Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial

Abstract

Importance: Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding.

Objective: To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration.

Design, setting, and participants: This phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018.

Interventions: Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks.

Main outcomes and measures: Mean change in BCVA from baseline at week 40.

Results: Of 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified.

Conclusions and relevance: At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation.

Trial registration: ClinicalTrials.gov Identifier: NCT03038880.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Khanani reported grants from Adverum Biotechnologies, Allergan, Chengdu Kanghong, Genentech Inc, Graybug, Gyroscope, Gemini Therapeutics, Kodiak, Novartis, Iveric Bio, Opthea, Oxurion, Recens Medical, Regenxbio, and Roche during the conduct of the study and is a consultant for Adverum Biotechnologies, Allergan, Bausch and Lomb, Chengdu Kanghong, DORC, Eyepoint Pharmaceuticals, Gemini Therapeutics, Genentech Inc, Graybug, Gyroscope, Kodiak Sciences, Novartis, Opthea, Oxurion, Recens Medical, and Regenxbio; and reports speaker fees from Allergan and Novartis. Dr Patel reported grants and personal fees from Genentech Inc/Roche during the conduct of the study; grants and personal fees from Allergan and grants and personal fees from Kodiak Sciences outside the submitted work; and grants from Aerie Pharmaceuticals, Apellis Pharmaceuticals, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Ionis Pharmaceuticals, Mylan, Novartis, Opthea, Ophthotech, OraPharma, Regeneron, Samsung, Stealth BioTherapeutics, Xbrane Biopharma, and ThromboGenics outside the submitted work. Dr Ferrone reported grants from Genentech Inc during the conduct of the study and other support from Genentech Inc outside the submitted work. Dr Osborne reported a patent to faricimab dosing regimen pending and is an employee of and holds stock options in Adverum Biotechnologies. Dr Sahni reported other support from F. Hoffmann-La Roche during the conduct of the study and outside the submitted work and is also an employee and shareholder at F. Hoffmann-La Roche. Dr Basu reported personal fees from Genentech Inc during the conduct of the study and is an employee of Roche Products (Ireland). Dr Ehrlich reported personal fees and other support from Genentech Inc and Kodiak Sciences outside the submitted work. Dr Haskova is an employee of Genentech Inc and reported other support from Genentech Inc during the conduct of the study and outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram of the STAIRWAY Study

Patients were randomized 1:2:2 into the ranibizumab, 0.5 mg, every 4 weeks; faricimab, 6.0 mg, every 12 weeks; and faricimab, 6.0 mg, every 16 weeks treatment arms. Only 1 eye was chosen as the study eye. aFive participants were removed from the analysis due to Good Clinical Practice (GCP) violations at a single site.

Figure 2.. Key Vision Outcome: BCVA Change From Baseline Over Time

Least squares means from linear model analysis of study eye best-corrected visual acuity (BCVA) change from baseline. Model includes categorical covariates of treatment group, visit, visit-by-treatment group interaction, and the continuous covariate of baseline BCVA. For those taking ranibizumab, 0.5 mg, every 4 weeks, there was a mean change of 9.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters after a mean of 12.9 injections to week 52. For those taking faricimab, 6.0 mg, every 12 weeks, there was a mean change of 10.1 ETDRS letters after a mean of 6.7 injections to week 52. For those taking faricimab, 6.0 mg, every 16 weeks, there was a mean change of 11.4 ETDRS letters after a mean of 6.2 injections to week 52. Error bars represent 80% CIs.

Figure 3.. Key Anatomic Outcomes

Central subfield thickness (CST) reduction from baseline over time. Least squares means from linear model analysis of study eye CST change from baseline. Model includes categorical covariates of treatment group, visit, visit-by-treatment group interaction, and the continuous covariate of baseline CST. For those taking ranibizumab, 0.5 mg, every 4 weeks, there was a mean change of −129.9 μm. For those taking faricimab, 6.0 mg, every 12 weeks, there was a mean change of −138.5 μm. For those taking faricimab, 6.0 mg, every 16 weeks, there was a mean change of −122.5 μm. Error bars represent 80% CIs.