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Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Pharmacodynamic effects: A suppression from baseline of median ocular free Ang-2 and free VEGF-A concentrations was observed from day 7 onwards in the four Phase III studies described hereafter.
nAMD: nAMD is characterised by pathological choroidal neovascularisation (CNV). Leakage of blood and fluid from CNV may cause retinal thickening with sub and/or intraretinal fluid accumulation (SRF, IRF) and haemorrhages, which can result in vision loss.
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).
Reductions in mean central subfield thickness (CST) were observed from baseline through to week 48 with Vabysmo, and were comparable to those observed with aflibercept. The mean CST reduction from baseline through the primary endpoint visits (averaged at weeks 40-48) was -137 μm and -137 μm for Vabysmo dosed up to every 16 weeks (Q16W) versus -129 μm and -131 μm with aflibercept, in TENAYA and LUCERNE, respectively.
At Week 48, in both studies there was a comparable effect of Vabysmo and aflibercept on the reduction of IRF, SRF, and pigment epithelial detachment (PED). There were also comparable changes in total CNV lesion area and reductions in CNV leakage area from baseline for patients in the Vabysmo and aflibercept treatment arms.
DMO: DMO is a consequence of DR and is characterised by increased vasopermeability and damage to the retinal capillaries, mediated in part due to VEGF and Ang2, which may result in vision loss.
In YOSEMITE and RHINE, anatomic parameters related to macular oedema were part of the disease activity assessments guiding treatment decisions in the Vabysmo up to Q16W adjustable dosing arm.
The mean CST reduction from baseline at the primary endpoint visits (averaged at weeks 48-56) were numerically greater than those observed with aflibercept, with -207 μm and -197 μm in patients treated with Vabysmo Q8W and Vabysmo 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 Vabysmo arms achieved absence of IRF and absence of DMO (defined as reaching CST below 325 μm) over time through year 2 as compared to aflibercept in both studies.
Clinical efficacy and safety: nAMD: The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, active comparator-controlled, 2-year studies in patients with nAMD, TENAYA and LUCERNE. A total of 1,329 treatment-naïve patients were enrolled in these and 1,326 patients received at least one dose (664 with Vabysmo). Patient ages ranged from 50 to 99 years with a mean of 75.9 years.
In both studies, patients were randomised in a 1:1 ratio to one of two treatment arms: Vabysmo 6 mg up to Q16W after four initial monthly doses; Aflibercept 2 mg Q8W after three initial monthly doses.
After the first four monthly doses (weeks 0, 4, 8, and 12) patients randomised to the Vabysmo arm received Q16W, every 12 weeks (Q12W) or Q8W dosing based on an assessment of disease activity at weeks 20 and 24, using objective pre-specified ETDRS-measured BCVA and SD-OCT CST criteria as well as treating physician clinical assessment of the presence/absence of macular haemorrhage. Patients remained on these fixed dosing intervals until week 60 without supplemental therapy.
Results: Both studies demonstrated efficacy in the primary endpoint, defined as the mean change from baseline in BCVA when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Table 1). In both studies, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W. Improvements from baseline BCVA at week 48 are shown in Figure 1 and Figure 2.
The proportion of patients on each of the different treatment intervals at week 48 in TENAYA and LUCERNE respectively was: Q16W, 46% and 45%; Q12W, 34% and 33%; Q8W, 20% and 22%. (See Table 1 and Figures 1 and 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageIn both TENAYA and LUCERNE, improvements from baseline in BCVA and CST at week 60 were comparable across the two treatment arms and consistent with those seen at week 48.
Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, lesion type, lesion size) in each study, and in the pooled analysis, were consistent with the results in the overall populations.
In both studies, Vabysmo up to Q16W demonstrated clinically meaningful improvements from baseline to week 48 in the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score that was comparable to aflibercept Q8W. Patients in Vabysmo arms in TENAYA and LUCERNE achieved a ≥4 point improvement from baseline in the NEI VFQ-25 composite score at week 48.
DMO: The safety and efficacy of Vabysmo were assessed in two randomised, multi-centre, double-masked, active comparator-controlled 2-year studies (YOSEMITE and RHINE) in patients with DMO. A total of 1,891 patients were enrolled in the two studies with 1,622 (85.8%) patients completing the studies through week 100. A total of 1,887 were treated with at least one dose through week 56 (1,262 with Vabysmo). Patient ages ranged from 24 to 91 with a mean of 62.2 years. The overall population included both anti-VEGF naïve patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%). In both studies, patients were randomised in a 1:1:1 ratio to one of the three treatment regimens: Vabysmo 6 mg Q8W after the first 6 monthly doses; Vabysmo 6 mg up to Q16W adjustable dosing administered in 4, 8, 12 or 16-week intervals after the first 4 monthly doses; Aflibercept 2 mg Q8W after the first 5 monthly doses.
In the up to Q16W adjustable dosing arm, the dosing followed a standardised treat-and-extend approach. The interval could be increased in 4-week increments or decreased in 4- or 8-week increments based on CST change as measured on OCT and/or BCVA change as measured by ETDRS letters, using data obtained only at study drug dosing visits.
Results: Both studies demonstrated efficacy in the primary endpoint, defined as the mean change from baseline in BCVA at year 1 (average of the week 48, 52, and 56 visits), measured by the ETDRS Letter Score. In both studies, Vabysmo up to Q16W treated patients had a comparable mean change from baseline in BCVA, as the patients treated with aflibercept Q8W at year 1, and these vision gains were maintained through year 2. Detailed results of both studies are shown in Table 2, Figure 3, and Figure 4 as follows.
After 4 initial monthly doses, the patients in the Vabysmo up to Q16W adjustable dosing arm could have received between the minimum of 6 and the maximum of 21 total injections through week 96. At week 52, 74% and 71% of patients in the Vabysmo up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in YOSEMITE and RHINE, respectively (53% and 51% on Q16W, 21% and 20% on Q12W). Of these patients, 75% and 84% maintained ≥Q12W dosing without an interval reduction below Q12W through week 96; of the patients on Q16W at week 52, 70% and 82% of patients maintained Q16W dosing without an interval reduction through week 96 in YOSEMITE and RHINE, respectively. At week 96, 78% of patients in the Vabysmo up to Q16W adjustable dosing arm achieved a Q16W or Q12W dosing interval in both studies (60% and 64% on Q16W, 18% and 14% on Q12W). 4% and 6% of patients were extended to Q8W and stayed on ≤Q8W dosing intervals through week 96; 3% and 5% received only Q4W dosing in YOSEMITE and RHINE, respectively. The proportion of patients in YOSEMITE and RHINE, respectively, who received >15 injections in the PTI arms through week 96 was 13% and 18%.
Detailed results from the analyses of YOSEMITE and RHINE studies are listed in Table 2 and Figures 3 and 4 as follows. (See Table 2 and Figures 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageEfficacy results in patients who were anti-VEGF treatment naïve prior to study participation and in all the other evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, baseline visual acuity) in each study were consistent with the results in the overall populations.
An additional key efficacy outcome in DMO studies was the change in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline to week 52. Of the 1,891 patients enrolled in Studies YOSEMITE and RHINE, 708 and 720 patients were evaluable for DR endpoints.
The ETDRS-DRSS scores ranged from 10 to 71 at baseline.
The majority of patients, approximately 60%, had moderate to severe nonproliferative DR (DRSS 43/47/53) at baseline.
At week 52, the proportion of patients improving by ≥2 steps on the ETDRS-DRSS was 43% to 46% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 36% and 47% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively. The results at week 96 were 43% to 54% across the Vabysmo Q8W and Vabysmo adjustable up to Q16W arms in both studies, compared to 42% and 44% in aflibercept Q8W arms of YOSEMITE and RHINE, respectively. Comparable results across the treatment arms were observed in both studies in the proportions of patients improving by ≥3 steps on the ETDRS-DRSS from baseline at week 52, and these results were maintained at week 96.
The results from the ≥2-step and ≥3-step ETDRS-DRSS improvement analyses from baseline at week 52 and at week 96 are shown in Table 3 as follows. Clinically meaningful proportions of patients achieved ≥2-step DRSS improvement from baseline at Week 52 in all three treatment arms (faricimab Q8W, faricimab PTI and aflibercept Q8W), and these outcomes were maintained at Week 96. (See Table 3.)
Click on icon to see table/diagram/imageAcross studies, Vabysmo Q8W and up to Q16W adjustable dosing showed improvements in the pre-specified efficacy endpoint of mean change from baseline to week 52 in the NEI VFQ-25 composite score that were comparable to aflibercept Q8W and exceeded the threshold of 4 points. Vabysmo Q8W and up to Q16W adjustable dosing also demonstrated clinically meaningful improvements in the prespecified efficacy endpoint of change from baseline to week 52 in the NEI VFQ-25 near activities, distance activities, and driving scores, that were comparable to aflibercept Q8W. The magnitude of these changes corresponds to a 15-letter gain in BCVA. Comparable proportions of patients treated with Vabysmo Q8W, Vabysmo up to Q16W adjustable dosing, and aflibercept Q8W experienced a clinically meaningful improvement of ≥4-points from baseline to week 52 in the NEI VFQ-25 composite score, a pre-specified efficacy endpoint. These results were maintained at week 100.
DR treatment effects in the subgroup of patients who were anti-VEGF naïve prior to study participation were comparable to those observed in the overall DR evaluable population. Treatment effects in evaluable subgroups (e.g. by age, gender, race, baseline HbA1c, and baseline visual acuity) in each study were generally consistent with the results in the overall population.
Pharmacokinetics: Vabysmo is administered intravitreally (IVT) to exert local effects in the eye.
Absorption and Distribution: Based on a population pharmacokinetic analysis (including nAMD and DMO 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 DMO 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 6000-fold lower than in aqueous and vitreous humour respectively and below the binding affinity for VEGF and Ang-2. Therefore, systemic pharmacodynamics 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.
Biotransformation and Elimination: Faricimab is a protein-based therapeutic hence its metabolism and elimination have not been fully characterised. Faricimab is expected to be catabolized 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 7.5 days.
Special populations: Elderly: In the four Phase III clinical studies, approximately 60% (1,149/1,929) of patients randomised to treatment with Vabysmo were ≥65 years of age. Population pharmacokinetic analysis has shown an effect of age on ocular pharmacokinetics of faricimab, which was not considered clinically meaningful. No dose adjustment is required in patients 65 years and above.
Renal impairment: No specific studies in patients with renal impairment have been conducted with Vabysmo. Pharmacokinetic analysis of patients in all Phase III clinical studies of which 64% had renal impairment (mild 38%, moderate 24%, and severe 2%), revealed no differences with respect to systemic pharmacokinetics of faricimab after intravitreal administration of Vabysmo. No dose adjustment is required in patients with renal impairment.
Hepatic impairment: No specific studies in patients with hepatic impairment have been conducted with Vabysmo. 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.
Other special populations: 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.
Toxicology: Preclinical safety data: No studies have been conducted on the carcinogenic or mutagenic potential of Vabysmo.
In pregnant cynomolgus monkeys, IV injections of Vabysmo 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 Vabysmo should be regarded as potentially teratogenic and embryo-/foetotoxic.
Systemic exposure after ocular administration of Vabysmo is very low.
