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The trials and errors in MS therapy.

Search strategy and selection criteria: Studies were identified by querying PubMed from 2002 until April 2007 with the term "multiple sclerosis" and combining it with "therapy", "treatment trials", "failed treatment trials" and "adverse events". Studies were also identified from conference information and personal communications of the authors. Abstracts and reports from meetings were included because failed trials are sometimes not published in scientific journals.

Introduction

Treatment options in multiple sclerosis (MS) have undoubtedly broadened over the past decade: immunosuppressants (e.g. mitoxantrone) as well as immunomodulatory drugs (beta-interferons [IFN[beta]], glatiramer acetate [GA]) are nowadays frequently applied. The recent approval of the monoclonal antibody natalizumab has opened a new era of immunoselective MS therapy. However, available substances are only partially effective and some of them are associated with considerable long-term toxicity. Moreover, the definite risk-to-benefit ratio is not yet entirely clear. Consequently, there is still tremendous research activity to develop novel compounds for future MS therapy. (1,2)

Despite considerable progress in the care of MS patients one has to keep in mind that overall, there are few successful agents in MS and many face a large number of therapeutic disappointments (3-5) (those investigated before 2002 were discussed by the authors in a previous review (4) and will not be mentioned again in this article). The medical community had to experience that rational pathophysiological concepts, valid data from animal models or even promising Phase I/II studies do not guarantee final efficacy and translation into the clinic. In addition, some compounds are associated with unforseen adverse effects when tested in humans making the risk-to-benefit ratio unacceptable (Table 1). Whereas positive studies usually cause a sensation and find their way into prestigious journals, many well-designed but negative trials in the past have unfortunately never been published. (6) Although this publication bias has already been reduced nowadays the situation is still unsatisfactory since there is a lot to learn from negative results, and critical reflection is highly important for understanding human MS pathogenesis and improving future clinical trial design.

This review summarizes the pharmacological background, the experimental basis and the clinical trial data of yet unlicensed compounds which were ineffective, led to early trial termination for other reasons or were associated with considerable adverse effects when tested in human Phase I-III studies in relapsing-remitting (RR) and secondary-progressive (SP) MS since 2002.

Failed Trials of Novel Immunomodulators: Phosphodiesterase Inhibitors, Hydrolytic Enzymes

Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) inhibitors are anti-inflammatory by modulating intracellular cyclic adenosine (cAMP) and cyclic guanosine (cGMP) monophosphate concentrations. (7) Moreover, they are able to alter the local cytokine milieu, T-cell priming and co-stimulatory signalling thus skewing the immune balance towards Th2-driven responses. (8) Treatment with PDE inhibitors has proven to be effective in several experimental autoimmune encephalomyelitis (EAE) models. (9-12) PDE inhibitors can be applied orally.

The non-specific PDE inhibitor ibudilast induced a favourable immune shift in certain T-cell subtypes and natural killer (NK) cells in human MS. (13) However, an open-label, cross-over study of 18 patients testing the PDE-4 specific inhibitor rolipram was recently terminated due to lack of clinical efficacy. Another Phase I/II clinical trial on rolipram in MS was recently discontinued after enrolment of only eight patients as an increase in the average number of new and total Gadolinium (Gd)-enhancing lesions was observed in MRI. (14) Clinical outcome measures remained stable or improved. Despite aggravated MRI activity, rolipram seems immunologically active in vivo in the expected manner since T-cell proliferation and the production of Th1 cytokines were inhibited.

The concept of PDE inhibition can be regarded as a genuine example of immunomodulation. However, data from animal experiments are partially contradictory and net effects in the human system are difficult to predict. While the use of first-generation PDE inhibitors was significantly limited by concomitant nausea and emesis, second-generation compounds have largely been improved concerning their sideeffect profile. The anti-inflammatory properties of PDE inhibitors are thought to result from changes in the levels of intracellular cAMP and cGMP. However, cAMP is probably a key player in regulating T-cell-mediated immune suppression. (15,16) Therefore, down-regulation of cAMP could in parallel impede regulatory T-cell function, thus counteracting the anti-inflammatory effects of PDE. These competing effects might explain the dissociation between immunological, clinical and MRI outcome measures observed in the above mentioned Phase I/II study.

Hydrolytic Enzymes

Hydrolytic enzymes (HE), e.g. phlogenzym consisting of bromelain, trypsin and the anti-oxidant rutosid, have a long tradition as potential therapy for various diseases and are popular among laymen. Proponents of HE argue that these substances increase the specific hydrolytic activity on putatively ingested (auto)antigens in the serum. (17-19) Oral administration of phlogenzym nearly completely protected from EAE which was associated with a shift towards an anti-inflammatory Th2 cytokine profile and increased Tcell activation thresholds. (20)

So far only one, but large, clinical trial was performed to test the safety and efficacy of oral HE in MS. (21) This randomized, double-blind, placebo-controlled study included 301 patients suffering from RRMS. The study drug was well tolerated but failed to show any treatment effect on clinical or MRI parameters. (21)

HE belong to a group of "popular" MS drugs that are accompanied by considerable non-scientific media hype. Unsubstantiated hopes are raised in patients because of single case observations, but fundamental proof of efficacy is mostly lacking. Nonetheless, their use among MS patients is common partly due to uncritical prescription by physicians. This well-designed study contributes valid negative data and underlines that the administration of HE cannot be recommended in MS.

Failed Trials on Anti-Infective Therapies: Virostatics, Antibiotics

Infectious particles have been thought to represent "environmental triggers or causes" for MS for a long time. In particular, certain viruses and bacteria have been linked to disease development or maintenance and conceptually their eradication could cure or prevent MS. (22)

Virostatics

Viral infections (e.g. human herpesvirus 6 [HHV-6], Epstein-Barr-Virus [EBV]) trigger approximately 25% of MS relapses and often precede disease onset. (23-27) Consequently, several virostatics have been tested in clinical trials. In a double-blind, placebo-controlled study 60 RRMS patients received aciclovir (800 mg/day) acting against herpes viruses, or placebo over 2 years. In summary, there was a statistically non-significant trend towards fewer relapses (~34% reduction) in individuals on antiviral medication but clear proof of efficacy was lacking. (28) Moreover, valaciclovir, another virostatic agent addressing the family of herpes viruses, was tested in a Phase II randomized, double-blind, placebo-controlled study in 70 patients using new active MRI lesions defined as new Gd-enhancing lesions, new non-enhancing T2 lesions not observed previously, enlarged non-enhancing lesions or recurrent lesions as paraclinical read-out parameter. The study period comprised 24 weeks. (29) While valaciclovir had no influence on active MRI lesions in the whole cohort, a subgroup analysis suggested a beneficial effect in patients with very active disease. Both aciclovir and valaciclovir were well tolerated in MS even during continuous long-term application.

Antibiotics

The obligate intracellular bacterium Chlamydia pneumoniae (CP) was proposed to be the long searched pathogen that triggers MS in genetically susceptible individuals (30) and a previous report suggested that relapses in MS patients are linked to CP infections. (31) Moreover, intrathecal antibody production against CP has been described in MS patients as part of the polyspecific immune response. (32) However, serologically defined (but clinically asymptomatic) CP carrier status is common among healthy persons as well as MS patients and individuals suffering from other neurological diseases making causal interpretations difficult. Moreover, epidemiological studies evaluating the correlation between CP infections and the development of MS have been inconclusive so far. (33,34) To further address the role of CP in MS, the US National Multiple Sclerosis Society funded a proof-of-principle trial on the use of rifampicin (300 mg twice daily) and azithromycin (500 mg every other day) versus placebo over 6 months in eight female RRMS patients. Both substances show profound activity against CP. The bacterium was eradicated from the cerebrospinal fluid (CSF) in three out of four women that had received the antibiotics. Interestingly, the number and volume of Gd-enhancing MRI lesions tended to increase only in the placebo group during the observation period. The investigators concluded that these results provide a rationale for a larger study on the safety and efficacy of antibiotic treatment in MS. (35)

Although a large number of epidemiological observations suggest a correlation of viral and bacterial infections with the development and maintenance of MS, most clinical trials on anti-infective therapies were negative or inconclusive at best. The fact that persistent infections by common pathogens are very frequent among healthy individuals, as well as MS patients significantly limits any statements on causality. Nevertheless, EBV is still the candidate that best fulfils the requirements of an "environmental trigger" for MS. (25-27,36,37) Recent data suggest that repeated or chronic infections with EBV and even nonpathogenic viruses (e.g. TT virus) can induce the expansion of T-cells specific for conserved viral peptides which are identical (and thus cross-reactive) to tissue-derived antigens (molecular mimicry). Against this background, it is doubtful that elimination of viruses after MS onset would still be beneficial since during this stage of the disease adaptive immune responses might promote central nervous system (CNS) inflammation independently from the initial trigger. Moreover, this approach is limited by the fact that agents which are capable of completely eradicating persisting (herpes) viruses do not exist. Available data on the true efficacy of antibiotics in MS are likewise scarce and a causal relation between bacterial infections and MS is still unproven. The reported positive effects of certain tetracyclines such as minocyclin (38-40) are most likely not related to their antimicrobial properties per se but due to other mechanisms like inhibition of matrix metalloproteinases and reduced leukocyte transmigration. (41)

Targeting the Adhesion Molecule LFA-1: Anti-LFA-1 Monoclonal Antibody (Hu23F2G)

One critical step in the pathophysiology of MS is recruitment of autoreactive leukocytes from the periphery to the CNS. This process is regulated by cell adhesion molecules expressed on the surface of infiltrating cells and their respective counterparts on the endothelium. It therefore appears plausible that specific antibodies directed against these structures can potently reduce leukocyte migration across the blood-brain barrier.

Certainly, the most exciting development in MS therapy during the last few years is the approval of the humanized monoclonal antibody (mAb) natalizumab which targets [alpha]4[beta]1-integrin (VLA-4) on the surface of encephalitogenic leukocytes. (42) Numerous excellent articles have dealt with the specific risks and benefits of natalizumab in MS and other diseases. (43-45) Natalizumab has meanwhile been successfully reintroduced to the market and its clinical efficacy in active MS patients is without doubt. However, long-term safety remains to be determined and carefully monitored over the next years specifically after the first occurrence of two additional cases of progressive multifocal leukoencephalopathy (PML) under natalizumab monotherapy.

The LFA-1/ICAM pathway also critically mediates attachment of leukocytes to the vascular endothelium. (46) Hu23F2G, a humanized anti-LFA-1 (CD11/CD18) antibody, specifically targets this engagement. Although Hu23F2G caused high saturation of LFA-1 on circulating lymphocytes and subsequent inhibition of cell migration in vivo when administered in an open Phase I study including 24 patients with MS (47) primary and secondary endpoints (MRI activity and clinical outcome parameters) were missed in the following Phase II trial. (48)

In contrast to the blockade of the [alpha]4[beta]1/[beta]7-integrin (VLA-4) pathway by natalizumab disruption of LFA-1/ICAM interactions using anti-LFA-1 mAb was ineffective in RRMS. This demonstrates that at least some mechanisms that regulate cell-cell contacts at the blood-brain barrier are redundant and can be replaced by others. While VLA-4 seems to be rather dominant at this site, the interference with LFA-1/ICAM is obviously less important.

Targeting Chemotaxis: CCR1 Antagonist BX-471

The cellular composition of (active) MS plaques is amongst other parameters determined by the local spectrum of secreted chemokines which contribute to the directional movement of leukocytes. (49-51) Several chemokines and chemokine receptors are up-regulated in MS and EAE. (52-55) Moreover, ablation of chemokines using transgenic mice was protective in models of CNS inflammation. (51,56-58) Pharmacological interference with the chemokine network has therefore been regarded as a promising strategy against MS. (59,60)

BX-471 (ZK81 1752) is an oral chemokine receptor 1 (CCR1) antagonist which has been developed for the treatment of autoimmune diseases, especially MS. Following positive safety evaluation (61), a randomized, placebo-controlled multicentre Phase II trial in RRMS was conducted to investigate safety and efficacy of 600 mg BX-471 (three times daily) in 90 patients over 1 6 weeks. (62) The substance was well tolerated but could not reduce the number of new MS plaques on MRI. However, differences in T2 lesion volume between the verum group and patients on placebo at the end of treatment suggest an effect on further plaque development. (62) The immunological parameters assessed were inconclusive after CCR1 blockade. Two Phase I studies and one Phase II trial are currently underway to investigate the efficacy of inhibiting another CCR, CCR2, in MS.

Possible explanations for the inefficacy of current strategies of CCR antagonism in MS comprise the high redundancy and complexity of the chemokine network. Moreover, chemokine receptors are probably difficult to antagonize as ligand binding involves a large surface of molecular interactions. (51) Therefore, CCR1 might simply have been the wrong target in MS. Further progress in understanding leukocyte trafficking from the periphery to the CNS is required, and the differential expression of specific CCR on certain cell populations (e.g. encephalitogenic cells versus regulatory cells) and during different stages of MS has to be known before specific CCR antagonists are likely to be of use.

Targeting Co-Stimulatory Molecules: CTLA-4-Ig, Anti-CD40L

Two distinct types of signals are necessary for effective T-cell and B-cell activation: signal one constitutes the ligation of the T-cell receptor complex and its co-receptors (CD4 and CD8) to an antigenic peptide bound to the presenting MHC molecule ("trimolecular complex"); signal two either depends on soluble factors or the binding of cell surface molecules that provide essential co-stimulatory signals complementary to T-cell receptor engagement. (63) Blockade of co-stimulation has been proposed as a promising strategy against autoimmune disorders. (2)

CTLA-4-Ig (Abatacept, RG2077)

CTLA-4 is part of the B7/CD28-CTLA-4 pathway and a negative regulator of T-cell function. (64) Mice deficient in CTLA-4 spontaneously develop severe inflammation in various organ systems which is fatal soon after birth. (65,66) Moreover, anti-CTLA-4 treatment increases symptoms of EAE in rodents (67-69) and certain CTLA-4 gene polymorphisms seem to be linked to human MS (70-72), although these associations were not consistent in every cohort. (73)

Maybe the most promising modulator of the B7/CD28-CTLA-4 pathway currently under investigation is CTLA-4-Ig, a chimeric protein consisting of the extracellular domain of human CD152 fused to the Fc region of human IgG-1. (74,75) CTLA-4 binding affinity to CD80 (B7.1) and CD86 (B7.2) is higher than to CD28 thereby interfering with the most important second signal of T-cell co-stimulation. The CTLA-4-Ig abatacept (BMS 1 88667) was effective in patients with severe rheumatoid arthritis and approved by the FDA for this indication in December 2005. (76,77)

Consequently, a double-blind, placebo-controlled Phase II trial of abatacept was performed in RRMS. A total of 330 patients received abatacept infusions at doses of 2 mg/kg or 10 mg/kg on Days 1, 15, 29, and then every 4 weeks until Day 197. Surprisingly, subjects randomized to low-dose abatacept had the highest rate of relapses and increased inflammatory MRI activity leading to premature interruption of the trial by the safety board. (78) Efficacy analysis was limited but revealed that patients in the 10 mg/kg arm developed fewer new Gd-enhancing lesions and less relapses.

The abatacept in RRMS trial was halted prematurely due to increased disease activity in the low-dose group. However, unblinding of data revealed a randomization bias rather than a true CTLA-4-Ig-induced exacerbation of MS: patients subjected to low-dose abatacept already had the highest disease activity among all groups at the time of study initiation. This is reflected by the fact that 80% of patients with more than 10 Gd-enhancing lesions received 2 mg/kg of abatacept. Unfortunately, final interpretation of the study is still pending and available data on CTLA-4-Ig in MS is too limited to allow any firm conclusions with respect to safety and efficacy. However, evidence from other autoimmune diseases indicate that this compound has considerable potential. (75,79) From a mechanistic point of view, one would expect that CTLA-4-Ig mainly works in the early phase of MS, where T-cell mediated inflammation plays the pivotal role whilst advanced stages with significant neurodegeneration should not be positively affected.

Anti-CD40L (Anti-CD154, IDEC-131)

The CD40L molecule is expressed on the surface of T-cells, B-cells and antigen-presenting cells and belongs to the tumour necrosis factor (TNF) superfamily. (80,81) Functionally, CD40-CD40L binding enhances antigen-specific T-cell proliferation and promotes B-cell differentiation through immunoglobulin isotype switching and the formation of memory B-cells. Interruption of the CD40L-CD40 pathway ameliorated disease severity in a variety of animals models, including EAE. (82,83) Against the background of encouraging experimental data, a monoclonal antibody against CD40L (IDEC-131) was developed and tested in several autoimmune disorders. (84)

In MS, the pilot study of anti-CD40L mAb (IDEC-131) was initiated at the Dartmouth Medical School in 1999 and included 15 patients. The substance was well tolerated and the complete cohort was free of relapses for at least 6 months while MRI activity was silenced in parallel. (84,85) As a consequence, a Phase II study using 15 mg/kg anti-CD40L mAb over 5 weeks and then every month over 3 months in 46 RRMS patients was launched in 2002. However, the trial had to be halted soon after randomization of the first patients because one woman in a study of anti-CD40L mAb in Crohn's disease developed severe thromboembolism. The complete clinical programme was stopped afterwards. In-depth review of trial data by the FDA revealed that pathological thrombus formation, which in the meantime had occurred in two additional subjects receiving IDEC-131, was probably not related to the studied drug as the affected patients had pre-existing risk factors for enhanced clotting. However, regulatory authorities could not definitely rule out that binding of anti-CD40L to the surface of activated platelets facilitated thromboembolism. (86) Although permission was granted to continue all trials in 2003, the further development of the anti-CD40L mAb programme was finally stopped by the distributing company due to incalculable safety concerns.

The experience with IDEC-131 points out that the interests of the pharmaceutical industry and those of the scientific community and patients are sometimes divergent. Despite encouraging clinical results and a clear pathogenically-driven mechanism of drug action, the development of the anti-CD40L mAb was ceased since an unfavourable risk-to-profit calculation was expected. Even if thromboembolism was caused by anti-CD40L crossreactivity with platelet CD40L modification of the antibody structure (e.g. by humanization) may have prevented further complications. (84)

Targeting the Leukocyte Differentiation Molecule CD52: Alemtuzumab (Campath-1H)

Among the "biologicals" in the treatment of many autoimmune disorders, mAbs are considered highly attractive candidates. (45) Biotechnological engineering now allows highly specific targeting of molecular structures at low immunogenicity using humanized antibodies.

The CD52 molecule is a cell surface glycoprotein of mostly unknown function that is expressed on T-cells and B-cells, NK cells and professional antigen-presenting cells. (87) In the late 1980s, rodent-derived mAbs specific for CD52 were the first to be "humanized". (88) One of the most successful drugs among these is alemtuzumab (Campath-1H), the humanized version of rat anti-CD52b mAb, developed at the Cambridge University, Department of Pathology. (89) The antibody is already approved for the treatment of chronic lymphatic leukaemia and causes rapid and persistent lymphocyte depletion via activation of complement and direct antibodydependent/cell-mediated cytotoxicity. (90-95)

In an open-label study, 36 patients with SPMS who had experienced an increase in the expanded disability status score (EDSS) by one point during the prior year, were treated with alemtuzumab. (96) The treatment regime comprised five doses of 20 mg of alemtuzumab given on five consecutive days. Following administration CD4 cells were depleted for a median of 61 months and CD8 cells for 30 months. There was an impressive effect on inflammatory disease parameters such as relapse rate and the number of Gd-enhancing MRI lesions (90% decline) during the first years. (96) However, these encouraging results were outweighed by the observation of continued disease progression in 32 from 36 subjects after a mean follow-up of 7.5 years. (97) Unexpectedly, autoimmune hyperthyroidism (Graves' disease) was reported in 27% of the patients. (98) Alemtuzumab was also investigated in 22 patients with RRMS, most of which had been treatment naive. (97) This cohort had very active disease as expressed by an annualized relapse rate of 2.2. After application of alemtuzumab, the relapses declined by 94% and the EDSS decreased from 4.8 to 2.1 during the 2 years of follow-up. In both study groups several infections (e.g. measles, herpes zoster, pyogenic granuloma) were judged as treatment-related (97) and 12 out of 14 subjects experienced transient worsening of MS symptoms that coincided with peak plasma levels of cytokines released during lymphocyte depletion. (99)

As a next step, a Phase II, randomized, open-label study comparing two different doses of alemtuzumab against IFNB-1 a sc (Rebif[R] 44 pg three times weekly) was performed including 334 patients with active RRMS over 2 years. (100,101) Time to sustained accumulation of disability was chosen as the primary endpoint. Secondary outcome parameters comprised of relapse rate and MRI surrogate markers of disease activity. Relapses were reduced by 75% and sustained disability by 60% in patients receiving alemtuzumab. Importantly, the positive effects persisted at comparable magnitudes after 3 years. (102) However, these encouraging results were tempered by six cases of idiopathic thrombocytopenic purpura (ITP), one with a fatal outcome leading to intermittent interruption of the trial. The rate of Graves' disease was given as 6.5% in this study. (101)

Alemtuzumab (possibly) represents an agent with extraordinary efficacy (even when tested against an active comparator). However, this is opposed by a considerable risk of (severe) adverse effects. The substance can be viewed as a mild but long-lasting form of selective immune ablation. Two major caveats arise from analyzing the available data on alemtuzumab in MS: 1) the dissociation between the profound suppression of inflammation and progressive CNS tissue loss and patient disability in SPMS, and 2) the induction of severe side effects. The first observation implies that in SPMS disease progression is probably not caused by active inflammation but rather seems to be due to concomitant neurodegeneration. Indeed, sustained axonal loss was detected in the SPMS cohort on the basis of MRI spectroscopy. (96) The mechanism that underlies the development of Graves' disease is unknown at present. The fact that this complication has not been observed following alemtuzumab treatment in oncology implies that there might be a unique predisposition for Graves' disease in MS and one might speculate that common pathomechanisms are operative. Both thyroid disease and ITP may be linked to the prevalent overdrive of B-cell (auto)reactivity following alemtuzumab administration leading to B-cell mediated autoimmunity.

In summary, evidence exists that even a single course of five infusions of alemtuzumab induces long-lasting lymphocyte depletion (only one infusion cycle per year would be necessary when used in clinical practice!) (103) and that the substance seems highly beneficial in suppressing inflammation in RRMS. (103) If the upcoming Phase III trials (CARE-MS1, CARE-MS2) corroborate the encouraging findings from previous studies, alemtuzumab might complement current treatment options in MS in the future. However, very careful patient selection and recurrent screening for possible side effects (e.g. serial blood examinations on thrombocytopenia) would be mandatory especially since the major adverse effects are treatable, if timely recognized. (103)

Concluding Remarks

Despite tremendous progress in MS therapy during the last decade, the list of compounds that "failed" when tested in MS patients is considerable and probably will be extended in the future. One should note that it is difficult to clearly define the term "failure". This judgement depends on many factors including demands of regulatory authorities, the common perception in the scientific community, perspective, expectations or interpretation. Thus, the spectrum between a clear miss, a near hit or a definite hit represents rather a continuum than a clear-cut figure.

Recent examples for true treatment failures--that means plausible rationale from pre-clinical investigations, but clear lack of efficacy under clinical conditions in the absence of major side effects--include the CCR1 antagonist BX-471, hydrolytic enzymes, anti-LFA-1 and anti-infective agents. Although secondary or tertiary endpoints were met in some cases, one would not really see a major perspective to further test these substances in larger clinical trials. The negative experiences with CCR1 and LFA-1 antagonization also serve as good examples for the complexity and redundancy of pathogenetic pathways involved in MS including their differences between animals and humans.

Agents that were withdrawn before any in-depth analysis of their true risk-to-benefit ratio had been performed comprise the anti-CD40 ligand IDEC-131 and CTLA-4-Ig (RG2077). Although adverse events occurred during these studies, their relation to the study drug is not entirely clear. One should also be aware that some promising candidates are not further developed due to internal decisions made by the pharmaceutical industry, which are often based on economical and political considerations rather than on scientific or clinical arguments. A contrasting example is the anti-CD52 mAb alemtuzumab (Campath-1H): in spite of several (serious) complications, the substance is still under clinical investigation in MS. Due to its assumed extraordinary efficacy and the possibility to timely recognize specific side-effects this approach seems justifiable especially in patients with uncontrollable disease activity. However, one has to keep in mind that selective and long-lasting immunosuppression might keep patients prone to serious infections. This happened after immunosuppressive treatment with natalizumab (four cases of PML due to human polyoma [JC] virus infection) or very recently in individuals receiving fingolimod (FTY720) in an ongoing Phase III trial in RRMS (one fatal case of varicella zoster virus encephalitis, one case of herpes simplex virus encephalitis). These tragic cases point out the uncertainties novel immunoselective substances bear regarding long-term safety and underline the unconditional need to continuously re-evaluate the risk-to-benefit ratio even after a drug has been brought to the market.

Taken together, the mentioned compounds, though ineffective, harmful or at least suspect when tested in patients, clearly add to our growing understanding of MS pathology and can help to improve future trial design.

Key Points

* A significant number of trials in MS therapy have failed in the past

* Negative trials are often not published

* This publication bias can negatively influence the understanding of MS pathophysiology and the design of future trials

* The definition of a "failed" trial is complex and can be related to lack of efficacy, inadmissible adverse effects or premature trial termination, e.g. due to financial considerations

* There are many lessons to learn from negative trials, including the influence on our understanding of MS-pathophysiology, strengths and weaknesses of trial designs, the relevance of patient selection or disease heterogeneity

Acknowledgements

The work of Heinz Wiendl is supported by the Deutsche Forschungsgemeinschaft (SFB 581), the Interdisziplinares Zentrum fur Klinische Forschung (IZKF), University of Wurzburg, Germany, the Deutsche Multiple Sklerose Gesellschaft (DMSG), the Thyssen-Krupp Stiftung and industrial support.

We are thankful to Ms Anke Bauer for editing the manuscript.

Conflict of interests

Christoph Kleinschnitz received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec/Elan, Bayer Healthcare/Bayer Vital, Merck Serono, Boehringer Ingelheim and Sanofi-Aventis and serves as a consultant for Merck Serono.

Sven G Meuth received honoraria for lecturing and travel expenses for attending meetings from Bayer Healthcare/Bayer Vital and Merck Serono and serves as a consultant for Merck Serono.

Heinz Wiendl received honoraria for lecturing and travel expenses for attending meetings and received financial research support from Bayer Healthcare/Bayer Vital, Biogen Idec/Elan, Sanofi-Aventis, Merck Serono and Teva Pharmaceuticals. He has served or serves as a consultant for Merck Serono, Medac, Sanofi-Aventis/TEVA, Biogen Idec/Elan and Bayer Healthcare/Bayer Vital.

Received: 6 May 2008

Accepted: 1 July 2008

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Christoph Kleinschnitz, Sven G Meuth, Heinz Wiendl

Department of Neurology, University of Wurzburg, Wurzburg, Germany

Address for correspondence:

Prof. Heinz Wiendl, Department of Neurology,

Julius-Maximilians-University Wurzburg,

Josef-Schneider-Str.11,97080 Wurzburg,

Germany.

Phone: +49 931 201 23755;

Fax: +49 931 201 23488

E-mail: heinz.wiendl@klinik.uni-wuerzburg.de
Table 1: Treatment trials in MS that have failed, been halted
prematurely or associated with adverse effects

                        (Assumed)               Characteristics/
Agent                   Mechanism of action     Trial design

Anti-CD52               Depletion of            Dose-comparison
(Alemtuzumab,           pathogenetic            study; (12 mg/day
Campath-1)              relevant T-cells        and 24 mg/day iv),
                                                head-to-head design
                                                versus IFNB-1a 44
                                                [micro]g sc, Phase II

                                                Open-label study; 36
                                                patients; 5 doses of
                                                20 mg on 5
                                                consecutive days

Co-stimulatory molecules

CTLA-4-Ig               Negative regulator      Pilot study; 1 6
(abatacept, RG2077)     of T-cell function;     patients; single
                        effects on CD4+ and     infusions (2, 10, 20
                        CD25+ regulatory        or 35 mg/kg) or
                        cells                   multi/dose of 10
                                                mg/kg 330 patients;
                                                double/blind,
                                                placebo/controlled,
                                                multicentre, Phase II

                                                trial (2, 10 mg/kg
                                                infusions on Days 1,
                                                15 and 29, and than
                                                every 4 weeks until
                                                Day 197)

Anti-CD40L              Antibody                Pilot study
(anti-CD154,            interacting with        (IDEC-1 31);
IDEC-131)               the co-stimulatory      15 patients
                        pathway CD40-CD40L
                                                46 patients;
                                                double-blind,
                                                placebo-controlled,
                                                Phase II trial;
                                                (15 mg/kg) iv for
                                                5 weeks and then
                                                every month for
                                                3 months

Anti-adhesion molecules

Anti/LFA1               LFA1/ICAM-antagonist,   Open Phase 1 study
(CD11/CD18, Hu23F2G)    inhibition of cell      (24 patients) and a
                        adhesion between        subsequent Phase II
                        leukocytes and          study (169 patients)
                        vascular endothelial    with humanized
                        cells                   anti-LFA1 (Hu23F2G)

Chemotaxis

CCR1 antagonist         Chemokine receptor      600 mg orally 3 times
(BX-471)                antagonist, reduces     per day, Phase II
                        transmigration of
                        autoreactive T-cells
                        to the CNS

Novel immunomodulators

Phosphodiesterase       Down-regulation of      Open-label,
inhibitors              inflammatory            cross-over study;
(ibudilast, rolipram)   responses by changing   18 patients
                        levels of cAMP and      (rolipram)
                        cGMP; shifting the
                        cytokine milieu to
                        Th2-driven responses

Hydrolytic enzymes      Increase the specific   Oral drug (90 mg
                        hydrolytic activity     bromelain + 48 mg
                        on putative ingested    trypsin + 100 mg
                        (auto) antigens in      rutosid); Phase III
                        the serum

Anti-infectious therapies

Antiviral agents        Eradication of          Double-blind,
(aciclovir,             potential infectious    placebo-controlled
valaciclovir)           MS triggers             trial; aciclovir
                                                (800 mg) for 2 years;
                                                60 patients

                                                Phase II,
                                                valaciclovir for
                                                24 weeks, randomized,
                                                double-blind,
                                                placebo-controlled;
                                                70 patients

Antibiotics             Eradication of          Pilot study of
(rifampicin,            potential infectious    rifampicin (300 mg
azithromycin)           MS triggers             twice daily) and
                                                azithromycin (500 mg
                                                every other day) over
                                                6 months; 8 patients

Agent                   Disease course          Outcome MRI

Anti-CD52               RRMS                    Positive
(Alemtuzumab,
Campath-1)              SPMS                    Positive

Co-stimulatory molecules

CTLA-4-Ig               RRMS                    --
(abatacept, RG2077)
                        RRMS                    Accumulation of
                                                inflammatory
                                                MRI activity
                                                (low-dose verum
                                                group); fewer
                                                new Gd-T1 enhancing
                                                lesions in 10 mg/kg
                                                group

Anti-CD40L              RRMS                    Positive
(anti-CD154,
IDEC-131)               RRMS                    --

Anti-adhesion molecules

Anti/LFA1               SPMS, RRMS              Negative
(CD11/CD18, Hu23F2G)

Chemotaxis

CCR1 antagonist         RRMS                    Negative
(BX-471)

Novel immunomodulators

Phosphodiesterase       RRMS, SPMS              --
inhibitors
(ibudilast, rolipram)

Hydrolytic enzymes      RRMS                    Negative

Anti-infectious therapies

Antiviral agents        RRMS                    Not used
(aciclovir,
valaciclovir)           RRMS                    Marginal beneficial
                                                effects in patients
                                                with high disease
                                                activity on MRI

Antibiotics             RRMS                    Positive
(rifampicin,
azithromycin)

                        Outcome                 Further/Ongoing
Agent                   Clinical/side-effects   trials

Anti-CD52               Positive                Finished
(Alemtuzumab,           1 fatal case of ITP;    Phase III study
Campath-1)              autoimmune              planned
                        hyperthyroidism

                        Negative                Finished
                        Continued disease
                        progression in
                        32/36 patients

Co-stimulatory molecules

CTLA-4-Ig               No major                Finished
(abatacept, RG2077)     adverse effects

                        Accumulation of         Study was prematurely
                        relapses in low-dose    halted
                        verum group; less
                        relapses in
                        10 mg/kg group

Anti-CD40L              No relapses for at      Finished
(anti-CD154,            least 6 months
IDEC-131)
                        MS study halted,        Stopped, although all
                        because 3 patients      patients had
                        developed               pre-existing risk
                        thrombembolism in       factors for
                        a study of Crohn's      thromboembolism
                        disease

Anti-adhesion molecules

Anti/LFA1               Negative                Finished
(CD11/CD18, Hu23F2G)

Chemotaxis

CCR1 antagonist         Negative                Finished; trials on
(BX-471)                                        other CCR antagonists
                                                (CCR2--2
                                                Phase I and I
                                                Phase II;
                                                CCR5--Phase II
                                                and III trial in
                                                HIV) planned/ongoing

Novel immunomodulators

Phosphodiesterase       Negative                Terminated due to
inhibitors                                      lack of clinical
(ibudilast, rolipram)                           efficacy;
                                                dose-dependent
                                                side-effects, e.g.
                                                nausea and emesis

Hydrolytic enzymes      Negative                Finished

Anti-infectious therapies

Antiviral agents        Not significant         Finished
(aciclovir,             Tendency towards
valaciclovir)           fewer exacerbations

                        Negative                Finished

Antibiotics             Negative                Finished
(rifampicin,
azithromycin)

Agent                   Comments

Anti-CD52               High
(Alemtuzumab,           anti-inflammatory
Campath-1)              potential,
                        considerable adverse
                        effect profile (ITP,
                        hyperthyroidism)

Co-stimulatory molecules

CTLA-4-Ig               Reason for worse
(abatacept, RG2077)     outcome in the verum
                        group probable
                        randomization
                        failure; the clinical
                        efficacy in MS
                        remains unclear

Anti-CD40L              Cross-reactivity with
(anti-CD154,            platelet CD40L
IDEC-131)               possible

Anti-adhesion molecules

Anti/LFA1               Proof of efficacy
(CD11/CD18, Hu23F2G)    lacking

Chemotaxis

CCR1 antagonist         Complexity of the
(BX-471)                cytokine system,
                        determination of the
                        most promising CCR
                        difficult

Novel immunomodulators

Phosphodiesterase       Regarded as true
inhibitors              immunomodulatory
(ibudilast, rolipram)   treatment; first
                        generation of PDE
                        inhibitors with
                        problems concerning
                        side-effects; proof
                        of efficacy lacking

Hydrolytic enzymes      Use in clinical
                        practice obsolete

Anti-infectious therapies

Antiviral agents        Casual role of
(aciclovir,             viruses in MS
valaciclovir)           unproven. Efficacy
                        of eradication
                        questionable due
                        to molecular
                        mimicry/antigen
                        spreading

Antibiotics             Causal role of
(rifampicin,            bacteria in MS
azithromycin)           unproven; positive
                        effects most likely
                        not directly related
                        to antimicrobial
                        properties

cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine
monophosphate; CCR-1: chemokine receptor 1; HIV: human
immunodeficiency virus; ICAM: intracellular adhesion molecule 1;
IFNB: interferon beta; ITP: idiopathic thrombocytopenic purpura;
iv: intravenously; MRI: magnetic resonance imaging; PDE:
phosphodiesterase; RRMS: relapsing-remitting multiple sclerosis;
sc: subcutaneously; SPMS: secondary-progressive multiple sclerosis.
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Author:Kleinschnitz, Christoph; Meuth, Sven G.; Wiendl, Heinz
Publication:The International MS Journal
Article Type:Report
Date:Nov 1, 2008
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