Comment
Trial and error in clinical studies: lessons from ATAMS Published Online March 6, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70050-X
Steve Gschmeissner/Science Photo Library
See Articles page 353
340
Multiple sclerosis is one of the most prevalent neurological diseases in young adults and causes progressive and permanent disability in about a third of patients. Thus a treatment that halts or, even better, reverses disease progression is desperately needed, but unfortunately is not on the horizon. Nevertheless, substantial progress has been made in research into the treatment of multiple sclerosis during the past 20 years. The consensus is that at least the majority of multiple sclerosis cases have an autoimmune pathogenesis, so existing treatment protocols focus mainly on immune modulation. As well as T lymphocytes, B lymphocytes have attracted increased attention. In 2008, a study of rituximab,1 a humanised anti-CD20 monoclonal antibody that depletes B cells in peripheral lymphoid organs, generated a great deal of interest, and the strategy of targeting B cells continued with a study2 of the fully humanised anti-CD20 monoclonal antibody ocrelizumab.2 Not only were these drugs fairly safe, but they also proved to be highly efficacious, and the benefits were surprisingly long-lasting, suppressing disease activity for up to 12 months.1,2 It therefore seemed reasonable to assume that modulation of B-cell differentiation might also provide therapeutic benefit in multiple sclerosis. In The Lancet Neurology, Ludwig Kappos and colleagues report the results of the ATAMS study,3 a phase 2 trial to assess safety and efficacy of the fusion protein atacicept in the treatment of multiple sclerosis. Atacicept has
previously been tested in patients with rheumatoid arthritis4 and systemic lupus erythematosus,5 two autoimmune diseases in which B cells are crucial for pathogenesis. It consists of the extracellular ligandbinding portion of the human TACI receptor (also known as TNFRSF13B) linked to a recombinant Fc domain of human immunoglobulin G. It therefore binds to BLyS (also known as TNFSF20) and APRIL (also known as TNFSF13), two factors that are essential in B-cell differentiation, maturation, and survival.6 These differentiation factors have been implicated in the effects of immunomodulatory multiple sclerosis treatments—eg, the increased transcription of BLyS in response to interferon beta.7 In the ATAMS study,3 patients received weekly subcutaneous injections of 25 mg (n=63), 75 mg (n=64), or 150 mg (n=65) of atacicept, or placebo (n=65). Notably, the relapse rate at least doubled in all atacicept groups compared with placebo, leading to the early termination of the trial. Fortunately, the increased relapse rate had no effect on disease progression or lesion load. What happened in the ATAMS study, and what could account for the differences between atacicept and the anti-CD20 drugs that showed benefits in previous trials? B cells have long been thought to have an important role in multiple sclerosis pathogenesis, as suggested by oligoclonal bands in the CSF of most patients. Furthermore, antibody deposition has been reported in acute demyelinating lesions, and tertiary lymphoid organs containing B cells that are able to undergo germinal-centre reactions, and therefore contribute to local immunoglobulin production, have been detected in the meninges of patients with chronic multiple sclerosis.8 CD20 is a surface molecule expressed during many stages of B-cell differentiation. Targeting of CD20 by a monoclonal antibody results in almost complete (more than 95% compared with baseline) B-cell depletion in the periphery.2 Immunoglobulin concentrations, however, are not greatly affected because CD20 is not expressed on the surface of long-lived plasma cells in the bone marrow, which are the main source of immunoglobulins. By contrast, targeting of BLyS and APRIL disrupts B-cell development and survival, but does not immediately kill the cells. Thus in ATAMS3 www.thelancet.com/neurology Vol 13 April 2014
Comment
the B-cell counts were reduced by a maximum of only 60–70%. Concentrations of all subtypes of immunoglobulin were also substantially reduced (by between 20–40% [immunoglobulin G] and 50–70% [immunoglobulin M]),3 because of the disruption of B-cell differentiation by atacicept. This substantial fall in serum immunoglobulin concentrations might preclude non-specific occupation of Fc receptors on antigen-presenting cells such as macrophages. But Fc-receptor blockade might be beneficial for patients, in line with previous suggestions that intravenous immunoglobulins might have therapeutic benefit. A probably more important issue is the types of B cell that are preferentially depleted. Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation: transgenic mice with T-cell and B-cell receptors for myelin oligodendrocyte glycoprotein antigen have provided strong evidence that spontaneous demyelinating disease occurs when both receptors are brought together,9 suggesting that antigen-specific B cells could provide the essential stimulus for antigenspecific T cells. By contrast, interleukin-10-producing B cells can have a regulatory effect, constraining the activation of antigen-specific T cells and thereby reducing disease severity.10 Since BLyS is believed to be involved in the differentiation of these regulatory B cells,11 the targeting of BLyS might disturb the finetuned balance of conventional and regulatory B cells in favour of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS. Furthermore, rituximab depletes all peripheral B-cell subpopulations including memory B cells, whereas atacicept might spare memory B cells, which could stimulate T-effector functions in patients with multiple sclerosis.12 Finally, pathogenic T-cell responses are diminished and regulatory T cells are expanded in response to rituximab,13 which could be the result of B-cell depletion or of an unidentified mechanism; this effect could very well aid the therapeutic efficacy of antiCD20 monoclonal antibodies, but be absent in the case of atacicept. It is important that well-designed multiple sclerosis trials are reported even when they yield unexpected negative results. For example, much has been learnt from the lenercept study14 concerning the multifaceted role of tumour necrosis factor α in the inflamed nervous www.thelancet.com/neurology Vol 13 April 2014
system. That another cytokine has failed as a target in the pathogenesis of multiple sclerosis pathogenesis is unsurprising—many other candidates have gone the same way. B cells should still be regarded as a valid target, but there are good and bad B cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable. Fred Lühder, *Ralf Gold Department of Neuroimmunology, Institute for Multiple Sclerosis Research, The Hertie Foundation, Göttingen, Germany (FL); Max Planck Institute for Experimental Medicine, University of Göttingen Medical School, Göttingen, Germany (FL); and Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany (RG) [email protected] FL has received grants from Teva and Sanofi-Genzyme. RG has received speaker’s fees and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Talecris, TEVA, and Wyeth. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, and TEVA. 1 2
3
4
5
6 7
8
9 10 11
12
13 14
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676–88. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378: 1779–87. Kappos L, Hartung H-P, Freedman MS, et al, for the ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol 2014; published online March 6. http://dx.doi.org/10.1016/S1474-4422(14)70028-6. Genovese MC, Kinnman N, de La Bourdonnaye G, Pena Rossi C, Tak PP. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum 2011; 63: 1793–803. Dall’Era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 2007; 56: 4142–50. Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2002; 2: 465–75. Krumbholz M, Faber H, Steinmeyer F, et al. Interferon-β increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 2008; 131: 1455–63. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14: 164–74. Berer K, Wekerle H, Krishnamoorthy G. B cells in spontaneous autoimmune diseases of the central nervous system. Mol Immunol 2011; 48: 1332–37. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 2010; 10: 236–47. Yang M, Sun L, Wang S, et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol 2010; 184: 3321–25. Harp CT, Ireland S, Davis LS, et al. Memory B cells from a subset of treatment naïve relapsing remitting multiple sclerosis patients elicit CD4+ T cell proliferation and IFN-γ production in response to MBP and MOG. Eur J Immunol 2010; 40: 2942–56. Pillai S, Mattoo H, Cariappa A. B cells and autoimmunity. Curr Opin Immunol 2011; 23: 721–31. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53: 457–65.
341
Trial and error in clinical studies: lessons from ATAMS Published Online March 6, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70050-X
Steve Gschmeissner/Science Photo Library
See Articles page 353
340
Multiple sclerosis is one of the most prevalent neurological diseases in young adults and causes progressive and permanent disability in about a third of patients. Thus a treatment that halts or, even better, reverses disease progression is desperately needed, but unfortunately is not on the horizon. Nevertheless, substantial progress has been made in research into the treatment of multiple sclerosis during the past 20 years. The consensus is that at least the majority of multiple sclerosis cases have an autoimmune pathogenesis, so existing treatment protocols focus mainly on immune modulation. As well as T lymphocytes, B lymphocytes have attracted increased attention. In 2008, a study of rituximab,1 a humanised anti-CD20 monoclonal antibody that depletes B cells in peripheral lymphoid organs, generated a great deal of interest, and the strategy of targeting B cells continued with a study2 of the fully humanised anti-CD20 monoclonal antibody ocrelizumab.2 Not only were these drugs fairly safe, but they also proved to be highly efficacious, and the benefits were surprisingly long-lasting, suppressing disease activity for up to 12 months.1,2 It therefore seemed reasonable to assume that modulation of B-cell differentiation might also provide therapeutic benefit in multiple sclerosis. In The Lancet Neurology, Ludwig Kappos and colleagues report the results of the ATAMS study,3 a phase 2 trial to assess safety and efficacy of the fusion protein atacicept in the treatment of multiple sclerosis. Atacicept has
previously been tested in patients with rheumatoid arthritis4 and systemic lupus erythematosus,5 two autoimmune diseases in which B cells are crucial for pathogenesis. It consists of the extracellular ligandbinding portion of the human TACI receptor (also known as TNFRSF13B) linked to a recombinant Fc domain of human immunoglobulin G. It therefore binds to BLyS (also known as TNFSF20) and APRIL (also known as TNFSF13), two factors that are essential in B-cell differentiation, maturation, and survival.6 These differentiation factors have been implicated in the effects of immunomodulatory multiple sclerosis treatments—eg, the increased transcription of BLyS in response to interferon beta.7 In the ATAMS study,3 patients received weekly subcutaneous injections of 25 mg (n=63), 75 mg (n=64), or 150 mg (n=65) of atacicept, or placebo (n=65). Notably, the relapse rate at least doubled in all atacicept groups compared with placebo, leading to the early termination of the trial. Fortunately, the increased relapse rate had no effect on disease progression or lesion load. What happened in the ATAMS study, and what could account for the differences between atacicept and the anti-CD20 drugs that showed benefits in previous trials? B cells have long been thought to have an important role in multiple sclerosis pathogenesis, as suggested by oligoclonal bands in the CSF of most patients. Furthermore, antibody deposition has been reported in acute demyelinating lesions, and tertiary lymphoid organs containing B cells that are able to undergo germinal-centre reactions, and therefore contribute to local immunoglobulin production, have been detected in the meninges of patients with chronic multiple sclerosis.8 CD20 is a surface molecule expressed during many stages of B-cell differentiation. Targeting of CD20 by a monoclonal antibody results in almost complete (more than 95% compared with baseline) B-cell depletion in the periphery.2 Immunoglobulin concentrations, however, are not greatly affected because CD20 is not expressed on the surface of long-lived plasma cells in the bone marrow, which are the main source of immunoglobulins. By contrast, targeting of BLyS and APRIL disrupts B-cell development and survival, but does not immediately kill the cells. Thus in ATAMS3 www.thelancet.com/neurology Vol 13 April 2014
Comment
the B-cell counts were reduced by a maximum of only 60–70%. Concentrations of all subtypes of immunoglobulin were also substantially reduced (by between 20–40% [immunoglobulin G] and 50–70% [immunoglobulin M]),3 because of the disruption of B-cell differentiation by atacicept. This substantial fall in serum immunoglobulin concentrations might preclude non-specific occupation of Fc receptors on antigen-presenting cells such as macrophages. But Fc-receptor blockade might be beneficial for patients, in line with previous suggestions that intravenous immunoglobulins might have therapeutic benefit. A probably more important issue is the types of B cell that are preferentially depleted. Experimental evidence in animal models suggests that B cells potentially have a dual role in the pathogenesis of neuroinflammation: transgenic mice with T-cell and B-cell receptors for myelin oligodendrocyte glycoprotein antigen have provided strong evidence that spontaneous demyelinating disease occurs when both receptors are brought together,9 suggesting that antigen-specific B cells could provide the essential stimulus for antigenspecific T cells. By contrast, interleukin-10-producing B cells can have a regulatory effect, constraining the activation of antigen-specific T cells and thereby reducing disease severity.10 Since BLyS is believed to be involved in the differentiation of these regulatory B cells,11 the targeting of BLyS might disturb the finetuned balance of conventional and regulatory B cells in favour of the conventional cells, eventually resulting in increased disease activity, as seen in ATAMS. Furthermore, rituximab depletes all peripheral B-cell subpopulations including memory B cells, whereas atacicept might spare memory B cells, which could stimulate T-effector functions in patients with multiple sclerosis.12 Finally, pathogenic T-cell responses are diminished and regulatory T cells are expanded in response to rituximab,13 which could be the result of B-cell depletion or of an unidentified mechanism; this effect could very well aid the therapeutic efficacy of antiCD20 monoclonal antibodies, but be absent in the case of atacicept. It is important that well-designed multiple sclerosis trials are reported even when they yield unexpected negative results. For example, much has been learnt from the lenercept study14 concerning the multifaceted role of tumour necrosis factor α in the inflamed nervous www.thelancet.com/neurology Vol 13 April 2014
system. That another cytokine has failed as a target in the pathogenesis of multiple sclerosis pathogenesis is unsurprising—many other candidates have gone the same way. B cells should still be regarded as a valid target, but there are good and bad B cells in multiple sclerosis, and the net effect of a particular treatment on this complex scenario can be unpredictable. Fred Lühder, *Ralf Gold Department of Neuroimmunology, Institute for Multiple Sclerosis Research, The Hertie Foundation, Göttingen, Germany (FL); Max Planck Institute for Experimental Medicine, University of Göttingen Medical School, Göttingen, Germany (FL); and Department of Neurology, St Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany (RG) [email protected] FL has received grants from Teva and Sanofi-Genzyme. RG has received speaker’s fees and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Talecris, TEVA, and Wyeth. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, and TEVA. 1 2
3
4
5
6 7
8
9 10 11
12
13 14
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676–88. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378: 1779–87. Kappos L, Hartung H-P, Freedman MS, et al, for the ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol 2014; published online March 6. http://dx.doi.org/10.1016/S1474-4422(14)70028-6. Genovese MC, Kinnman N, de La Bourdonnaye G, Pena Rossi C, Tak PP. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum 2011; 63: 1793–803. Dall’Era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 2007; 56: 4142–50. Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2002; 2: 465–75. Krumbholz M, Faber H, Steinmeyer F, et al. Interferon-β increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain 2008; 131: 1455–63. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14: 164–74. Berer K, Wekerle H, Krishnamoorthy G. B cells in spontaneous autoimmune diseases of the central nervous system. Mol Immunol 2011; 48: 1332–37. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 2010; 10: 236–47. Yang M, Sun L, Wang S, et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol 2010; 184: 3321–25. Harp CT, Ireland S, Davis LS, et al. Memory B cells from a subset of treatment naïve relapsing remitting multiple sclerosis patients elicit CD4+ T cell proliferation and IFN-γ production in response to MBP and MOG. Eur J Immunol 2010; 40: 2942–56. Pillai S, Mattoo H, Cariappa A. B cells and autoimmunity. Curr Opin Immunol 2011; 23: 721–31. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53: 457–65.
341
![[Lessons from Field Studies].](/assets/img/hold.png)
