Francesco Brizzi (1)*, Tamara van Donge (1)*, Daniela Willen (1), Vincent Buchheit (1), Denise Sickert (1), Gregor Jordan (2), Federica Storti (3), Zeinab Barekati (3), Valerie Cosson (1) * Equal contribution
(1) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland (2) Roche Pharma Research & Early Development (pRED), Pharmaceutical Sciences, Bioanalysis & Biomarkers, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, 82377, Germany (3) Roche Pharma Research and Early Development, Ophthalmology Translational Medicine, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Objectives: Vamikibart is an anti-interleukin 6 (IL-6) monoclonal antibody specifically designed for intravitreal injection (IVT) and is under development for the treatment of ocular diseases such as diabetic macular edema (DME) and uveitic macular edema (UME). Dysregulated IL-6 secretion can lead to blood-retinal barrier disruption, vascular leakage and formation of macular edema. The objectives of this analysis were to characterize the pharmacokinetics (PK) of vamikibart in aqueous humor (AH) in patients with DME and UME, determining the effect of disease and demographic characteristics (such as age, weight and gender) on the PK.
Methods: Data from DOVETAIL, a dose-escalation Phase I, multicenter, nonrandomized, open-label, multi-part study investigating the safety, efficacy and PK/pharmacodynamic (PD) of IVT administered vamikibart in the study eye in patients with DME and UME was used for the current analysis. This study includes DME patients receiving two IVT injections (0.01 mg to 5.0 mg) six weeks apart (Q6W) and UME patients receiving three IVT injections (0.25 mg to 2.5 mg) four weeks apart (Q4W). . Aqueous humor (AH) samples were collected from those study eyes to investigate the PK concentrations of vamikibart. Vamikibart AH concentrations were measured using validated high-sensitive immunoassays. The lower limit of quantification (LLOQ) was set at 0.02 ug/mL. A population PK analysis was conducted using nonlinear mixed effects modeling implemented in NONMEM Version 7.4. A covariate analysis was carried out by sequentially adding covariates to the vitreous clearance parameter. Covariates were considered to be associated with the PK if statistically significant at an alpha (5%) level. The AH Cmax accumulatio ratios between the first and second doses were computed for the dose of 1 mg following Q4W and Q6W using simulations.
Results: In total, 85 patients were enrolled in the Phase I study (48 DME and 37 UME). 47% were female, median age was 64 years. A total of 310 AH PK samples (29% below limit of quantification (BLOQ) of 0.02 ug/mL) were included in the popPK analysis (177 DME (28.8% BLOQ), 133 UME (29.3% BLOQ)). The final PK model comprises linear two compartments: the first one representing vitreous humor (VH), where the drug is injected, and the second one is AH, where the drug concentration is measured. Vamikibart is cleared from VH to AH through a first-order rate constant, and from AH to the blood also through a first-order rate. The compartments were parameterized in terms of clearance(s) and volume(s) of distribution. FOCEI was employed to estimate the model parameters together with the M3 method to account for BLOQ data. Vitreous humor (volume of distribution) was fixed to 4.5 mL. VH clearance of vamikibart was estimated to be 4.32 10-4 L/day (5.2 %RSE, 42% inter-individual variability), which reflects an ocular half-life of 7.2 days [95% CI 6.6 – 8 days]. Disease type (DME or UME) was not identified as a statistically significant covariate affecting VH clearance. Other baseline characteristics such as age, weight and gender were also not identified as statistically significant covariates affecting the PK. The AH Cmax accumulation between the first and second doses were very low with 1.08 for Q4W and 1.04 for Q6W.
Conclusions: The ocular half-life of vamikibart was estimated at 7.2 days, which is similar to other monoclonal antibodies for ocular treatment with similar molecular size [1]. Vamikibart clearance is independent of disease state and no accumulation was predicted between the first and second dose at least 4 weeks apart. Learnings on the PK of vamikibart have been leveraged to select three dosing regimens that are currently further evaluated as part of two Phase 2 studies.
References:
[1] Hutton-Smith LA, et al. Ocular Pharmacokinetics of Therapeutic Antibodies Given by Intravitreal Injection: Estimation of Retinal Permeabilities Using a 3-Compartment Semi-Mechanistic Model. Mol Pharm. 2017 Aug 7;14(8):2690-2696.
Reference: PAGE 32 (2024) Abstr 10986 [www.page-meeting.org/?abstract=10986]
Poster: Drug/Disease Modelling - Other Topics