Intravitreal Nesvacumab (Anti-Angiopoietin-2) Plus Aflibercept in Neovascular AMD: Phase 2 ONYX Randomized Trial
NCT02713204 | ONYX Trial | Heier et al. (2023)_Intravitreal
Heier JS, Ho AC, Boyer DS, et al. Intravitreal Nesvacumab (Anti-Angiopoietin-2) Plus Aflibercept in Neovascular AMD: Phase 2 ONYX Randomized Trial. J VitreoRetinal Dis, 2023; 7(1):8-15.
Locations
77 sites in the United States
Study Period
March 2016 – October 2017
Study Design
Phase 2, randomized, double-masked, active-controlled, multicenter trial
Study Population
Experimental Group
Control Group
Follow-up Time: 36 weeks
Outcomes
Durability
Number of Intravitreal Injections
The number of intravitreal injections over the 32-week in mean ± SD:
• LD combo q8w: 6.6 ± 0.93
• HD combo q8w: 5.1 ± 0.45
• IAI q8w: 4.9 ± 0.27
• IAI q12w: 5.9 ± 0.40
Vision
Best-corrected visual acuity (BCVA)
The mean change in BCVA from baseline to Week 12 (Primary Outcome):
• LD combo: +5.2 letters
• HD combo: +5.6 letters
• IAI: +5.4 letters
• Comparison: LD vs. IAI (p=0.9894); HD vs. IAI (p=0.8346).
The mean change in BCVA from baseline to Week 36:
• LD combo: +5.9 letters
• HD combo: +6.0 letters
• IAI q8w: +6.9 letters
• IAI q12w: +4.2 letters.
Other
N/A
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Central subfield thickness (CST) reduction at Week 12
The mean change from baseline in CST at week 12:
• LD combo: -182.2 µm
• HD combo: -200.0 µm
• IAI: -178.6 µm
• Comparison: LD vs. IAI (p=0.4130), HD vs. IAI (p=0.6587)
The mean change from baseline in CST at week 36:
• LD combo: -174.6 µm
• HD combo: -216.6 µm
• IAI q8w: -198.4 µm
• IAI q12w: -169.7 µm
Macular Thickness
Normalization of macular thickness (CST ≤300 µm) at Week 12:
• LD combo: 57.6%
• HD combo: 60.7%
• IAI: 59.9%
• Comparison: LD combo vs IAI, nominal (p = .7589); HD combo vs IAI, nominal (p = .8938)
Retinal Fluid
The proportion of eyes with complete resolution of retinal fluid at week 12:
• LD combo: 49.1%
• HD combo: 50.8%
• IAI: 43.6%
The proportion of eyes with complete resolution of retinal fluid at week 32:
• LD combo q8w: 46.6%
• HD combo q8w: 39.7%
• IAI q8w: 38.2%
• IAI q12w: 27.4%.
Safety
Ocular AEs (study eye)
Patients with any ocular AEs:
• LD combo: 30.0%
• HD combo: 42.6%
• IAI: 29.0%
Most common: Conjunctival hemorrhage (LD combo: 3.3%; HD combo: 4.9%; IAI: 2.7%).
Ocular Serious AEs (SAEs)
Patients with any ocular serious AEs:
• LD combo: 3.3%
• HD combo: 2.5%
• IAI: 0
Non-ocular SAEs
Patients with any non-ocular serious AEs:
• LD combo: 15.0%
• HD combo: 13.9%
• IAI: 15.3%.
Death
• LD combo: 1.7%
• HD combo: 1.6%
• IAI: 3.8%
Conclusion
Intravitreal nesvacumab + aflibercept did not show additional BCVA or CST benefit over IAI monotherapy in nAMD at 36 weeks, although some trends in anatomical outcomes warrant further investigation.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “One eye per eligible patient was randomized (1:2:3) via an interactive voice/web response system to receive…”
“In general, the baseline characteristics were balanced across the 3 treatment groups …”
Missing Outcome Data
Low risk
Note: “For efficacy analyses, missing data were imputed using the last observation carried forward…” which is not supposed to correct for bias due to missing outcome data.
However, according to the Suppl. Figure 1 Patients Disposition, the missingness at Week 12 for each arm is less than 5%, and the missingness is balanced between each group.
Selection of the Reported Results
Low risk Note: registration with the protocol
Deviations from Intended Observations
Low risk Note: This is a double-masked study. “The full analysis set, which included all randomized patients who received any study treatment and had a baseline BCVA measurement and 1 or more post-baseline BCVA measurements was used to analyze …”
Measurement of the Outcome
Some concerns Note: This is a double-masked study. However, as a multiple-site study, the BCVA assessment may exist in various sites.
Overall
Some concerns
Categories: Wet AMD