Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study

Christian Wolf, Jagdev Sidhu, Christian Otoul, Dexter L Morris, Jennifer Cnops, Jorg Taubel, Barbara Bennett, Christian Wolf, Jagdev Sidhu, Christian Otoul, Dexter L Morris, Jennifer Cnops, Jorg Taubel, Barbara Bennett

Abstract

Background: Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).

Objective: Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS.

Methods: Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.

Results: Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.

Conclusions: CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.

Trial registration: ClinicalTrials.gov NCT00726648.

Conflict of interest statement

Competing Interests: This study was funded by UCB Pharma and Biogen Idec, which were jointly developing CDP323 as a potential treatment for multiple sclerosis. Dr. Morris has been an employee of and holds stock in GlaxoSmithKline and is currently employed by and has received stock options from UCB Biosciences Inc. Among my coauthors, Dr. Wolf was a salaried employee of UCB Pharma S.A. during the time the study was conducted and has been a consultant for Novartis and Synthon. Dr. Sidhu was a salaried employee of and received stock in UCB Pharma during the time the study was conducted. Dr. Otoul is an employee of UCB Pharma. Dr. Taubel is employed by Richmond Pharmacology, which received financial remuneration for their clinical involvement in this study. Dr. Bennett was a salaried employee of UCB Biosciences Inc. during the time the study was conducted and is now an independent consultant. Dr. Cnops reports no conflicts of interest. This does not alter the authors’ adherence to all of the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Subject disposition.
Figure 1. Subject disposition.
Figure 2. Geometric mean time profile for…
Figure 2. Geometric mean time profile for total lymphocyte count by administered treatment (per protocol population).
bid = twice daily; qd = once daily.
Figure 3. Mean change (95% CI) in…
Figure 3. Mean change (95% CI) in (A) lymphocyte VCAM-1 binding and (B) VCAM-1–binding cell α4 integrin expression following CDP323 administration.
bid = twice daily; CI = confidence interval; qd = once daily; VCAM-1 = vascular adhesion molecule-1.

References

    1. Stadelmann C, Wegner C, Brück W (2011) Inflammation, demyelination, and degeneration–recent insights from MS pathology. Biochim Biophys Acta 1812: 275–282.
    1. Ferguson TA, Mizutani H, Kupper TS (1991) Two integrin-binding peptides abrogate T cell-mediated immune responses in vivo. Proc Natl Acad Sci U S A 88: 8072–8076.
    1. Chan PY, Aruffo A (1993) VLA-4 integrin mediates lymphocyte migration on the inducible endothelial cell ligand VCAM-1 and the extracellular matrix ligand fibronectin. J Biol Chem 268: 24655–24664.
    1. D'hooghe MB, Nagels G, Bissay V, De Keyser J (2010) Modifiable factors influencing relapses and disability in multiple sclerosis. Mult Scler 16: 773–785.
    1. Müller WA (2011) Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol 6: 323–344.
    1. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, et al. (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356: 63–66.
    1. Soilu-Hanninen M, Roytta M, Salmi A, Salonen R (1997) Therapy with antibody against leukocyte integrin VLA-4 (CD49d) is effective and safe in virus-facilitated experimental allergic encephalomyelitis. J Neuroimmunol 72: 95–105.
    1. Lee SJ, Benveniste EN (1999) Adhesion molecule expression and regulation on cells of the central nervous system. J Neuroimmunol 98: 77–88.
    1. Davenport RJ, Munday JR (2007) Alpha4-integrin antagonism–an effective approach for the treatment of inflammatory diseases? Drug Discov Today 12: 569–576.
    1. Polman CH, O'Connor PW, Havrdová E, Hutchinson M, Kappos L, et al. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899–910.
    1. Kent SJ, Karlik SJ, Cannon C, Hines DK, Yednock TA, et al. (1995) A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis. J Neuroimmunol 58: 1–10.
    1. Rudick RA, Sandrock A (2004) Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother 4: 571–580.
    1. Radue EW, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, et al. (2010) Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. J Neurol Sci 292: 28–35.
    1. Muro F, Iimura S, Yoneda Y, Chiba J, Watanabe T, et al. (2008) Identification of 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist. Bioorg Med Chem 16: 9991–10000.
    1. Kenyon NJ, Liu R, O'Roark EM, Huang W, Peng L, et al. (2009) An alpha4beta1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice. Eur J Pharmacol 603: 138–146.
    1. Vanderslice P, Woodside DG, Caivano AR, Decker ER, Munsch CL, et al. (2010) Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin alpha4beta1. Biochem Biophys Res Commun 400: 619–624.
    1. Baker M, Shock A, Parton T, Hales P, Parker G (2006) Pharmacokinetic and pharmacodynamic properties of the VLA-4 inhibitor CDP323. Mult Scler 12: S106.
    1. Miller D, Khan O, Sheremata W, Blumhardt L, Rice G, et al. (2001) Results of a double-blind, randomized, placebo-controlled, phase II trial of Antegren (natalizumab) in subjects with relapsing multiple sclerosis (MS). Mult Scler 7: S16.
    1. Polman C, Bowen J, Barkhof F, Bates D, Wynn D, et al.. (2010) Double-blind, placebo-controlled, randomized phase II serial MRI, safety and tolerability study of two doses of CDP323 in subjects with relapsing forms of multiple sclerosis over 24 weeks. Presented at the 62nd Annual Meeting of the American Academy of Neurology, Toronto, Canada.
    1. Kong L, Koch G, Liu T, Wang H (2005) Performance of some multiple testing procedures to compare three doses of a test drug and placebo. Pharmaceut. Statist. 4: 25–35.
    1. Kovarik JM, Schmouder R, Barilla D, Riviere GJ, Wang Y, et al. (2004) Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol 44: 532–537.
    1. Niino M, Bodner C, Simard ML, Alatab S, Gano D, et al. (2006) Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 59: 748–754.
    1. Krumbholz M, Meinl I, Kumpfel T, Hohlfeld R, Meinl E (2008) Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71: 1350–1354.
    1. Putzki N, Baranwal MK, Tettenborn B, Limmroth V, Kreuzfelder E (2010) Effects of natalizumab on circulating B cells, T regulatory cells and natural killer cells. Eur Neurol 63: 311–317.
    1. Lichterfeld M, Martin S, Burkly L, Haas R, Kronenwett R (2000) Mobilization of CD34+ haematopoietic stem cells is associated with a functional inactivation of the integrin very late antigen 4. Br J Haematol 110: 71–81.
    1. Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, et al. (2008) The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 111: 3893–3895.
    1. Bonig H, Wundes A, Chang KH, Lucas S, Papayannopoulou T (2008) Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 111: 3439–3441.
    1. Jing D, Oelschlaegel U, Ordemann R, Holig K, Ehninger G, et al. (2010) CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function. Bone Marrow Transplant 45: 1489–1496.
    1. Neumann F, Zohren F, Haas R (2009) The role of natalizumab in hematopoietic stem cell mobilization. Expert Opin Biol Ther 9: 1099–1106.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir