Faricimab: Two in the Bush Is Proving Better than One in the Hand?

The last decade in the treatment of vascular pathologies of the retina has largely been limited to one cytokine: the vascular endothelial growth factor (VEGF) and its interaction with the receptor by blocking the downstream pathway. VEGF plays a role in unregulated neovascularisation and impaired vascular permeability secondary to hypoxia involving all the common retinal pathologies, such as neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vascular occlusions (RVOs). Though anti-VEGF agents have saved millions of eyes from going blind to these pathologies, there have been a subset of patients who did not have optimal response to this therapy.^1,2 This suboptimal response to anti-VEGF therapies can be pinpointed to two reasons, the first being, administration of inadequate therapy due to a multitude of reasons, and the other being, non-response of the disease to adequate number of injections. While there have been various regimens that are being tried to provide lesser number of injections without compromising outcomes such as Treat and Extend (T&E) to counteract the first scenario, tackling the second problem requires novel therapeutic targets to be identified and analyzed for their role in inflammation and angiogenesis.

The Tie-2 pathway is one of the few pathways involved in the pathogenesis of retinal vascular diseases that is being evaluated and targeted.³ Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (Tie-2) receptors is receptive to two angiopoietin ligands (Ang-1 and Ang-2). Tie-2 pathway activation promotes maintenance of vascular health by promoting endothelial cell (EC) survival, maturity, and stability, unlike VEGF pathway that promotes angiogenesis. Ang-1 is produced by smooth muscle cells, pericytes, and fibroblasts and is a complete agonist, while Ang-2 is produced by ECs and is an antagonist for majority of the scenarios, except for inflammation where it behaves as partial agonist. They have the same affinity for the same site on the receptor, while binding of Ang-1 results in the promotion of vascular stability and feedback inhibition of Ang-2 production.⁴ In cluster formation, Ang-1 cluster contains more molecules than Ang-2 clusters, which maintains strong activation of Tie-2 pathway that maintains EC health. Thus Ang-1 promotes vascular stability and feedback inhibition of Ang-2 production from the EC. Ang-2 binding disrupts Tie-2 clusters in most of the settings that induce abnormal vascular structure formation with increased vascular permeability and increased inflammation.^4–6 It is present at the highest level of the most highly vascularized region of the choroidal neovascular membrane (CNVM).⁷ Ang-2 is also increasingly expressed in the setting of hypoxia and hyperglycemia, increasing the vascular permeability by playing a partial role in fluid accumulation in different retinal layers.^5,8 Inhibition of Ang-2 may thus result in reduced neovascularization, as well as reduced vascular permeability and inflammation. Secondarily, in the absence of Ang-2, Ang-1 will have better binding to the Tie-2 receptor making the vessels that have already been formed more mature and stable. This may result in the conversion of exudative nAMD to non-exudative nAMD.⁹

The Tie-2-Ang-2 axis is being targeted as a new approach to treat retinal vascular pathologies. AXT107 is a peptide derived from the non-collagenous domain of type IV collagen, which aims to stimulate the Tie-2 pathway and inhibits VEGF action. The phase 1/2a was initiated with the first injection being administered in January 2021.¹⁰

Faricimab, on the other hand, is a bispecific antibody developed on the CrossMAb platform, which directly blocks Ang-2 as well as VEGF action. The lock and key model ensures heterodimerisation with each molecule having one anti-Ang-2 domain and one anti-VEGF domain. Our group has previously highlighted how the preclinical and phase I/II data have shown efficacy and longevity of the molecule with a probable q16w dosing.¹¹ The published data from the STAIRWAY trial have now confirmed a 16-week dosing regimen that maintained visual and anatomical improvements, with 61% of patients having no disease activity till 52 weeks.¹² The trial reported occurrence of ocular adverse event (OAE) in 39.4% of the patients who received at least one injection of faricimab, none of which were classified as serious OAE. None of the patients developed a systemic adverse event that was attributable to the drug.¹² The phase II trials of faricimab were compared head-to-head with ranibizumab while the phase III trials compare its action to aflibercept in various pathologies, including nAMD and DME. TENAYA and LUCERNE are the two identical, randomized, multicentre, double-masked, global phase III studies, evaluating 1,329 people living with nAMD, while YOSEMITE and RHINE are the two identical, randomized, multicentre, double-masked, global phase III studies, evaluating 1,891 people with DME for the response of faricimab compared to aflibercept.^13–16 All the four studies assessed faricimab given at fixed intervals of q8w, q12w, and q16w based on their disease activity at weeks 20 and 24, compared to aflibercept’s q8w regimen. At the end of the first year, 45.7% of patients in TENAYA and 44.9% in LUCERNE sustained the q16w dosing while an additional 34% of patients in TENAYA and 32.9% in LUCERNE held q12w dosing. 52.8% of faricimab patients in YOSEMITE and 51% in RHINE completed one year of study on q16w dosing with an additional 21% in YOSEMITE and 20.1% in RHINE maintained q12w dosing.¹⁷ If q12w dosing was considered, more than three-quarters of all the patients combined from the phase III trials were able to maintain the interval at the end of one year. The visual gains with faricimab in all these studies were non-inferior to aflibercept. In the wake of the recent inflammation-related events in the two most recently developed biologics for retinal vascular pathologies, brolucizumab and abicipar, the trials have also evaluated inflammation and other adverse events more in detail. No new or unexpected safety signals have been reported in the first topline data, but the detailed published result will allow us to understand the safety data better.

We are gaining new pathogenic insights into the evolution of neovascularization in nAMD with the help of optical coherence tomography angiography (OCTA). There is an evolving understanding by some of the groups that rather than aiming for the complete resolution of VEGF driven neovascularization, it would be helpful if any therapeutic option could help in the maturation of these new vessels which might, in turn, prevent exudation and subsequent damage.¹⁸ Faricimab by inhibiting Ang-2 might provide us with less vascular permeability and better endothelial stability theoretically making the nAMD non-exudative. In the context of incidences of inflammation related to brolucizumab which had a disconnect between clinical trials and real-world, long-term careful follow-up of patients treated with faricimab will be needed to study this effect as well as its safety in the real world. As of now, two in the bush (Anti-VEGF+ Tie 2) is seeming to be better than one (Anti-VEGF) in the hand. Thus, while the two birds in the bush seem better than one in the hand, until the entire dataset is scrutinized, a pragmatic scrutiny should continue.

Erratum

The nAMD trials (TENAYA and LUCERNE) assessed faricimab given at fixed intervals of q8w, q12w and q16w based on their disease activity at weeks 20 and 24, compared to the aflibercept’s q8w regimen. The DME trials (YOSEMITE and RHINE) evaluated faricimab’s q8w regimen and personalised treatment interval (PTI) with aflibercept’s q8w regimen. PTI is a treat and extend concept with initial 4 q4w loading doses which is gradually extended by 4 weeks to a maximum of q16w based on the response.

Disclosure statement

Dr Ashish: CONSULTANT: for Novartis, Allergan, Bayer and Intas

Francesco Bandello: CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, Fidia Sooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss

BD Kuppermann: CLINICAL RESEARCH: Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron, ThromboGenics; CONSULTANT: Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, Theravance Biopharma

Dr. Loewenstein reports other from Allergan, other from Novartis, other from Roche, other from Notal Vision, other from Forsightslabs, other from Beyeonics, other from Bayer Health Care

Dr Nilesh Kumar: None

Dr Nikulaa Parachuri: None

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.