy or any safety event, received active treatment when schedule was for sham or were reassigned to q8w regimen although no disease activity was identified by the Investigator.
Table A13. Protocol deviations by deviation category (RAN) in HARRIER study - week 48 analysis Brolucizumab 6 mg Aflibercept 2 mg Overall (N = 372) (N = 371) (N = 743) n (%) n (%) n (%) Number of subjects 43 (11.6) 43 (11.6) 86 (11.6) with at least 1 protocol deviation Inclusion / exclusion 22 (5.9) 24 (6.5) 46 (6.2) criteria not met Withdrawal criteria met 0 (0.0) 0 (0.0) 0 (0.0) but subject not withdrawn Deviation related to 17 (4.6) 13 (3.5) 30 (4.0) active treatment* Prohibited concomitant 3 (0.8) 2 (0.5) 5 (0.7) medication administered Other 6 (1.6) 7 (1.9) 13 (1.7) Source: HARRIER CSR. A subject with multiple occurrences of a protocol deviation category is counted only once in the protocol deviation category. A subject may have protocol deviations in more than 1 protocol deviation category. Percentages (%) are calculated based on N. *Deviations related to active treatment include subjects who were randomized but not treated, received wrong treatment, missed active treatment due to reason other than lack of efficacy or any safety event, received active treatment when schedule was for sham or were reassigned to q8w regimen although no disease activity was identified by the Investigator.
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