Pharmacokinetic/pharmacodynamic models for the depletion of Vβ5.2/5.3 T cells by the monoclonal antibody ATM‐027 in patients with multiple sclerosis, as measured by FACS

2区 · 医学

Article

作者: Mats O. Karlsson ; Charlotte Edenius ; Per-Henrik Zingmark

Aims(i) To model the effects of the monoclonal antibody ATM‐027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results.MethodsBased on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM‐027 and its effects on Vβ5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data.ResultsThe pharmacokinetics of ATM‐027 were characterized by a two‐compartment model with a total volume of distribution of 5.9 litres and a terminal half‐life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax‐model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 µg litre−1, respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM‐027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 µg litre−1 and 307 µg litre−1, respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study.ConclusionAll aspects of effects of the monoclonal antibody ATM‐027 on Vβ5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.

2002-04-01·Annals of Neurology1区 · 医学

Antibody‐mediated suppression of Vβ5.2/5.3⁺ T cells in multiple sclerosis: Results from an MRI‐monitored phase II clinical trial

1区 · 医学

Article

作者: Barkhof, Frederik ; Killestein, Joep ; Arfors, Leopold ; Blumhardt, Lance D. ; Fagius, Jan ; Wallstrom, Erik ; Landtblom, Anne-Marie ; Hillert, Jan ; Olsson, Tomas ; Khademi, Mohsen ; Svenningsson, Anders ; Edenius, Charlotte ; Polman, Chris H.

AbstractThe objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM‐027 in a baseline versus treatment magnetic resonance imaging‐monitored study. Expansion of Vβ5.2/5.3+ T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM‐027 depleted these cells in peripheral blood and, in parallel, T‐cell MBP reactivity and IFN‐γ expression were reduced. We studied 59 patients with relapsing‐remitting MS (47 on ATM‐027 and 12 on placebo) stratified for HLA‐DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T‐cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow‐up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM‐027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run‐in, active lesions were found in 78.7% (37/47) of patients treated with ATM‐027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm3 at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon‐γ messenger RNA, and decreased T‐cell reactivity to several myelin antigens were found in ATM‐027 treated patients. In conclusion, consistent suppression of Vβ 5.2/5.3+ T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.

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适应症	最高研发状态	国家/地区	公司	日期
多发性硬化症	临床3期	瑞典	-	-
多发性硬化症	临床3期	美国	AVANT Immunotherapeutics, Inc.	-
肿瘤	临床3期	美国	AVANT Immunotherapeutics, Inc.	-
肿瘤	临床3期	瑞典	-	-