Alienor Berges (1), Jonathan Bullman (2), Stewart Bates (3), David Krull (4)
(1)Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stockley Park, UK: (2) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Stevenage, UK: (3) Biopharm Biomarker Discovery, GlaxoSmithKline, Stevenage, UK: (4) Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina US.
Objectives: Amyotrophic Lateral Sclerosis (ALS) is a rare and ultimately fatal progressive neurodegenerative disease, associated with loss of upper and lower motor neurons and a high unmet medical need for efficacious treatments. Ozanezumab, under development for ALS, is a humanised IgG monoclonal antibody (mAb) that targets Nogo-A protein, an oligodendrocyte expressed negative regulator of neuronal growth and a potent neurite outgrowth inhibitor in the adult central nervous system[1,2]. While not significantly expressed in healthy skeletal muscle, Nogo‑A, has been shown to be over-expressed in the skeletal muscle of ALS subjects, and consequently proposed both as a biomarker of ALS and a potential therapeutic target[3-5].
We propose the development of a PK/PD model using laser scanning cytometry (LSC) data from muscles biopsies in a small patient study. The model is aimed to inform dose selection, based on target engagement.
Methods: Data was utilised from a placebo controlled, double blind, ascending dose study in ALS patients[6] Blood samples and skeletal muscle biopsies (pre-and post-dose) were taken from patients to evaluate the Ozanezumab PK and a variety of biomarkers. LSC evaluated the percentage of skeletal muscle cell membrane where Nogo-A co-localised with Ozanezumab (percentage of co-location). For each patient biopsy, LSC results were replicated three times on different sections of the muscle biopsy. Plasma Ozanezumab concentrations were estimated with a two-compartment linear PK model. PK and LSC data were used to develop a PK/PD model using a non-linear mixed effect approach in NONMEM V7[7].
Results: PK and LSC data were best described by an effect compartment model and a sigmoid equation. The model included the level 2 (L2) data item for NONMEM to group the replicate measurements such that the residual error was divided into a replicate-specific error and a common residual error. The PK/PD model performed fairly well in diagnostics, despite limited LSC data and sensitivity, and provided predictions of co-location between Ozanezumab and Nogo-A at various dosing regimens (in terms of dosing frequency and dose levels).In addition, based on a graphical evaluation, the PK profile in the effect compartment predicted from the PK/PD model appeared to be consistent with the few drug concentrations measured in the muscle biopsy.
Conclusions: The model will assist in estimating Ozanezumab co-localised with Nogo-A in different Ozanezumab dosing regimens.
References:
[1] Schwab ME. Nogo and axon regeneration. Current Opinion in Neurobiology. 2004; 14(1): 118-24.
[2] Schwab ME. Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci. 2010; 11(12): 799-811.
[3] Dupuis L, Gonzalez de Aguilar J-L, di Scala F, Rene F, de Tapia M, Pradat P-F, et al. Nogo Provides a Molecular Marker for Diagnosis of Amyotrophic Lateral Sclerosis. Neurobiology of Disease. 2002; 10(3): 358-65.
[4] Jokic N, Gonzalez de Aguilar J-L, Pradat P-F, Dupuis L, Echaniz-Laguna A, Muller A, et al. Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Annals of Neurology. 2005; 57(4): 553-6.
[5] Pradat P-F, Bruneteau G, Gonzalez de Aguilar J-L, Dupuis L, Jokic N, Salachas F, et al. Muscle Nogo-a expression is a prognostic marker in lower motor neuron syndromes. Annals of Neurology. 2007; 62(1): 15-20.
[6] ClinicalTrials.gov Identifier: NCT00875446. A single and repeat dose escalation study of the safety, pharmacokinetics and pharmacodynamics of GSK1223249 in ALS patients
[7] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA
Reference: PAGE 22 (2013) Abstr 2721 [www.page-meeting.org/?abstract=2721]
Poster: CNS