ONYX trial results: Combo therapy gives no added benefit when treating nAMD

The phase 2 ONYX trial of nesvacumab (Regeneron) plus aflibercept (Eylea, Regeneron) found that this combination used to treat neovascular age-related macular degeneration (nAMD) did not provide greater benefit to patients in visual acuity (VA) or central subfield thickness (CST) compared with aflibercept intravitreal injections alone,¹ according to the study investigators. Jeffery Heier, MD, the Director of the Vitreoretinal Service and Director of Retina Research at Ophthalmic Consultants of Boston, was the lead study author.

The investigators theorized that intravitreal nesvacumab, an anti-angiopoietin-2 therapy, plus aflibercept, an anti-vascular endothelial growth factor (VEGF) drug, in a fixed-dose combination would be advantageous for treating nAMD, in that “both antibodies can be individually optimized, ensuring a specific dose of each component is delivered.”

Studies of preclinical models of pathologic ocular angiogenesis have suggested that VEGF and angiopoietin-2 are co-regulated in nAMD and may work together to promote pathologic neovascularization and increase vascular permeability.^2-4

The phase 2 ONYX trial compared the efficacy and safety of intravitreal nesvacumab plus aflibercept fixed-dose combination with that of intravitreal aflibercept monotherapy injections in patients with nAMD. The primary endpoints were changes in the best-corrected VA (BCVA) and CST.

In this randomized trial, eyes were randomized (1:2:3) to nesvacumab 3 mg plus aflibercept 2 mg, the low-dose combination; nesvacumab 6 mg plus aflibercept 2 mg, the high-dose combination; or intravitreal aflibercept 2 mg at baseline, week 4, and week 8. The low-dose combination was administered every 8 weeks. At week 12, the high-dose combination was re-randomized to every 8 week or every 12 weeks and intravitreal aflibercept injection was re-randomized to every 8 weeks, every 12 weeks, or the high-dose combination every 8 weeks through week 32.

A total of 365 eyes were included in the study.

The authors reported that at week 12, the mean increases in the BCVA compared with the baseline values were similar among the 3 groups, ie, 5.2, 5.6, and 5.4 letters, respectively, in the low-dose and high-dose combination groups and the aflibercept group. The respective decreases in the mean CSTs also were similar, ie, 182.2, 200.0, and 178.6 µm, respectively.

At the 36-week evaluation, the mean changes in the BCVA and CST also were similar in the 3 groups.

At week 12, the respective values of complete retinal fluid resolution occurred in 49.1%, 50.8%, and 43.6% of eyes, and the proportions with a CST of 300 μm or less were similar across groups.

The numerical trends at week 32 toward complete retinal fluid resolution with combination treatment were not maintained at week 36, the investigators reported. Serious ocular adverse events were infrequent and comparable among the groups.

The investigators concluded, “The ONYX trial did not show additional benefits in VA or CST reductions with intravitreal nesvacumab plus aflibercept combination treatment over intravitreal aflibercept injection monotherapy in treatment-naive nAMD at 36 weeks, although there were some numeric trends toward greater anatomic effects (eg, retinal dryness), which may warrant further investigation of the role of anti-angiopoietin-2 in combination with anti-VEGF therapy.”

References:

1. Heier JS, Ho AC, Boyer DS, et al. Intravitreal nesvacumab (anti-angiopoietin-2) plus aflibercept in neovascular AMD: phase 2 ONYX randomized trial. J Vitreoretin Dis. 2022;7; published online Dec 30, 2022; https://doi.org/10.1177/2474126422112606

2. Oshima Y, Deering T, Oshima S, et al. Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor. J Cell Physiol. 2004;199:412-417

3. Peters S, Cree IA, Alexander R, et al. Angiopoietin modulation of vascular endothelial growth factor: effects on retinal endothelial cell permeability. Cytokine. 2007;40:144-150

4. Daly C, Eichten A, Castanaro C, et al. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res. 2013;73:108-118