Ocular Pharmacodynamics of Intravitreal Faricimab in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema
Cheikh Diack (1), Leonid Gibiansky (2), Felix Jaminion (1), Ekaterina Gibiansky(2), Valerie Cosson (1), and Katrijn Bogman(1)
(1)Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Switzerland. (2) QuantPharm LLC, Maryland, USA
Objectives: Faricimab is a bispecific antibody designed to inhibit angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A), promote vascular stability, and improve outcomes in neovascular age‑related macular degeneration (nAMD) and diabetic macular edema (DME) [1-2]. The purpose of this analysis was to evaluate the ocular pharmacodynamics (PD) of intravitreal faricimab and evaluate the relationship between dosing frequency and the suppression-time profiles of Ang-2 and VEGF-A.
Methods: Optional aqueous humour (AH) samples were collected from faricimab-treated patients from three phase 2 and four phase 3 clinical trials in nAMD and DME [3-4] and concentrations of free (unbound) VEGF-A and Ang-2 in aqueous humour were measured. Pharmacokinetic measurements of faricimab in plasma and AH were also obtained. A population PK model of faricimab in plasma, vitreous humour (VH), and AH was then established. Subsequently, separate indirect response models were developed to characterise the extent and duration of suppression of Ang-2 and VEGF-A concentrations in the AH. The correlation between AH Ang-2 and VEGF-A suppression time profiles and the faricimab durability observed (treatment intervals: Q4W, Q8W, Q12W and Q16W) in faricimab phase 3 trials were also investigated. The M3 method for handling observations that are below the limit of quantification (BLQ) was applied for post-dose BLQ observations.
Results: The PK dataset included 1095 faricimab AH concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential VH, AH, and plasma compartments. Flip-flop kinetics was observed, with faricimab VH elimination (to AH) half-life of approximately 7.5 days being the slowest process.
A total of 1345 VEGF-A AH observations from 302 patients and 1025 Ang-2 AH observations from 225 patients were available for the PKPD analyses. Among VEGF-A observations, only 82 (6.1%) were below the quantification limit. Among Ang-2 observations, 639 (62.3%) were below the quantification limit. VEGF-A and Ang-2 concentrations in AH following IVT-administered faricimab were described by indirect response models, as described by equations (Eq. 1-2):
dBAH/dt = BASEAH∙kout∙(1-EFF) - kout∙BAH. BAH(0)=BASEAH, (Eq. 1)
EFF = EMAX∙CVHγ/(EC50γ + CVHγ), (Eq. 2)
Here BAH is the AH concentrations of a biomarker B (i.e. VEGF-A or Ang-2); BASEAH is the baseline concentration of the biomarker in AH. The effect of faricimab on biomarker production rate was described by a sigmoid model (Eq. 2). where EMAX is the maximum inhibitory effect, CVH is the faricimab concentration in VH, EC50 is the VH faricimab concentration that provides half of the maximum inhibitory effect, and γ is the sigmoidicity (Hill) coefficient.
The popPKPD model predicted the observed data well. Ang-2 and VEGF-A concentration-time profiles for Q4W/Q8W patients were predicted to maintain >50% suppression of Ang-2 concentrations for the entire dosing period. Q12W/Q16W patients were predicted to have >50% Ang-2 suppression for ≥12 weeks, whereas 50% VEGF-A suppression was predicted to be maintained for 9–10 weeks. Suppression of free Ang-2 was greater with Q12W/Q16W treatment intervals than Q4W/Q8W treatment intervals in patients with nAMD or DME, suggesting a role for Ang-2 in faricimab durability.
Conclusions: PopPKPD analyses demonstrated that intravitreal faricimab leads to rapid and sustained suppression of AH Ang-2 and VEGF-A, with Ang-2 suppression through 16 weeks post dose, supporting the extended durability reported in phase 3 trials.
References:
[1] Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 2022;399:729–740.
[2] Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet 2022;399:741–755.
[3] Khanani AM, Guymer RH, Basu K, et al. TENAYA and LUCERNE: rationale and design for the phase 3 clinical trials of faricimab for neovascular age-related macular degeneration. Ophthalmol Sci 2021;1:100076.
[4] Eter N, Singh RP, Abreu F, et al. YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale. Ophthalmol Sci 2022;2:100111.