Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial

Abstract

Importance: Faricimab, the first bispecific antibody designed for intraocular use, simultaneously and independently binds and neutralizes angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A).

Objective: To assess the efficacy and safety of different doses and regimens of faricimab vs ranibizumab in patients with neovascular age-related macular degeneration (nAMD).

Design, setting, and participants: AVENUE was a 36-week, multiple-dose-regimen, active comparator-controlled, double-masked, phase 2 randomized clinical study performed at 58 sites in the United States. Eligible participants were anti-VEGF treatment naive with choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 73 (Snellen equivalent, 20/40) to 24 (Snellen equivalent, 20/320). Data were collected from August 11, 2015, to January 12, 2017, with the final patient visit completed September 26, 2017. Data were analyzed from August 11, 2015, to October 4, 2019.

Interventions: Patients were randomized 3:2:2:2:3 to receive ranibizumab, 0.5 mg every 4 weeks (arm A [n = 68]); faricimab, 1.5 mg every 4 weeks (arm B [n = 47]); faricimab, 6.0 mg every 4 weeks (arm C [n = 42]); faricimab, 6.0 mg every 4 weeks until week 12, then faricimab, 6.0 mg every 8 weeks (arm D [n = 47]); and ranibizumab, 0.5 mg every 4 weeks until week 8, then faricimab, 6.0 mg every 4 weeks (arm E [n = 69]).

Main outcomes and measures: Mean change in BCVA from baseline to week 36, proportion of participants gaining at least 15 letters, BCVA of 20/40 or better or 20/200 or worse, and ocular coherence tomographic outcomes in anti-VEGF treatment-naive participants (arms A, B, C, D) and from weeks 12 to 36 in those with incomplete response (participants in arms A and E with week 12 BCVA ETDRS letter score of ≤68 [Snellen equivalent, 20/50 or worse]).

Results: A total of 263 participants were included in the analysis (172 [65.4%] female; 258 [98.1%] white; mean [SD] age, 78.3 [8.7] years). At week 36, adjusted mean change in BCVA vs ranibizumab was 1.6 (80% CI, -1.6 to 4.7) letters for arm B (P = .52), -1.6 (80% CI, -4.9 to 1.7) letters for arm C (P = .53), and -1.5 (80% CI, -4.6 to 1.6) letters for arm D (P = .53). For arm E, adjusted mean change from week 12 was -1.7 (80% CI, -3.8 to 0.4) letters (P = .30).

Conclusions and relevance: AVENUE did not meet its primary end point of superiority of faricimab over ranibizumab in BCVA at week 36. Although not superior to monthly ranibizumab as given in this trial, overall visual and anatomical gains noted with faricimab support pursuing phase 3 trials for a potential alternative to monthly anti-VEGF therapy. Faricimab showed no new or unexpected safety signals.

Trial registration: ClinicalTrials.gov Identifier: NCT02484690.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Sahni reported receiving personal fees from F. Hoffmann-La Roche Ltd during the conduct of the study and outside the submitted work and being an employee and shareholder of F. Hoffmann-La Roche Ltd. Dr Patel reported receiving grants and personal fees from Genentech-Roche, Kodiak Sciences, Inc, and Allergan plc and grants from Novartis International AG, Aerie Pharmaceuticals, Inc, Apellis Pharmaceuticals, Inc, Boehringer Ingelheim, Chengdu Kanghong Pharmaceutical Group Co, Ltd, Clearside Biomedical, Inc, Ionis Pharmaceuticals, Mylan NV, Opthea Limited, Regeneron Pharmaceuticals, Inc, ORA, Samsung Pharm Co, Ltd, Stealth BioTherapeutics Corp, Thrombogenics NV, and Xbrane Biopharma outside the submitted work. Dr Berger reported receiving personal fees from Genentech Inc, during the conduct of the study and personal fees from Boehringer Ingelheim, Kodiak Sciences, Inc, Novartis Pharmaceutical Corp, KalVista Pharmaceuticals, and F. Hoffmann-La Roche Ltd outside the submitted work. Dr del Valle Rubido reported receiving personal fees from F. Hoffmann-La Roche Ltd outside the submitted work and being an employee and shareholder of F. Hoffmann-La Roche Ltd. Dr Szczesny reported having a patent to P35108-WO pending. Dr Schwab reported receiving personal fees from Roche Pharma Research and Early Development and being an employee and having stock options in F. Hoffmann-La Roche Ltd. Mr Weikert reported receiving personal fees from F. Hoffmann-La Roche Ltd outside the submitted work and having a patent to WO2019/154776 pending. No other disclosures were reported.

Figures

Figure 1.. AVENUE Study Participant Disposition

Patient disposition (CONSORT flow diagram). aTen participants were removed from the analysis due to Good Clinical Practice (GCP) violations at a single site.

Figure 2.. AVENUE Study Design

Arm A included ranibizumab, 0.5 mg every 4 weeks; arm B, faricimab, 1.5 mg every 4 weeks; arm C, faricimab, 6.0 mg every 4 weeks; arm D, faricimab, 6.0 mg every 4 weeks to week 12, followed by every 8 weeks; and arm E, ranibizumab, 0.5 mg every 4 weeks to week 8, followed by faricimab, 6.0 mg every 4 weeks.

Figure 3.. Best-Corrected Visual Acuity (BCVA) Change at Week 36

Group 1 (A) was assessed for change in mean BCVA from baseline and includes all participants treatment naive for anti–vascular endothelial growth factor (anti-VEGF) receiving ranibizumab, 0.5 mg every 4 weeks (arm A), faricimab, 1.5 mg every 4 weeks (arm B), faricimab, 6.0 mg every 4 weeks (arm C), and faricimab, 6.0 mg every 4 weeks to week 12 followed by every 8 weeks (arm D). Group 2 (B) was assessed for change in mean BCVA from week 12 baseline among participants with incomplete response to anti-VEGF treatment in arm A and those receiving ranibizumab, 0.5 mg every 4 weeks to week 8, followed by faricimab, 6.0 mg every 4 weeks (arm E). Data are expressed as least squares means from linear model analysis of study eye BCVA change with categorical covariates of treatment group, visit, and visit-by-treatment group interaction; randomization stratification factors; and the continuous covariate of baseline BCVA. Error bars represent 80% CI. ETDRS indicates Early Treatment Diabetic Retinopathy Study.