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J Neurol (2008) 255 [Suppl 6]:93–96
DOI 10.1007/s00415-008-6017-7
JO
N
6017
Sven G. Meuth
Christoph Kleinschnitz
Heinz Wiendl
Recent clinical trials and future therapies
Introduction
The possibilities to treat multiple sclerosis (MS) have
clearly improved over the past decade: the availability of
immunosuppressants (azathioprine, mitoxantrone, cy-
clophosphamide), the advent of disease modifying drugs
(beta-interferons (IFNβ), glatiramer acetate (GA)) in the
1990s and the recent approval of the monoclonal anti-
body natalizumab have broadened the therapeutic rep-
ertoire. However, all substances are only partially effec-
tive, some of them are associated with considerable
long-term toxicity or the risk-benefit ratio is not entirely
clear. There is tremendous activity in the search for new
drugs and strategies for MS therapy [15, 17]; the sense of
excitement in the field of MS therapeutics is reflected by
the soaring number of publications.
Some interesting substances include further mono-
clonal antibodies (e. g., daclizumab, alemtuzumab, ritux-
imab), oral agents (e. g., fingolimod, FTY720) or novel
immunosuppressants (e. g., cladribine) are currently be-
ing investigated in clinical trials. Concerning neuropro-
tective strategies, preclinical research created good sci-
entific rationale and partially prepared strategies or
agents, but none of these efforts has yet been realized in
clinical practice.
Daclizumab
The interaction of IL-2 and its receptor CD25 mediates
a pivotal signal for T cell activation and proliferation. In
general, anti-CD25 treatment aims to limit T cell prolif-
eration by blocking IL-2 signaling via its high affinity re-
ceptor. The IL-2 receptor(R) antagonist daclizumab is a
humanized mAb that interferes with the alpha chain of
the IL-2R. Three open-label studies in MS showed that
daclizumab is well tolerated and leads to a significant re-
duction in MRI activity and improvement in several
clinical outcome measures [5, 21, 22]. The positive re-
sults of the CHOICE study (phase II) have recently been
presented. On first glance, these results seem surprising
or even paradoxical because CD25 is expressed not only
on activated (pathogenic) T cells, but also on suppressor
T cells [23]. However, the network of putative regulatory
cells is complex and probably includes other subtypes of
inhibitory cells [4]. A phase IIb study is currently re-
cruiting patients to test the safety and efficacy of dacli-
zumab in a placebo-controlled, double-blind manner
[4].
■ Abstract Immunotherapy for
multiple sclerosis (MS) has devel-
oped extremely successfully during
the past decade and a number of
new strategies were developed for
the treatment of the disease.
Examples include therapeutic
strategies targeting leukocyte
differentiation molecules, costimu-
latory molecules, anti-adhesion
molecules, chemotaxis, novel im-
munomodulators, autologous stem
cell transplantation, anti-infectious
therapies and strategies for neuro-
protection, neurorepair and remy-
elination. Here we describe exam-
ples of monoclonal antibodies, a
novel immunosuppressant and
interesting neuroprotective strate-
gies.
■ Key words multiple sclerosis ·
monoclonal antibodies ·
neuroprotection
S. G. Meuth (�) · Ch. Kleinschnitz ·
H. Wiendl
Universität Würzburg
Klinik und Poliklinik für Neurologie
Josef-Schneider Str. 11
97080 Würzburg, Germany
E-Mail: meuth_s@klinik.uni-wuerzburg.de
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Alemtuzumab
Alemtuzumab (Campath-1) represents a very good ex-
ample of an agent with putatively high therapeutic effi-
cacy but a considerable risk of adverse effects. In partic-
ular, the phase II trial in the active RRMS population
demonstrated an impressively high therapeutic efficacy
with a clear reduction of immune activity (tested against
a high-dose interferon). Therefore the substance can be
viewed as a mild but long lasting form of selective im-
mune ablation. Campath-1 treatment triggers increased
antibody-mediated CNS damage by augmenting B cell
activity. For unknown reasons, about one third of Cam-
path-1 treated patients develop antibodies against the
thyrotropin receptor and subsequent carbimazole-re-
sponsive autoimmune hyperthyroidism (Grave’s dis-
ease) [9, 10]. A phase II clinical trial designed to compare
the safety and efficacy of alemtuzumab with IFNβ-1a in
RRMS showed highly impressive effects on relapse rates
and disease progression [8]. The trial was suspended but
relaunched because there was evidence of severe toxic-
ity (idiopathic thrombocytopenic purpura, ITP) includ-
ing one case of death. Currently, two phase III trials
(CARE-MS1, CARE-MS2) have been launched to evalu-
ate clinical efficacy and long-term safety for potential
approval.
Rituximab
Rituximab (mabthera) is a genetically engineered chi-
meric murine/human mAb against CD20, a differentia-
tion antigen that is found on normal and malignant pre-
B and mature B lymphocytes but which is absent on
hematopoietic stem cells, activated B cells (plasma cells)
and in normal tissues. CD20 is vital for the regulation of
cell cycle initiation and differentiation. Two trials inves-
tigated the potential use of rituximab in MS: the ritux-
imab in primary progressive (PP)MS trial (OLYMPUS),
which is a phase II/III trial, and a phase II study involv-
ing RRMS patients, the results of which were recently
published [14]: As compared with placebo, patients who
received rituximab had significantly reduced activity on
MRI (primary endpoint; newly occurring gadolinium-
enhancing lesions) as well as reduced relapses for about
a year. This is in line with a phase I open study using
rituximab, which also showed beneficial effects in re-
ducing MRI and clinical activity [1]. It is interesting to
note that the onset of clinical benefit was faster than it
could be expected just by depletion or reduction of pu-
tatively pathogenic antibodies. This clearly points to-
wards effects of anti-CD20 therapy other than reduction
of antibody production, e. g., the antigen-presenting
function of B cells [18].
FTY720
The compound FTY720 is derived from the fungus Isaria
sinclairii and exhibits profound and unique immuno-
regulatory effects [6, 7]. The therapeutic potency of this
agent has already been demonstrated in various EAE
models [13, 27]. In an international, double-blind, pla-
cebo-controlled phase II study of oral FTY720 involving
subjects with active RRMS [16], the total number of en-
hancing MS lesions on monthly MRI scans (primary
outcome) was significantly reduced and volumes of en-
hancing lesions and new T2-weighted lesions were sig-
nificantly diminished. In addition, a significantly higher
proportion of patients under FTY720 remained relapse-
free. The relapse rate under FTY720 treatment was re-
duced between 53 % and 55 %. Two large phase III stud-
ies of FTY720 in MS are currently launched. One study
is testing the safety and efficacy of two doses against pla-
cebo, the other is assessing the efficacy of FTY720 in a
head-to-head design against IFNβ-1a as an active com-
parator.
Phase III studies will demonstrate whether FTY720 is
able to document long-term efficacy and – even more
important – safety in larger numbers of patients. It is un-
predictable at the moment how chronic interference
with lymphocyte homing and migration might affect
immune surveillance of parenchymal organs including
the CNS during long-term application.
Cladribine
Cladribine is an adenosine deaminase-resistant nucleo-
side analogue with selective lymphotoxic specificity [2,
24]. Its long-lasting lymphocytotoxic activity suggests
that it could be useful in modulating conditions involv-
ing lymphocyte abnormalities. Thus, cladribine has
been tested for the treatment of lymphoid neoplasms
and autoimmune disorders, especially MS. Evidence on
the efficacy of cladribine in delaying disease progres-
sion mainly results from smaller placebo-controlled tri-
als in chronic progressive MS [3, 26] and RRMS patients
[20, 25]. The clinical observations were underlined by
remarkable MRI effects, e. g. nearly complete elimina-
tion of gadolinium-enhanced T1 lesions and stabiliza-
tion of T2 lesion volume [25]. Albeit phase I and II stud-
ies raised high expectations, a multicenter, double-blind,
placebo-controlled study of cladribine in patients with
SPMS and PPMS failed to show significant clinical ben-
efit after one year [19]. In addition, no effects on whole
brain volume and T1 “black holes” were observed [11,
12]. Since cladribine reduced the number and volume of
gadolinium-enhanced T1-weighted brain lesions and
overall T2 lesion load, there is a discrepancy between
those MRI endpoints and the observed clinical effects
[19]. Evaluation of the MRI data led to the conclusion
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that cladribine triggers strong and prolonged antiin-
flammatory effects by MRI criteria but may not influ-
ence the mechanisms of continuous tissue destruction
and neurodegeneration [11, 12]. The substance is mean-
while available as an oral formulation and a random-
ized, double-blind, placebo-controlled phase III study in
active inflammatory RR-MS has been conducted (CLAR-
ITY). Results are expected in 2009.
Neuroprotection
In general, strategies aimed at neuroprotection are chal-
lenging because assessment of neuroprotective effects in
clinical studies is complicated. Another level of com-
plexity is obtained by the question of patient selection
(RRMS, SPMS, PPMS). The ideal time window for thera-
peutic intervention is undefined so far and different ob-
servation periods throughout the clinical trials hamper
their comparability. Furthermore, in MS the situation is
even more complex due to the dissemination of destruc-
tive and reparative processes within the CNS, as com-
pared to other CNS disorders with a clearly defined on-
set and a single causality (e. g., stroke). Taken together,
the transfer from bench to bedside has been disappoint-
ing thus far, although a number of agents showed neuro-
protective potentials in vitro and in animal models of
MS. Reasons may lie in the study design and patient se-
lection, but also in the complex nature of MS lesion de-
velopment (including the lack of knowledge regarding
the “window of opportunity” for applying neuroprotec-
tive strategies) and difficulties in neuroprotection read-
out under clinical conditions. It is assumed that the
availability of true direct neuroprotective strategies or
agents for MS patients cannot be expected within the
next 5 years.
Taken together we conclude that some of these agents
will fulfill the key requirements in the treatment of a
non-fatal disorder, which is convenience of drug admin-
istration and long-term efficacy plus safety. It is to be ex-
pected that within the next few years, novel oral immu-
nomodulatory as well as further “biologicals” (e. g.,
monoclonal antibodies) or immunosuppressive agents
will be available for the treatment of MS patients which
will complement the currently available armamentar-
ium of disease modifying drugs.
■ Conflict of interest 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 has received honoraria for lecturing, travel ex-
penses for attending meetings and financial support for research
from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, Sanofi
Aventis, and TEVA. Christoph Kleinschnitz received honoraria for lec-
turing and travel expenses for attending meetings from Biogen Idec/
Elan, Schering, Serono, Bayer and Sanofi Aventis.
References
1. Bar-Or A, Calabresi PA, Arnlod D,
Markowitz C, Shafer S, Kasper LH,
Waubant E, Gazda S, Fox RJ, Panzara
M, Sarkar N, Agarwal S, Smith CH
(2008) Rituximab in relapsing-remit-
ting multiple sclerosis: a 72-week,
open-label, phase I trial. Ann Neurol
63:395–400
2. Beutler E (1992) Cladribine (2-chloro-
deoxyadenosine). Lancet 340:952–956
3. Beutler E, Sipe JC, Romine JS, Koziol
JA, McMillan R, Zyroff J (1996) The
treatment of chronic progressive
multiple sclerosis with cladribine. Proc
Natl Acad Sci USA 93:1716–1720
4. Bielekova B, Catalfamo M, Reichert-
Scrivner S, Packer A, Cerna M, Wald-
mann TA, McFarland H, Henkart PA,
Martin R (2006) Regulatory
CD56(bright) natural killer cells medi-
ate immunomodulatory effects of
IL-2Ralpha-targeted therapy (dacli-
zumab) in multiple sclerosis. Proc Natl
Acad Sci USA 103:5941–5946
5. Bielekova B, Richert N, Howard T,
Blevins G, Markovic-Plese S, McCartin
J, Frank JA, Wurfel J, Ohayon J, Wald-
mann TA, McFarland HF, Martin R
(2004) Humanized anti-CD25 (dacli-
zumab) inhibits disease activity in
multiple sclerosis patients failing to
respond to interferon beta. Proc Natl
Acad Sci USA 101:8705–8708
6. Brinkmann V, Davis MD, Heise CE,
Albert R, Cottens S, Hof R, Bruns C,
Prieschl E, Baumruker T, Hiestand P,
Foster CA, Zollinger M, Lynch KR
(2002) The immune modulator
FTY720 targets sphingosine 1-phos-
phate receptors. J Biol Chem 277:
21453–21457
7. Chiba K (2005) FTY720, a new class of
immunomodulator, inhibits lympho-
cyte egress from secondary lymphoid
tissues and thymus by agonistic activ-
ity at sphingosine 1-phosphate recep-
tors. Pharmacol Ther 108:308–319
8. Coles A, Group TCS (2007) Efficacy of
Alemtuzumab in Treatment-Naive
Relapsing-Remitting Multiple Sclero-
sis: Analysis after Two Years of Study
CAMMS223. Neurology 68(Suppl 1):
A100
9. Coles AJ, Wing M, Smith S, Coraddu F,
Greer S, Taylor C, Weetman A, Hale G,
Chatterjee VK, Waldmann H, Comp-
ston A (1999) Pulsed monoclonal anti-
body treatment and autoimmune thy-
roid disease in multiple sclerosis.
Lancet 354:1691–1695
10. Coles AJ, Wing MG, Molyneux P,
Paolillo A, Davie CM, Hale G, Miller D,
Waldmann H, Compston A (1999)
Monoclonal antibody treatment ex-
poses three mechanisms underlying
the clinical course of multiple sclero-
sis. Ann Neurol 46:296–304
11. Filippi M, Rovaris M, Iannucci G,
Mennea S, Sormani MP, Comi G (2000)
Whole brain volume changes in pa-
tients with progressive MS treated with
cladribine. Neurology 55:1714–1718
12. Filippi M, Rovaris M, Rice GP, Sormani
MP, Iannucci G, Giacomotti L, Comi G
(2000) The effect of cladribine on T(1)
'black hole' changes in progressive MS.
J Neurol Sci 176:42–44
13. Fujino M, Funeshima N, Kitazawa Y,
Kimura H, Amemiya H, Suzuki S, Li
XK (2003) Amelioration of experimen-
tal autoimmune encephalomyelitis in
Lewis rats by FTY720 treatment.
J Pharmacol Exp Ther 305:70–77
Page 4
96
14. Hauser SL, Waubant E, Arnold DL,
Vollmer T, Antel J, Fox RJ, Bar-Or A,
Panzara M, Sarkar N, Agarwal S,
Langer-Gould A, Smith CH (2008) B-
cell depletion with rituximab in re-
lapsing-remitting multiple sclerosis.
N Engl J Med 358:676–688
15. Hohlfeld R, Wekerle H (2004) Auto-
immune concepts of multiple sclerosis
as a basis for selective immunother-
apy: from pipe dreams to (therapeutic)
pipelines. Proc Natl Acad Sci USA 101:
14599–14606
16. Kappos L, Radu EW, Antel J (2005)
Promising results with a novel oral
immunomodulator-FTY720-in relaps-
ing multiple sclerosis. Mult Scler 11:
S13
17. Kleinschnitz C, Meuth SG, Kieseier BC,
Wiendl H (2007) Immunotherapeutic
approaches in MS: update on
pathophysiology and emerging agents
or strategies 2006. Endocr Metab
Immune Disord Drug Targets 7:35–63
18. McFarland HF (2008) The B cell – old
player, new position on the team.
N Engl J Med 358:664–665
19. Rice GP, Filippi M, Comi G (2000)
Cladribine and progressive MS: clini-
cal and MRI outcomes of a multicenter
controlled trial. Cladribine MRI Study
Group. Neurology 54:1145–1155
20. Romine JS, Sipe JC, Koziol JA, Zyroff J,
Beutler E (1999) A double-blind, pla-
cebo-controlled, randomized trial of
cladribine in relapsing-remitting
multiple sclerosis. Proc Association of
American Physician 111:35–44
21. Rose JW, Burns JB, Bjorklund J, Klein J,
Watt HE, Carlson NG (2007) Dacli-
zumab phase II trial in relapsing and
remitting multiple sclerosis: MRI and
clinical results. Neurology 69:785–789
22. Rose JW, Watt HE, White AT, Carlson
NG (2004) Treatment of multiple scle-
rosis with an anti-interleukin-2 recep-
tor monoclonal antibody. Ann Neurol
56:864–867
23. Sakaguchi S (2005) Naturally arising
Foxp3-expressing CD25+CD4+ regula-
tory T cells in immunological toler-
ance to self and non-self. Nat Immunol
6:345–352
24. Sipe JC (2005) Cladribine for multiple
sclerosis: review and current status.
Expert Rev Neurother 5:721–727
25. Sipe JC, Romine JS, Koziol J, Zyroff J,
McMillan R, Beutler E (1997) Cladrib-
ine improves relapsing-remitting MS: a
double blind placebo controlled study.
Neurology 48:A340
26. Sipe JC, Romine JS, Koziol JA,
McMillan R, Zyroff J, Beutler E (1994)
Cladribine in treatment of chronic
progressive multiple sclerosis [see
comments]. Lancet 344:9–13
27. Webb M, Tham CS, Lin FF, Lariosa-
Willingham K, Yu N, Hale J, Mandala S,
Chun J, Rao TS (2004) Sphingosine
1-phosphate receptor agonists attenu-
ate relapsing-remitting experimental
autoimmune encephalitis in SJL mice.
J Neuroimmunol 153:108–121
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