REVIEW ARTICLE
`
`Biodrugs 2010; 24 (4): 249-274
`1173-8804/10/0004-0249/$49.95/0
`ª 2010 Adis Data Information BV. All rights reserved.
`
`Therapeutic Approaches to Multiple Sclerosis
`An Update on Failed, Interrupted, or Inconclusive Trials of Immunomodulatory
`Treatment Strategies
`
`Jochen C. Ulzheimer,1,2 Sven G. Meuth,1,3 Stefan Bittner,1 Christoph Kleinschnitz,1 Bernd C. Kieseier4 and Heinz Wiendl3
`
`1 Department of Neurology, University of Wuerzburg, Wuerzburg, Germany
`2 Clinic of Neurology, Caritas Hospital Bad Mergentheim, Bad Mergentheim, Germany
`3 Department of Neurology Inflammatory Disorders of the Nervous System and Neurooncology, University of Muenster,
`Muenster, Germany
`4 Department of Neurology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
`
`Contents
`
`4.
`
`Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
`1.
`Immunopathology of Multiple Sclerosis and Therapeutic Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
`2. Modulation of T-Cell Differentiation and T Helper (Th)-1/Th2 Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
`2.1 Interleukin-12/23: p40 Neutralizing Monoclonal Antibody (Ustekinumab) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
`2.2 Phosphodiesterase Inhibitors (Ibudilast, Rolipram) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
`2.3 HMG-CoA-Dependent T-Cell Signaling: Statins (Atorvastatin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
`3. Modulation of T-Cell Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
`3.1 Cytotoxic T-Lymphocyte Antigen 4 (CTLA4): Chimeric CTLA4-Ig (Abatacept, RG2077) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
`3.2 CD40-CD40L: Blocking Monoclonal Anti-CD154 Antibody (Toralizumab) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
`3.3 Peroxisome Proliferator-Activated Receptor (PPAR)-g Agonists: Thiazolidinediones (Pioglitazone, Rosiglitazone). . . . . . . . . . . . 256
`Inhibition of Leukocyte Chemotaxis, Adhesion, and Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
`4.1 Chemokine Receptors: CCR1 Antagonists (BX-471, CP-481715) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
`4.2 Vascular Endothelial Cell Adhesion Molecules: Monoclonal Anti-LFA-1 (CD11/CD18) Antibody (Efalizumab, Hu23F2G) . . . . . . 259
`4.3 Matrix Metalloproteinases (Minocycline, Doxycycline) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
`Induction of Immunotolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
`5.1 Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
`5.2 Mesenchymal Non-Hematopoietic Stem Cell Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
`5.3 Myelin Peptide Therapy: MBP-8298 (Dirucotide) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
`5.4 DNA Vaccination: Myelin Basic Protein DNA Vaccine (BHT-3009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
`6. Modulation of Antigen Recognition and Disease Triggers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
`6.1 Putative Viral Triggers: Antiviral Agents (Acyclovir, Valacyclovir) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
`6.2 Putative Bacterial Triggers: Antibiotics (Rifampicin, Azithromycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
`6.3 Antigen Degradation: Hydrolytic Enzymes (Bromelain) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
`7. Other Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
`7.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
`8. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
`
`5.
`
`Abstract
`
`Multiple sclerosis (MS) continues to be a therapeutic challenge, and much effort is being made to develop
`new and more effective immune therapies. Particularly in the past decade, neuroimmunologic research has
`delivered new and highly effective therapeutic options, as seen in the growing number of immunotherapeutic
`agents and biologics in development. However, numerous promising clinical trials have failed to show
`
`Biogen Exhibit 2120
`Mylan v. Biogen
`IPR 2018-01403
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`250
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`Ulzheimer et al.
`
`efficacy or have had to be halted prematurely because of unexpected adverse events. Some others have
`shown results that are of unknown significance with regard to a reliable assessment of true efficacy versus
`safety. For example, studies of the highly innovative monoclonal antibodies that selectively target im-
`munologic effector molecules have not only revealed the impressive efficacy of such treatments, they have
`also raised serious concerns about the safety profiles of these antibodies. These results add a new dimension
`to the estimation of risk-benefit ratios regarding acute or long-term adverse effects.
`Therapeutic approaches that have previously failed in MS have indicated that there are discrepancies between
`theoretical expectations and practical outcomes of different compounds. Learning from these defeats helps to
`optimize future study designs and to reduce the risks to patients. This review summarizes trials on MS treatments
`since 2001 that failed or were interrupted, attempts to analyze the underlying reasons for failure, and discusses
`the implications for our current view of MS pathogenesis, clinical practice, and design of future studies. In order
`to maintain clarity, this review focuses on anti-inflammatory therapies and does not include studies on already
`approved and effective disease-modifying therapies, albeit used in distinct administration routes or under dif-
`ferent paradigms. Neuroprotective and alternative treatment strategies are presented elsewhere.
`
`1. Immunopathology of Multiple Sclerosis and
`Therapeutic Targets
`
`The therapeutic options for multiple sclerosis (MS) have
`been widened significantly over the past decade. However, the
`approved therapeutic agents (beta-interferons [IFNb], glatir-
`amer acetate, mitoxantrone, natalizumab) still have limited
`efficacy in preventing disease progression, and some of them
`are associated with either a considerable long-term toxicity or a
`still unclear risk-benefit ratio. There is a tremendous activity in
`the search for new therapeutics,[1,2] which is reflected by the
`soaring number of publications. However, one has to realisti-
`cally concede that few successful agents in MS stand apart from
`a large number of therapeutic disappointments.[3-5] Despite
`rational pathophysiologic concepts, conclusive data from
`animal models, promising phase I/II studies, and successful
`application in other autoimmune diseases, several trials testing
`new compounds in MS patients have shown no benefit. On the
`other hand, some effective treatments are associated with un-
`expected or unexpectedly severe adverse effects. Whereas pos-
`itive studies usually make it into prestigious journals, many
`negative trials are published merely as abstracts or are not
`published at all.[6] This is unfortunate because there is a lot to
`learn from negative results, and a critical reflection is highly
`important for understanding human MS immunopathogenesis
`and to help improve future clinical trial design.
`We here discuss the pathophysiologic rationale, the experi-
`mental basis, and the trial data of novel agents in MS therapy
`
`that were not effective and/or were associated with considerable
`unexpected adverse effects when tested in human phase I–III
`1
`This review focuses on
`studies in MS between 2001 and 2010.
`immunomodulatory strategies; neuroprotective and alternative
`treatment targets will be discussed in a separate article.
`
`2. Modulation of T-Cell Differentiation and T Helper
`(Th)-1/Th2 Balance
`
`One of the pivotal steps in the initial autoimmune inflam-
`matory pathogenesis of MS is the activation of autoreactive
`T cells in the periphery via T-cell receptor (TCR)-mediated
`recognition of major histocompatibility complex (MHC)-I
`presented antigens – possibly misled by antigenic mimicry.
`After transmigration across the blood-brain barrier and re-
`activation in the CNS, both CD4+ T helper (Th) cells and CD8+
`cytotoxic T cells trigger demyelination and primary axonal
`damage via a shift to a proinflammatory Th1 cytokine en-
`vironment.[7] This process seems to be perpetuated by dysre-
`gulation of apoptotic mechanisms in T cells. Therefore,
`modulation of T-cell differentiation and rebalancing of Th1 and
`Th2 response represents a critical mechanism for therapeutic
`intervention. Broad depletion of autoreactive T cells may be
`achieved by means of monoclonal antibodies against specific T-
`cell markers. After the overall negative results with the mono-
`clonal antibodies against CD3 (muromonab CD3) and CD4
`(priliximab) in MS trials,[5] other T-cell targets such as CD52
`
`1 Search strategy and selection criteria: studies were identified by a search of PubMed for publications published over the period January 2001 to
`March 2010, using the terms ‘multiple sclerosis’ and ‘therapy’ or ‘treatment’, and ‘trial’. Eligible studies were also identified from conference
`information and personal communications of the authors. Abstracts and reports from meetings were included, especially since failed trials are
`often not published in peer reviewed journals. Studies were excluded if they were not published in English.
`
`ª 2010 Adis Data Information BV. All rights reserved.
`
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`Therapeutic Approaches to Multiple Sclerosis
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`251
`
`and proinflammatory Th1 cytokines attracted considerable
`attention (table I).
`
`2.1 Interleukin-12/23: p40 Neutralizing Monoclonal Antibody
`(Ustekinumab)
`
`2.1.1 Background
`Two main proinflammatory populations of CD4+ T cells are
`Th1 and Th17 cells. Interleukin (IL)-12 and IL-23 are two
`cytokines involved in the differentiation of these two T-cell
`subsets. IL-12 and IL-23 are closely related, are secreted by
`myeloid cells and bind to specific receptors expressed on T cells.
`IL-12 has long been recognized as essential for generation of
`Th1 cells secreting interferon-g (IFNg), whereas IL-23 has re-
`cently been shown to induce a specific T-cell subset producing
`IL-17.[13,14] Both cytokines are heterodimers consisting of a
`common subunit (p40) and either p35 (IL-12) or p19 (IL-23).
`The common IL-12/IL-23 subunit p40 is detected in MS pla-
`ques, and administration of IL-12 can induce relapses in ex-
`perimental autoimmune encephalitis (EAE), an animal model
`of MS.[15] Therefore, p40 blockade has been expected to be a
`strategy for modulating autoimmune processes in EAE and
`MS.[16] Ustekinumab (CNTO-1275) is a human monoclonal
`antibody directed against the common IL-12/IL-23 p40 subunit
`that has been shown to prevent clinical disease and develop-
`ment of hyperintense lesions on a T2-weighted MRI in a mar-
`moset model of EAE.[17]
`
`2.1.2 Studies
`Tolerability of ustekinumab administered subcutaneously
`was proven in a phase I trial in relapsing-remitting MS (RRMS)
`patients.[8] Based on this study, Segal and coworkers[9] tested
`four widely spread doses (27–180 mg) of ustekinumab in 249
`patients with definite RRMS (Expanded Disability Status Scale
`[EDSS] range 0–6.5) over 19 weeks. Analysis of this random-
`ized, double-blind, placebo-controlled, dose-ranging, phase II
`study for new gadolinium-enhancing T1-weighted lesions
`(primary endpoint) revealed no significant difference compared
`with placebo, for any of the dosage regimens. Regarding clin-
`ical parameters, the authors observed no median change in
`EDSS from baseline to week 23, and most patients developed
`one relapse but not more than two relapses by week 23 without
`a significant difference across all subgroups. A high number of
`adverse events, predominantly infections, were reported in both
`arms (placebo 78% and verum 83%). However, serious adverse
`events occurred only in 3% and 2% of the patients treated with
`ustekinumab and placebo, respectively.[9]
`
`2.1.3 Comment
`One possible reason for the negative results found in this
`study might be a reduced CNS penetration of ustekinumab with
`subcutaneous administration, since the positive results in the
`marmoset model of EAE were obtained with intravenous ad-
`ministration. However, active MS lesions are associated with
`disruption of the blood-brain barrier, which should permit
`significant penetration of the antibody to potential sites of ac-
`tion. Alternatively, the neutralizing antibody might have been
`administered outside the therapeutic window, since IL-12 and
`IL-23 expression in CNS may precede opening of the blood-
`brain barrier. By contrast, ustekinumab seems to be active in
`EAE as well as in psoriasis and inflammatory bowel disease,
`suggesting pathogenic and immunologic differences in these
`entities. In general, basic differences in the immunopathogen-
`esis of EAE and MS have to be kept in mind, especially con-
`cerning the relative importance of Th17 cells in EAE versus
`MS.[18]
`It may also be possible that distinct actions of the IL-12
`heterodimer and its subunits at the IL-12 receptor (IL-12R)
`result in a lack of effect of this neutralizing antibody. As
`mentioned above, IL-12 consists of a p40 subunit (which is
`shared by IL-23) and a p35 subunit forming the IL-12 p70
`heterodimer. Levels of IL-12 p40 and IL-12 p70 are in-
`dependent, and p40 is produced in excess over IL-12 p70 by
`5- to 500-fold, which can result in the formation of IL-12 p80
`homodimers.[19] The IL-12R consists of a b1 and a b2 subunit,
`of which only the latter transmits intracellular signals upon
`ligation.[20] The IL-12 p40 subunit exclusively binds to the
`IL-12Rb1 subunit, which lacks signal transmission if the b2
`subunit is disengaged. Excess IL-12 p40 is thus able to com-
`petitively antagonize binding of IL-12 p70 heterodimer to its
`receptor.[21] In turn, IL-12 p80 homodimers are able to occupy
`IL-12R to a higher affinity and block signal transmission by
`noncompetitive antagonism to IL-12 p70 heterodimers[22] and
`thus act in an anti-inflammatory way. The functional relevance
`of antagonization of IL-12 p70 signaling by excess IL-12 p40
`monomers or homodimers has been shown in vitro.[23,24] Thus,
`neutralization of IL-12 p40 by ustekinumab might pre-
`dominantly block the IL-12 antagonizing activity of a p40 ex-
`cess and outscale the net blocking effect on proinflammatory
`IL-12 p70 signaling.
`
`2.2 Phosphodiesterase Inhibitors (Ibudilast, Rolipram)
`
`2.2.1 Background
`Phosphodiesterases (PDEs) are involved in the regulation of
`intracellular levels of the second messengers cyclic adenosine
`
`ª 2010 Adis Data Information BV. All rights reserved.
`
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`252
`
`Ref./clinical
`trial ID
`[NCTy]
`
`Further/ongoing
`trials
`
`Comment
`
`Finished
`
`Negative results: no clinical
`efficacy
`
`8
`
`clinical adverse
`effects
`
`Ustekinumab was
`well tolerated
`
`Table I. Modulation of T-cell differentiation and T helper (Th)-1/Th2 balance
`
`Agent
`
`(Assumed) mechanism
`of action
`
`Characteristics
`
`Disease
`course
`
`Outcome
`
`MRI
`
`IL-12/-23 p40
`neutralizing
`mAb
`(ustekinumab,
`CNTO-1275)
`
`Blockade of
`differentiation of naive T
`cells to Th1 cells (IL-12),
`modulation of
`macrophage function by
`blockade of IL-23
`
`RRMS
`
`RRMS
`
`Phase I, db, pc,
`sequential dose
`escalation;
`20 pts
`
`Phase II, r, db,
`pc, mc; 249 pts;
`repeated SC
`administration
`
`High variability in T2
`lesion volume and
`total number of
`GdEL
`
`9 0
`
`0207727
`
`Finished
`
`Negative, new GdEL No significant
`differences for new
`GdEL T1 lesions
`and no significant
`effect on clinical
`parameters
`
`ol, co; 18 pts
`
`RRMS,
`SPMS
`
`Negative
`
`PDE inhibitors
`(ibudilast)
`
`Downregulation of
`inflammatory responses
`by changing levels of
`cAMP and cGMP;
`shifting the cytokine
`milieu towards Th2-
`driven responses
`
`Atorvastatin
`(alone or add-
`on to IFNb-1a
`SC)
`
`Modulation of HMG-CoA
`reductase-dependent
`T-cell signaling
`pathways, shift of Th1 to
`Th2 response
`
`Phase II, ol, btt;
`36 pts
`
`RRMS
`
`Reduction in number
`and volume of GdEL
`when all or IFN-
`treated pts were
`analyzed. No
`significant effect in
`pts without IFN
`
`In all pts and all
`strata, a
`significantly
`improved MSFC
`was found,
`whereas EDSS
`was not
`significantly
`influenced
`
`Terminated due
`to lack of clinical
`efficacy; dose-
`dependent
`adverse effects,
`e.g. nausea and
`emesis
`
`10
`
`Regarded as
`immunomodulating
`treatment; first-generation of
`PDE inhibitors with
`considerable adverse
`effects; second-generation
`compounds are improved in
`this regard
`
`Finished
`
`No parallel groups, effect
`possibly due to IFN
`treatment, short observation
`period with low number of pts
`
`11
`00616187
`
`Ulzheimer et al
`
`RRMS
`
`r, db, pc, 0 mg/
`40 mg/80 mg,
`add-on to IFN;
`26 pts
`
`Negative; more new
`T2 lesions or GdEL
`in verum group
`(8/17) vs placebo
`(1/9)
`btt = baseline-to-treatment; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; co = crossover; db = double-blind; EDSS = Expanded Disability Status
`Scale; GdEL = gadolinium-enhancing lesions; ID = identifier; IFN = interferon; IL = interleukin; mAb = monoclonal antibodies; mc = multicenter; mo = month(s); MRI = magnetic resonance
`imaging; MSFC = multiple sclerosis functional scale; ol = open-label; pc = placebo-controlled; PDE = phosphodiesterase; pt(s) = patient(s); r = randomized; Ref. = reference; RRMS =
`relapsing-remitting multiple sclerosis; SC = subcutaneous; SPMS = secondary-progressive multiple sclerosis.
`
`Finished
`
`Negative; more
`relapses in verum
`group (4/17) vs
`placebo (1/9)
`
`High number of pts not
`adhering to study drug
`protocol, low number of pts
`
`12
`
`ª 2010 Adis Data Information BV All rights reserved
`
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`Therapeutic Approaches to Multiple Sclerosis
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`253
`
`monophosphate (cAMP) and cyclic guanosine monophos-
`phate (cGMP) by hydrolysis of the respective cyclic nucleo-
`tides. The 11 known PDE subtypes differ in their substrate
`specificity and their pharmacologic properties, e.g. PDE-4 is
`activated by elevated levels of cAMP and inhibited by rolipram.
`Inhibition of PDE reduces tumor necrosis factor-a (TNFa)
`production by activated monocytes and macrophages, resulting
`in a lower immune response and a shift of the cytokine milieu to
`Th2-driven responses. Treatment with PDE inhibitors has
`previously shown clinical and histopathologic amelioration in
`several EAE models.[25] In human MS, the unspecific PDE
`inhibitor ibudilast was shown to influence cytokine production
`of T-cell lineages and natural killer cells.[10]
`
`pathways in T cells.[28,29] Simvastatin, for example, has been
`shown to interfere with IL-17 production of human T lym-
`phocytes,[30] and other statins shift the cytokine response to-
`wards a Th2 pattern.[31,32] Moreover, statins interfere with cell
`infiltration via the blood-brain barrier by downregulation of
`cell adhesion molecules like lymphocyte function-associated
`antigen-1 (LFA-1)[33] and reduction of chemokine produc-
`tion by endothelial cells.[34] Statins have also been shown to be
`effective in the EAE model,[31,35] and it is known from clinical
`practice that they generally have good tolerability and an ex-
`cellent safety record. It therefore seemed reasonable to in-
`vestigate a potential beneficial effect of statins on MS in clinical
`trials.
`
`2.2.2 Studies
`An open-label, crossover, phase I/II clinical trial of the
`specific PDE-4 inhibitor rolipram had to be terminated pre-
`maturely because of lack of clinical efficacy, after enrolling only
`eight MS patients. Unexpectedly, the number of contrast-
`enhancing lesions increased significantly (0.44–1.71 lesions/
`patient/month), while rolipram was otherwise immunologically
`active and inhibited Th1 and Th17 cells in MS patients.[26]
`Furthermore, the acceptance of the oral formulation was
`hampered by dose-dependent adverse effects, e.g. nausea and
`emesis.
`
`2.2.3 Comment
`The first clinical evaluations of PDE inhibitors showed that
`they have to be regarded as immunomodulating treatment, but
`they also display considerable adverse effects. However, the
`observed dissociation between expected immunologic effects
`and the negative clinical outcome measures raises concerns
`about the clinical perspective of these drugs. Besides the ob-
`served lack of efficacy in MS, clinical development has also
`been halted in depression, the other major target of PDE in-
`hibitors.[27] The second-generation compounds, which target
`only a subset of PDE-4 enzymes, are improved in this regard
`and could perhaps be worthwhile to try in a well designed MS
`treatment trial.
`
`2.3 HMG-CoA-Dependent T-Cell Signaling: Statins
`(Atorvastatin)
`
`2.3.1 Background
`HMG-CoA reductase inhibitors (statins) are known to
`have pleiotropic effects in vivo, and considerable experimen-
`tal evidence points towards an immunomodulatory influence
`of statins by influencing HMG-CoA-dependent signaling
`
`2.3.2 Clinical Trials
`An early open-label, single-arm, crossover study compared
`disease activity by MRI in 30 RRMS patients before and after
`6 months of treatment with simvastatin.[36] The number and
`volume of gadolinium-enhancing lesions declined by ~40%.
`Four years later, a randomized, double-blind pilot study was
`launched including 26 subjects with RRMS receiving atorva-
`statin versus placebo as add-on therapy to IFNb-1a therapy.[12]
`Surprisingly, statin-treated patients showed a significantly in-
`creased relapse rate and an increased number of new lesions as
`assessed by MRI. These unexpected results are in contrast to
`other clinical studies, which underline clinical safety and effi-
`cacy of statin treatment in MS.[11,36,37]
`
`2.3.3 Comment
`A possible explanation for these conflicting data on statins in
`neuroinflammation might be related to putative proinflam-
`matory and harmful effects of statins. They have been reported
`to increase IFNg, IL-12,[38] and IL-12p70[39] production, and to
`augment the proteolytic activity of matrix metalloproteinases
`(MMPs).[40] Moreover, statins were shown to hamper CNS
`remyelination by blocking oligodendrocyte progenitor cell
`differentiation[41] and mature oligodendrocyte function. In
`summary, oral add-on therapies with clinically approved agents
`in other indications, like statins, still represent an attractive
`strategy for improving MS therapy, but careful studies will be
`necessary to rule out a putative harmful interaction between
`statin and interferon treatment in MS.
`
`3. Modulation of T-Cell Activation
`
`Autoreactive T cells in the systemic immune compartment
`recognize specific autoantigens presented by MHC class II
`
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`
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`Ulzheimer et al.
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`molecules on the surface of antigen-presenting cells. Activation
`of T cells as well as B cells requires a dual signaling, one signal of
`which comes from a ‘trimolecular complex’ consisting of the
`TCR complex and its co-receptors CD4 and CD8 bound to the
`antigenic peptide presented by the MHC molecule. The second
`signal originates from soluble factors such as IL-2, or from
`binding of co-stimulatory cell surface ligands.[42] These co-
`stimulatory signals seem to be critical for the regulation of
`T-cell activation and for the balance between Th1 and Th2
`cell differentiation.[43] Therefore, blockade of co-stimulatory
`pathways may be an interesting therapeutic approach for
`treating autoimmune disorders such as MS. A well character-
`ized co-stimulatory pathway includes CD28 on T cells, which
`has two ligands on antigen-presenting cells: B7-1 (CD80)
`and B7-2 (CD86). Alternatively, an additional counter-receptor
`on T cells, cytotoxic T-lymphocyte antigen 4 (CTLA4), can
`bind both CD80 and CD86, acting as a negative regulator of T-
`cell function. In this regard, mainly the CD28-CTLA-4/B-7 and
`the CD40-CD40-ligand system revealed a promising target,
`since in the EAE model, recombinant or pharmacologic mod-
`ulation of the CD28-B-7 network influenced disease develop-
`ment and progression.[44,45] Further, both systems contribute to
`the (dys)regulation of autoreactive T cells in MS[46-48] (table II).
`
`3.1 Cytotoxic T-Lymphocyte Antigen 4 (CTLA4): Chimeric
`CTLA4-Ig (Abatacept, RG2077)
`
`3.1.1 Background
`CTLA4 (CD152) is expressed on T cells and is similar to the
`co-stimulatory molecule CD28, as they both are able to bind to
`CD80 and CD86 on antigen-presenting cells. CTLA4, however,
`is known to be an important negative regulator of T-cell
`function[44,45] and has also been implicated in the mechanism of
`action of CD4+CD25+ regulatory T cells (Treg) cells.[55] In the
`EAE model, anti-CTLA4 treatment exacerbates the severity of
`the disease.[56-58] In addition, certain CTLA4 gene poly-
`morphisms seem to be associated with human MS.[48,59,60]
`Taken together, these observations highlight the potential role
`of CTLA4 in the control of autoimmunity.
`The B7/CD28-CTLA4 pathway can be modulated by
`CTLA4-Ig, a chimeric protein consisting of the extracellular
`domain of human CTLA4 fused to the Fc region of human
`IgG-1.[61,62] CTLA4-Ig inhibits T-cell activation by binding
`with higher affinity to B7-1 and B7-2 than CD28. In patients
`with refractory rheumatoid arthritis, the CTLA4-Ig protein
`abatacept (RG2077) demonstrated significant clinical benefits
`(for review see Westhovens and Verschueren[49]) and was thus
`approved by the US FDA in December 2005. It is also currently
`
`under investigation for the treatment of type 1 diabetes mellitus
`and for ulcerative colitis.
`
`3.1.2 Studies
`A small pilot study assessed the safety and immune mech-
`anisms of CTLA4-Ig (abatacept) and has recently been pub-
`lished.[50] In this study, 20 subjects with RRMS received either
`single intravenous infusions of abatacept 2, 10, 20, or 35 mg/kg
`or a multi-dose of 10 mg/kg. No major adverse effects were
`observed and immunologic assessment showed a reduction in
`the proliferation of myelin basic protein (MBP)-specific T-cell
`lines with a reduced production of IFNg.
`A double-blind, placebo-controlled, multicenter, phase II
`trial of abatacept included 219 patients with RRMS, random-
`ized between abatacept at one of two doses (2 or 10 mg/kg)
`or placebo, administered by infusion on days 1, 15, and 29,
`and then every 4 weeks until day 197.[51] Of the 219 patients in
`the study, 127 received at least one infusion of the study med-
`ication. The study, albeit thoroughly designed and adequately
`powered, was prematurely terminated by the safety board
`because of an increased relapse rate and inflammatory MRI
`activity in the low-dose verum group. Preliminary efficacy
`analysis revealed that, compared with patients in the 2 mg/kg
`arm and the placebo group, those in the 10 mg/kg group had
`fewer new gadolinium-T1 enhancing lesions and fewer relapses.
`
`3.1.3 Comment
`The abatacept trial in RRMS was halted prematurely be-
`cause of the occurrence of higher relapse rates in one of the two
`verum groups (lower dose). Initially, the investigators were
`concerned about disease (re)activation by CTLA4-Ig, similar to
`that seen earlier in the TNFa MS trial.[63] However, unblinding
`of the patient cohort revealed that the low-dose group already
`had higher disease activity at the time of study inclusion; for
`example, 80% of patients with more than 10 gadolinium-T1
`enhancing lesions were randomized to the low-dose abatacept
`treatment group. Therefore, rather than a true ‘treatment fail-
`ure’ or CTLA4-Ig-induced immune exacerbation, these results
`likely occurred because of a randomization problem. Final
`interpretation of the study is still pending and published data
`on CTLA4-Ig in MS is too scarce to allow any firm conclusions
`regarding its safety and potential efficacy. Trial experiences in
`other autoimmune diseases as well as in transplantation gen-
`erally indicate that this therapy has considerable potential.[62,64]
`The experience with CTLA4-Ig illustrates the risk of in-
`appropriately stopping a trial because of a small number of
`adverse events, which instead of being caused by the study drug
`
`ª 2010 Adis Data Information BV. All rights reserved.
`
`Biodrugs 2010; 24 (4)
`
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`

`

`Therapeutic Approaches to Multiple Sclerosis
`
`Ref./clinical
`trial ID
`[NCTy]
`
`49,50
`
`51
`00035529
`
`Characteristics
`
`Disease
`course
`
`Outcome
`
`MRI
`
`clinical adverse effects
`
`Further/ongoing
`trials
`
`Comment
`
`RRMS
`
`RRMS
`
`Pilot study, 20 pts,
`single infusions (2, 10,
`20, 35 mg/kg) or multi-
`dose of 10 mg/kg
`
`db, pc, mc, phase II
`trial, 330 pts, (2 or
`10 mg/kg infusions on
`days 1, 15, 29 and
`then every 4 wk until
`day 197)
`
`No major adverse
`effect
`
`Finished
`
`Accumulation of
`inflammatory MRI
`activity (low-dose
`verum group); fewer
`new GdEL in
`10 mg/kg group
`
`Accumulation of
`relapses in low-dose
`verum group; less
`relapses in 10 mg/kg
`group
`
`Study was
`prematurely
`halted
`
`Reason for worse
`outcome in the verum
`group probable due to
`randomization failure; the
`clinical benefit in MS
`remains unclear
`
`Table II. Modulation of T-cell activation
`
`Agent
`
`CTLA4-Ig
`(abatacept,
`RG2077)
`
`(Assumed)
`mechanism of
`action
`
`Negative
`regulator of T-
`cell function;
`effects on
`CD4+CD25+
`Treg cells
`
`Anti-CD40L
`(anti-CD154,
`toralizumab)
`
`Antibody
`interacting
`with the
`co-stimulatory
`pathway
`CD40-CD40L
`
`Pilot study (IDEC-
`131) in 15 pts
`
`RRMS
`
`Positive
`
`No relapses for at least
`6 mo
`
`Finished
`
`Potential interference
`with the thrombocyte
`system
`
`RRMS
`
`46 pts, db, pc, phase II
`trial (15 mg/kg) IV for
`5 wk and then every
`mo for 3 mo
`
`Study was halted
`because 1 pt
`developed
`thromboembolism in
`another study of Crohn
`disease (later, 2 more
`pts)
`
`Stopped,
`although all pts
`had pre-existing
`risk factors for
`clotting
`
`PPAR-g agonists:
`thiazolidinediones
`(pioglitazone,
`rosiglitazone)
`
`Inhibition of T-
`cell activation,
`reduction of
`proinflammatory
`cytokines
`
`Phase I/II pilot study,
`21 pts taking IFNb-1a
`using pioglitazone.
`Observation period:
`1 y
`
`RRMS
`
`Positive
`
`Finished
`
`Clinical potential in MS
`unclear, broad
`experience in other
`disease entities,
`candidate for
`continuation
`
`52
`
`53
`
`54
`
`255
`
`db = double-blind; CTLA4 = cytotoxic T-lymphocyte antigen 4; GdEL = gadolinium-enhancing lesions; ID = identifier; IFN = interferon; IV = intravenous; mc = multicenter; mo = month(s);
`MRI = magnetic resonance imaging; MS = multiple sclerosis; pc = placebo-controlled; PPAR = peroxisome proliferator-activated receptor; pt(s) = patient(s); Ref. = reference; RRMS =
`= regulatory T cells; wk = week(s); y = year(s).
`relapsing-remitting MS; Treg
`
`ª 2010 Adis Data Information BV All rights reserved
`
`Biodrugs 2010; 24 (4)
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`256
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`Ulzheimer et al.
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`could also be due to chance, unbalanced baseline character-
`istics, or complex dose-response interactions. This trial em-
`phasizes the need to utilize trial designs that protect against this
`occurrence (e.g. adaptive designs).
`
`3.2 CD40-CD40L: Blocking Monoclonal Anti-CD154
`Antibody (Toralizumab)
`
`3.2.1 Background
`CD40L (CD154) is a member of the TNF family of cell surface
`interaction molecules, which is expressed on CD4 T cells, B cells,
`macrophages, and dendritic cells.[65,66] The CD40-CD40L path-
`way has been shown to have multiple roles in the immune system,
`e.g. it enhances the antigen-specific T-cell response thr