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Pharmacology: Pharmacodynamics: Mechanism of action: Faricimab is a humanized bispecific immunoglobulin G1 (IgG1) antibody that acts through inhibition of two distinct pathways by neutralization of both Ang-2 and vascular endothelial growth factor A (VEGF-A).
Ang-2 causes vascular instability by promoting endothelial destabilization, pericyte loss, and pathological angiogenesis, thus potentiating vascular leakage and inflammation. It also sensitizes blood vessels to the activity of VEGF-A resulting in further vascular destabilization. Ang-2 and VEGF-A synergistically increase vascular permeability and stimulate neovascularization.
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 decrease from baseline of ocular free Ang-2 and free VEGF-A concentrations was observed from day 7 onwards throughout the treatment interval (in most patients) in the four Phase III clinical studies.
In Phase III studies in patients with nAMD (TENAYA, 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 week 48 with VABYSMO, and were comparable to those observed with aflibercept. The mean CST reduction from baseline to 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.
There was a comparable effect of VABYSMO and aflibercept on the reduction of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). At the primary endpoint visits (min-max, weeks 40-48), the proportion of patients in TENAYA and LUCERNE, respectively, with absence of IRF was: 76%-82% and 78%-85% in VABYSMO vs. 74%-85% and 78%-84% in aflibercept; absence of SRF: 70%-79% and 66%-78% in VABYSMO vs. 66%-78% and 62%-76% in aflibercept; absence of PED: 3%-8% and 3%-6% in VABYSMO vs. 8%-10% and 7%-9% in aflibercept.
At week 48, there was comparable change in total CNV lesion area from baseline across treatment arms (0.0 mm2 and 0.4 mm2 in VABYSMO vs. 0.4 mm2 and 1.0 mm2 in aflibercept, in TENAYA and LUCERNE, respectively). There was a comparable reduction in CNV leakage area from baseline across treatment arms (-3.8 mm2 and -3.2 mm2 in VABYSMO and -3.0 mm2 and -2.2 mm2 in aflibercept, in TENAYA and LUCERNE, respectively).
In Phase III studies in patients with DME (YOSEMITE and RHINE), anatomic parameters related to macular edema were part of the disease activity assessments guiding treatment decisions.
The reductions in mean CST from baseline were numerically greater in patients treated with VABYSMO every 8 weeks (Q8W) and VABYSMO up to Q16W adjustable dosing as compared to aflibercept Q8W from week 4 to week 100 in both YOSEMITE and RHINE. Greater proportions of patients in both VABYSMO arms achieved absence of IRF and absence of DME (defined as reaching CST below 325 µm) as measured on Spectral Domain Optical Coherence Tomography (SD-OCT) over time in both studies, compared to the aflibercept arm. Comparable reductions in SRF were observed across both VABYSMO and aflibercept treatment arms over time in both studies.
The mean reduction of CST from baseline to the primary endpoint visits (averaged at weeks 48-56) was 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. These mean CST reductions were maintained through year 2. The proportion of patients with absence of DME at primary endpoint visits (min-max, weeks 48-56) were 77%-87% and 80%-82% in patients treated with VABYSMO Q8W and VABYSMO up to Q16W adjustable dosing, as compared to 64%-71% in aflibercept Q8W patients in YOSEMITE; results were 85%-90%, 83%-87%, and 71%-77%, respectively in RHINE. These results were maintained through year 2.
At week 16, the proportion of patients with absence of IRF was numerically greater in patients receiving VABYSMO Q8W or VABYSMO up to Q16W adjustable dosing versus aflibercept Q8W dosing in both studies (YOSEMITE: 16% and 22% vs. 13%; RHINE: 20% and 20% vs. 13%). The proportions of patients with absence of IRF at primary endpoint visits (min-max, weeks 48-56) were 42%-48% and 34%-43% in patients treated with VABYSMO Q8W and VABYSMO up to Q16W adjustable dosing, as compared to 22%-25% in aflibercept Q8W patients in YOSEMITE; results were 39%-43%, 33%-41%, and 23%-29%, respectively in RHINE.
Clinical efficacy and safety: Treatment of nAMD: The safety and efficacy of VABYSMO (faricimab) were assessed in two randomized, multi-center, double-masked, active comparator-controlled studies in patients with nAMD, TENAYA (NCT03823287) and LUCERNE (NCT03823300). A total of 1,329 patients were enrolled in these studies, and 1,326 patients received at least one dose (664 with VABYSMO). Patient ages ranged from 50 to 99 with a mean of 75.9 years.
In both studies, patients were randomized 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 randomized 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 visual and anatomic criteria as well as treating physician clinical assessment. Patients remained on these fixed dosing intervals until week 60 without supplemental therapy.
The primary efficacy endpoint was the change from baseline in BCVA based on an average at weeks 40, 44, and 48, measured by the Early Treatment Diabetic Retinopathy Study (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.
The proportion of patients on each of the different treatment intervals at week 48 in TENAYA and LUCERNE, respectively was: Q16W: 46%, 45%; Q12W: 34%, 33%; Q8W: 20%, 22%. (See Table 1 and Figures 1 & 2.)
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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.
Treatment of DME: The safety and efficacy of VABYSMO were assessed in two randomized, multi-centre, double-masked, active comparator-controlled 2-year studies (YOSEMITE and RHINE) in patients with DME. A total of 1,891 patients were enrolled in the two studies with 1,622 (86%) patients completing the studies through week 100. A total of 1,887 patients 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 naive patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%). In both studies, patients were randomized 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 Q16W adjustable dosing arm, the dosing interval could be increased in 4-week increments or could be decreased in 4- or 8-week increments based on automated objective assessment of pre-specified visual and anatomic disease activity criteria.
Both studies demonstrated efficacy in the primary endpoint, defined as the 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.
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 & 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 naive 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.
Across 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 National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite score that was 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 pre-specified 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.
An additional key efficacy outcome in DME 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 non-proliferative 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. The proportion of patients with a ≥ 2-step improvement on the ETDRS-DRSS at baseline, week 16, week 52 and at week 96 are shown in Figures 5 and 6 as follows. (See Table 3 and Figure 5 & 6.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe proportions of patients with new proliferative DR diagnosis (defined by ETDRS-DRSS 61 or worse) from baseline to week 96 were comparable between the VABYSMO Q8W, VABYSMO up to Q16W adjustable dosing and aflibercept Q8W dosed patients in both YOSEMITE and RHINE studies.
Almost no patients required vitrectomy (0 to 4 per group) or Panretinal Photocoagulation (PRP) (1 to 2 per group) during the two year duration of the studies.
DR treatment effects in the subgroup of patients who were anti-VEGF naive 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.
Treatment effects in subgroups by DR severity at baseline were different and showed the greatest ≥ 2-step DRSS improvements among patients with moderately severe and severe non-proliferative DR with approximately 90% of patients achieving improvements. These results were comparable across the study arms, and comparable in overall and anti-VEGF treatment-naive populations.
Immunogenicity: Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to VABYSMO with the incidence of antibodies to other products may be misleading.
In the nAMD and DME studies, the pre-treatment incidence of anti-faricimab antibodies was approximately 1.8% and 0.8%, respectively. After initiation of dosing, anti-faricimab antibodies were detected in approximately 10.4% and 8.4% of patients with nAMD and DME respectively, treated with VABYSMO across studies and across treatment groups. As with all therapeutic proteins, there is the potential for immune response to VABYSMO.
Pharmacokinetics: Absorption: VABYSMO is administered intravitreally (IVT) to exert local effects in the eye. There have been no clinical studies performed with other routes of administration.
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) plasma Cmax are estimated 0.23 (0.07) µg/mL and 0.22 (0.07) µg/mL respectively in nAMD and in DME/DR 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.
Distribution: Maximum plasma free faricimab concentrations are predicted to be approximately 600 and 6000-fold lower than in aqueous and vitreous humor respectively and are below the binding affinity for VEGF and Ang-2. 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.
Metabolism: The metabolism of faricimab has not been directly studied, as monoclonal antibodies are cleared principally by catabolism.
Elimination: The estimated mean apparent systemic half-life of faricimab is 7.5 days after IVT administration.
Pharmacokinetics in special populations: Pediatric Population: The safety and efficacy of VABYSMO in pediatric patients have not been established.
Geriatric Population: In the four Phase III clinical studies, approximately 60% (1,149/1,929) of patients randomized to treatment with VABYSMO 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.
Renal impairment: No formal pharmacokinetic study has been conducted in patients with renal impairment.
Hepatic impairment: No formal pharmacokinetic study has been conducted in patients with hepatic impairment.
Other: The systemic pharmacokinetics of VABYSMO are not influenced by race. Gender was not shown to have a clinically meaningful influence on systemic pharmacokinetics of VABYSMO.
Toxicology: Preclinical safety data: Impairment of fertility: While the anti-VEGF and anti-Ang2 components could mean a potential theoretical mechanism-based risk to reproduction, the systemic exposure stemming from intravitreal treatment suggests that this risk may be negligible. No effects on fertility were observed in a 6-month cynomolgus monkey study with VABYSMO.
Genotoxicity: No studies have been performed to establish the mutagenic potential of VABYSMO.
Reproductive toxicity: VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF inhibition has also been shown to affect follicular development, corpus luteum function, and fertility. No dedicated studies addressing the effects of Ang-2 inhibition on pregnancy are available. Based on non-clinical information Ang-2 inhibition may lead to effects comparable to VEGF inhibition. Systemic exposure after ocular administration of VABYSMO is very low.
No effects on reproductive organs were observed in a 6-month cynomolgus monkey study with VABYSMO. No effects on pregnancy or fetuses were observed in an embryo-fetal development study in pregnant cynomolgus monkeys given 5 weekly IV injections of VABYSMO starting on day 20 of gestation at 1 mg/kg or 3 mg/kg. Serum exposure (Cmax) in monkeys at the no observed adverse effect level (NOAEL) dose of 3 mg/kg was more than 500 times that in humans at a dose of 6 mg given by intravitreal injection once every 4 weeks.
Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of VABYSMO.
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