Vascular endothelial growth factor inhibitors (anti-VEGF) have revolutionized the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), diabetic retinopathy (DR), and retinal vein occlusion (RVO). The current treatment options, however, carry a significant treatment burden, and the visual acuity gains achieved in randomized clinical trials are not seen in the real world.^1-3 There is a current unmet need for treatment options that can decrease treatment burden by lowering the frequency of injections and clinic visits.

MECHANISM OF ACTION

Faricimab (Genentech), formerly known as RG7716 and RO6867461, is a first-in-class bispecific antibody designed for intravitreal use (Figure 1). Faricimab is composed of 2 heavy chains and 2 light chains.⁴ It is a molecule with 2 targets: one ligand-binding arm binds VEGF-A and the other binds angiopoietin-2 (Ang2). The efficacy of inhibiting VEGF-A is well established, and current available treatments block VEGF-A. Recent studies have demonstrated that the tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (Tie2) plays a critical role in angiogenesis as well as vascular stability, and inhibiting Ang2 leads to Tie2 activation.^4,5 Tie2 is a transmembrane receptor located on the endothelial cells and it serves as a binding site for the angiopoietin family of ligands, which includes angiopoietin-1 (Ang1) and Ang2.^4,5 Once bound to Tie2, Ang1 functions to phosphorylate the receptor and then activates the downstream pathways that ultimately suppress vascular permeability and maintain vascular stability.^4,5 Ang2 is an endogenous, partial agonist of Tie2 that competes with Ang1 to downregulate the phosphorylation and the activation of Tie2. Ang2 levels are elevated in retinal vascular diseases, including nAMD, DR, proliferative DR, and RVO.⁴

The interaction between the angiopoietin family and VEGF has been studied in the ocular setting using mice that express VEGF-A and Ang1.^4,5 When expressed simultaneously with VEGF-A, Ang1 expression prevented retinal detachment and blocked neovascularization. Despite Ang1 effectively suppressing neovascularization, there was no impact on lesions that were previously established. Early studies using mice have demonstrated that despite increased expression of VEGF in the inner surface of the retina, neovascularization and vascular leakage do not occur unless in the presence of elevated levels of Ang2.^4-7 Ang2 has also been studied for its role in upregulating inflammation via a mechanism of inducing endothelial cells to become more sensitive to the effect of tumor necrosis factor-alpha (TNFα).^4-7 Ang2 is believed to be stored within endothelial cells in Weibel–Palade bodies, where it is rapidly released under the influence of angiogenic, inflammatory, and other cytokines. Further significance of Ang2 is established from studies that have shown elevated levels of Ang2 and VEGF-A in the vitreous of diabetic patients undergoing a vitrectomy.⁵ The expression of Ang2 and VEGF-A were shown to correlate with each other as well as disease severity. Thus, Ang2 appears to play a considerable role in angiogenesis, vascular instability, and inflammation, which makes it an attractive therapeutic target.

Faricimab was developed using CrossMAb technology. Regula et al reported data regarding faricimab binding and neutralizing human VEGF‐A and Ang2 with high potency and also tested it in a laser‐induced model of CNV in nonhuman primates.^4,5 The simultaneous inhibition of VEGF-A and Ang2 showed increased efficacy compared to inhibition of either VEGF-A or Ang2 alone. The authors also showed that faricimab is capable of binding to VEGF-A and, simultaneously, to Ang2 without any binding to Ang1. In addition, the Fc region of faricimab has been engineered to abolish binding interactions with all Fc gamma receptors and neonatal Fc receptors, resulting in lower systemic concentrations compared to wild-type IgG1 antibodies, and a reduced potential for platelet activation.⁴

It has been demonstrated that faricimab was safe and well tolerated, with no unexpected adverse events, in a phase 1 clinical trial in previously treated patients with nAMD.⁸ This study consisted of 2 treatment groups: a single ascending dose group and a multiple ascending dose group. In the single ascending dose group, patients received 0.5 mg, 1.5 mg, 3 mg, or 6 mg with a study duration of up to 16 weeks.⁸ In the multiple ascending group, patients received either 3 mg or 6 mg of the drug with a total of 3 administrations in monthly intervals for a study duration of 24 weeks. The single ascending dose group documented a median improvement of best-corrected visual acuity (BCVA) of 7 letters, while the multiple ascending group demonstrated a median improvement in BCVA of 7.5 letters.⁸

A 224-patient randomized, double-masked phase 2 study assessed the safety and efficacy of faricimab in patients with DME (BOULEVARD). The AVENUE and STAIRWAY phase 2 studies assessed the efficacy and durability of faricimab in treating neovascular AMD. In the BOULEVARD study, treatment-naive patients with DME were treated with 0.3 mg ranibizumab (Lucentis; Genentech), 1.5 mg faricimab, and 6.0 mg faricimab.⁹ The primary objective of the BOULEVARD study was to assess the efficacy of faricimab compared with ranibizumab in anti-VEGF treatment-naïve patients at week 24. This study showed faricimab demonstrated robust BCVA gains in patients at 6 months, with mean of +13.9 letters gained from baseline. Secondly, it demonstrated statistically significant BCVA gains over ranibizumab at 6 months (mean gain of +3.6 letters, P=.03). Faricimab also resulted in better central subfield thickness reductions and DRSS improvements compared to ranibizumab as well as no new or unexpected safety signals.⁹ In the STAIRWAY study, patients were treated with faricimab 6.0 mg every 16 weeks (Q16W), 6.0 mg every 12 weeks (Q12W), and ranibizumab 0.5 mg every 4 weeks (Q4W).¹⁰ The results showed 65% of faricimab-treated patients had no disease activity 12 weeks after the loading injections. BCVA outcomes for patients receiving faricimab every 16 weeks and every 12 weeks were comparable to those receiving ranibizumab every 4 weeks.¹⁰ Patients gaining 15 letters or more and not losing 15 or more letters in BCVA were also comparable between faricimab Q16W, faricimab Q12W, and ranibizumab Q4W. Central subfield thickness improvements and choroidal neovascularization lesion size reductions were also comparable among all 3 groups. There were no new safety signals identified. The overall safety profile of faricimab across all trials was consistent with the safety profile of intravitreal anti-VEGF treatments.

CONCLUSION

The data from the BOULEVARD phase 2 study established the superior efficacy and durability of faricimab in patients with DME compared to monthly ranibizumab. The results from the STAIRWAY study confirmed extended durability of faricimab in patients with nAMD compared to monthly ranibizumab. The phase 3 YOSEMITE/RHINE studies are ongoing and are evaluating efficacy and durability of faricimab in patients with DME compared to aflibercept. The phase 3 trials to evaluate efficacy and durability of faricimab in patients with nAMD will start in 2019. RP

REFERENCES

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