Faricimab is a humanised bispecific immunoglobulin G1 (IgG1) antibody that acts through inhibition of two distinct pathways by neutralisation of both angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A).
Ang-2 causes vascular instability by promoting endothelial destabilisation, pericyte loss, and pathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitises blood vessels to the activity of VEGF-A resulting in further vascular destabilisation. Ang-2 and VEGF-A synergistically increase vascular permeability and stimulate neovascularisation.
By dual inhibition of Ang-2 and VEGF-A, faricimab reduces vascular permeability and inflammation, inhibits pathological angiogenesis and restores vascular stability.
A suppression from baseline of median ocular free Ang-2 and free VEGF-A concentrations was observed from day 7 onwards in the six Phase III studies described hereafter.
In TENAYA and LUCERNE, objective, pre-specified visual and anatomic criteria, as well as treating physician clinical assessment, were used to guide treatment decisions at the disease activity assessment time points (week 20 and week 24).
The mean central subfield thickness (CST) reduction from baseline at the primary endpoint visits (averaged at weeks 40-48) was comparable to those observed with aflibercept, with -137 μm and -137 μm in patients treated with faricimab dosed up to every 16 weeks (Q16W) as compared to -129 μm and -131 μm with aflibercept, in TENAYA and LUCERNE, respectively. These mean CST reductions were maintained through year 2.
At week 48, in both studies there was a comparable effect of faricimab and aflibercept on the reduction of intraretinal fluid (IRF), subretinal fluid (SRF), and PED. These effects in IRF, SRF, and PED were maintained at year 2. There were also comparable changes in total CNV lesion area and reductions in CNV leakage area from baseline for patients in the faricimab and aflibercept treatment arms.
In YOSEMITE and RHINE, anatomic parameters related to macular oedema were part of the disease activity assessments guiding treatment decisions.
The mean CST reduction from baseline at the primary endpoint visits (averaged at weeks 48-56) was numerically greater than those observed with aflibercept, with -207 μm and -197 μm in patients treated with faricimab Q8W and faricimab up to Q16W adjustable dosing as compared to -170 μm in aflibercept Q8W patients in YOSEMITE; results were 196 μm, 188 μm, and 170 μm, respectively in RHINE. Consistent reductions in CST were observed through year 2. Greater proportions of patients in both faricimab arms achieved absence of IRF and absence of DME (defined as reaching CST below 325 μm) over time through year 2 as compared to aflibercept in both studies.
In Phase III studies in patients with branch retinal vein occlusion (BRVO; BALATON) and central/hemiretinal vein occlusion (C/HRVO; COMINO), reductions in mean CST were observed from baseline to week 24 with faricimab Q4W and were comparable to those seen with aflibercept Q4W. The mean CST reduction from baseline to week 24 was 311.4 μm for faricimab Q4W versus 304.4 μm for aflibercept Q4W, in BALATON, and 461.6 μm versus 448.8 μm in COMINO for faricimab and aflibercept, respectively. CST reductions were maintained through week 72 when patients moved to a faricimab up to Q16W adjustable dosing regimen.
Comparable proportions of patients in both faricimab Q4W and aflibercept Q4W arms achieved absence of IRF, absence of SRF, and absence of macular edema (defined as reaching CST below 325 μm) over time through week 24, in both studies. These results were maintained through week 72 when patients moved to a faricimab up to Q16W adjustable dosing regimen.
Faricimab is administered intravitreally to exert local effects in the eye.
Based on a population pharmacokinetic analysis (including nAMD and DME N=2 246), maximum free (unbound to VEGF-A and Ang-2) faricimab plasma concentrations (Cmax) are estimated to occur approximately 2 days post-dose. Mean (±SD [standard deviation]) plasma Cmax are estimated 0.23 (0.07) μg/mL and 0.22 (0.07) μg/mL respectively in nAMD and in DME patients. After repeated administrations, mean plasma free faricimab trough concentrations are predicted to be 0.002-0.003 μg/mL for Q8W dosing.
Faricimab exhibited dose-proportional pharmacokinetics (based on Cmax and AUC) over the dose range 0.5 mg-6 mg. No accumulation of faricimab was apparent in the vitreous or in plasma following monthly dosing.
Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6 000-fold lower than in aqueous and vitreous humour respectively. Therefore, systemic pharmacodynamic effects are unlikely, further supported by the absence of significant changes in free VEGF and Ang-2 concentration in plasma upon faricimab treatment in clinical studies.
Population pharmacokinetic analysis has shown an effect of age and body weight on ocular or systemic pharmacokinetics of faricimab respectively. Both effects were considered not clinically meaningful; no dose adjustment is needed.
Faricimab is a protein-based therapeutic hence its metabolism and elimination have not been fully characterised. Faricimab is expected to be catabolised in lysosomes to small peptides and amino acids, which may be excreted renally, in a similar manner to the elimination of endogenous IgG.
The faricimab plasma concentration-time profile declined in parallel with the vitreous and aqueous concentration-time profiles. The estimated mean ocular half-life and apparent systemic half-life of faricimab is approximately 7.5 days.
Pharmacokinetic analysis of patients with nAMD, DME, and RVO (N=2 977) has shown that the pharmacokinetics of faricimab are comparable in nAMD, DME, and RVO patients.
In the six Phase III clinical studies, approximately 58% (1,496/2,571) of patients randomised to treatment with faricimab were ≥65 years of age. Population pharmacokinetic analysis has shown an effect of age on ocular pharmacokinetics of faricimab. The effect was considered not clinically meaningful. No dose adjustment is required in patients 65 years and above.
No specific studies in patients with renal impairment have been conducted with faricimab. Pharmacokinetic analysis of patients in all clinical studies of which 63% had renal impairment (mild 38%, moderate 23%, and severe 2%), revealed no differences with respect to systemic pharmacokinetics of faricimab after intravitreal administration of faricimab. No dose adjustment is required in patients with renal impairment.
No specific studies in patients with hepatic impairment have been conducted with faricimab. However, no special considerations are needed in this population because metabolism occurs via proteolysis and does not depend on hepatic function. No dose adjustment is required in patients with hepatic impairment.
The systemic pharmacokinetics of faricimab are not influenced by race. Gender was not shown to have a clinically relevant influence on systemic pharmacokinetics of faricimab. No dose adjustment is needed.
No studies have been conducted on the carcinogenic or mutagenic potential of faricimab.
In pregnant cynomolgus monkeys, IV injections of faricimab resulting in serum exposure (Cmax) more than 500-times the maximum human exposure did not elicit developmental toxicity or teratogenicity, and had no effect on weight or structure of the placenta, although, based on its pharmacological effect faricimab should be regarded as potentially teratogenic and embryo-/foetotoxic.
Systemic exposure after ocular administration of faricimab is very low.
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