Carlos Perez-Ruixo1, Lingjue Li2, Hong Sun3, Wendy Galpern3, and Juan Jose Perez-Ruixo1
1. J&J Innovative Medicine, Clinical Pharmacology and Pharmacometrics, Beerse, Belgium; 2. J&J Innovative Medicine, Clinical Pharmacology and Pharmacometrics, Titusville, USA; 3. J&J Innovative Medicine, Neuroscience, Titusville, USA
Introduction/Objectives: Posdinemab (JNJ-63733657) is a humanized IgG1 monoclonal anti-tau antibody in clinical development for the treatment of Alzheimer’s Disease (AD)1,2. JNJ-63733657 binds to human phosphorylated tau (pTau), which is hypothesized to prevent the spreading of tauopathy in the brain by interacting with and neutralizing pTau in the interstitial fluid (ISF)3. The objective of this analysis is to describe the time-course of JNJ-63733657 concentrations in serum and cerebrospinal fluid (CSF) after intravenous (IV) administration using clinical data, and characterize the relationship between JNJ-63733657 and pTau levels in CSF in healthy participants and participants with AD.
Methods: A total of 69 subjects were included in the study, 53 (76.8%) subjects received intravenous (IV) JNJ-63733657 at dosages ranging from 1 to 60 mg/kg given as a single dose or multiple doses every 28 days (Q4W) for 13 weeks whereas the remaining 16 participants (23.2%) were assigned to placebo. A mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model was developed using NONMEM® VII software. After the IV infusion, free JNJ-63733657 was distributed into the central compartment (V1), and was eliminated from the central compartment according to a first-order process, characterized by the systemic clearance, CL. The non-specific distribution from the central compartment into the peripheral compartment was characterized by intercompartmental clearance (Q) and the peripheral volume of distribution (V2), while the specific distribution to CSF from the central compartment was characterized by intercompartmental clearance (QCSF). The free JNJ-63733657 in CSF was distributed into the brain interstitial fluid (ISF), this distribution was assumed to be a linear process and described by the intercompartmental clearance (QISF). Free pTau in CSF was assumed to be produced following a zero-order process, characterized by ksyn, and degraded by a first-order process with an elimination-rate constant, represented by kc. The free JNJ-63733657 in CSF was eliminated by a linear pathway, quantified by the first order constant kc. The JNJ-63733657-pTau complex was formed and dissociated according to a quasi-steady state constant (kss) or was eliminated following a first order process, characterized by the rate constant kint. The effect of selected participant covariates on model parameters was investigated.
The described PK-PD model used to characterize the observed data was extended to account for JNJ-63733657 uptake and the seeding process of extracellular pTau in the ISF. The impact of JNJ-63733657 dosing and consequently the percentage of bound pTau in CSF and ISF as a function of baseline pTau in ISF and the JNJ-63733657 to pTau affinity was evaluated under several physio-pathological assumptions of AD.
Results: JNJ-63733657 serum PK had a systemic linear clearance (CL) and the central volume (V1) and peripheral (V2) volumes of distribution were 0.22 L/day, 3.12 L and 2.87 L with interindividual variability (CV%) of 23.3%, 17.7% and 22.2% respectively. The free JNJ-63733657 in CSF was distributed with a Vss of 350.9 mL while QCSF and QISF were estimated to be 8.20 × 10-7 (27.3%) and 3.77 × 10-5 L/day, yielding a total 0.35% of CSF JNJ-63733657 concentration relative to serum. The kss was estimated to be 1970 pM, whereas kint was 0.252 h-1 (42.1%). Baseline free CSF pTau was estimated to be 0.813 pM (67.6%) in healthy participants, while it was 7.35-fold higher in participants with AD. The kc was 0.034 h-1 (23.7%). Body weight was found to correlate with CL, V1, V2, and intercompartment clearance (Q). Model-based simulations informed of the dose level and dosing interval which could provide adequate pTau reduction in ISF (>90%) at steady-state.
Conclusions: The mechanistic PK-PD model successfully described the available clinical data and demonstrated JNJ-63733657 PK in serum is dose-proportional and time-independent. The model provides a simulation-framework which allows investigation of different PK-PD profiles under various dosing regimens.
References:
[1] Janssen Research & Development, LLC. A study to investigate safety and tolerability, pharmacokinetics and pharmacodynamics of JNJ-63733657 in healthy subjects and subjects with Alzheimer’s disease; ClinicalTrials.gov Identifier: NCT03375697; December 18, 2017.
[2] Janssen Research & Development, LLC. A study to investigate safety and tolerability, pharmacokinetics and pharmacodynamics of JNJ-63733657 in healthy subjects and subjects with Alzheimer’s disease; ClinicalTrials.gov Identifier: NCT03375697; December 18, 2017.
[3] Galpern Wendy R, Mercken Marc, Van Kolen Kristof, et al. A single and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-phospho-tau antibody JNJ-63733657 in healthy subjects. July 2019, Alzheimer’s & dementia: the journal of the Alzheimer’s Association 15(7): p252-p253, 2019 doi: 10.1016/j.jalz.2019.06.077.
Reference: PAGE 32 (2024) Abstr 10768 [www.page-meeting.org/?abstract=10768]
Poster: Drug/Disease Modelling - CNS