Author: Lars Hattenbach (Germany)
Patients with macular edema due to retinal vein occlusion (RVO) have a high treatment burden which results in the majority of the patients requiring long-term treatment with frequent clinic visits for monitoring and injections to ensure vision gains are maintained over the long term. Real world evidence indicates that patients with branch or central RVO require an average of 8 injections of anti-vascular endothelial growth factor (VEGF) in the first year of therapy. Therefore, an unmet need exists for both improved vision outcomes, and for more durable treatments (requiring less frequent monitoring and fewer injections). Dual inhibition of angiopoietin (Ang)-2 and VEGF-A with faricimab, the first bispecific antibody designed for intraocular use, has shown excellent visual acuity gains with strong durability in Phase 3 studies in patients with diabetic macular edema (DME) and age-related macular degeneration (nAMD). The strong durability findings in patients with DME and nAMD suggest that faricimab may meet the unique needs of patients with RVO by potentially reducing the number of injections required to maintain visual acuity. Our goal was to design a study to investigate the effects of faricimab on visual acuity and treatment durability in patients with RVO.
High levels of Ang-2 have been observed in RVO and Ang-2 has been implicated in RVO pathology; including pathologic neovascularisation, endothelial destabilisation, vascular exudation, and retinal inflammation. Unlike DME or nAMD, patients with RVO less frequently have underlying chronic systemic or ocular disorders that further promote the progression of the disease. Thus, the benefits of dual Ang-2/VEGF inhibition may be more pronounced in patients with RVO than other retinal diseases. We designed the phase 3, multicenter, randomized, double-masked, active comparator-controlled BALATON (NCT04740905) and COMINO (NCT04740931) trials, to compare faricimab with aflibercept in patients with macular edema due to RVO.
Anti-VEGF treatment-naïve patients with foveal centre-involved macular edema due to branch RVO (BALATON; n=570) or central/hemiretinal RVO (COMINO; n=750), best-corrected visual acuity (BCVA) 73─19 letters (20/40─20/400 Snellen equivalent), and central subfield thickness (CST) ≥325μm (Spectralis/Zeiss) or ≥315μm (Cirrus/Topcon) will be included. Patients with prior macular laser/pan-retinal laser <3 months before screening, prior steroids (intravitreal/implants), ≥moderate non-proliferative diabetic retinopathy, and advanced nAMD, will be excluded. Both studies will compare 6x monthly injections of faricimab 6.0 mg with aflibercept 2.0 mg (Part 1). All patients will roll over to faricimab 6.0 mg administered in up to 16-weekly intervals using a personalized treatment interval (PTI) dosing regimen (Week 24─72; Part 2). PTI adjustments are based on changes in CST and BCVA from reference values at previous dosing visits via an interactive (voice-/web-based) response system (IxRS). PTI allows adjustment of dosing in 4-week increments up to a maximum 16-week interval, and down in 4 or 8 week increments to a minimum 4-week interval if needed. To maintain masking, at study visits without faricimab injection sham injections will be administered, and CST and BCVA values will be collected for safety/efficacy purposes (not considered by the IxRS system for PTI interval determination).
The primary endpoint is non-inferiority of faricimab versus aflibercept, with the potential to demonstrate superiority, in the mean change from baseline in BCVA at Week 24. Secondary endpoints include mean change from baseline in BCVA, CST, and NEI VFQ-25 composite score, and proportion of patients gaining/ avoiding a loss of ≥15, ≥10, ≥5, or >0 letters through Week 24. Additional secondary endpoints measured through Week 72 will include change from baseline in BCVA and CST, proportion of patients on a 4-weekly (Q4W), 8-weekly (Q8W), 12-weekly (Q12W), or 16-weekly (Q16W) treatment, number of study drug injections received from Week 24 through Week 72, and assessment of the other Week 24 secondary endpoints. Imaging assessments will include spectral domain or swept-source optical coherence tomography, color fundus photography, and fundus fluorescein angiography. Incidence and severity of ocular and non-ocular adverse events, plasma concentration of faricimab over time, and the development of anti-drug antibodies will be assessed.
BALATON and COMINO are designed to evaluate whether dual inhibition of angiopoietin-2 and VEGF-A with faricimab may improve outcomes beyond anti-VEGF monotherapy in patients with macular edema due to RVO. The PTI phase is designed to examine the potential for individualized faricimab therapy, tailored according to patient needs, to reduce treatment burden while maintaining efficacy.