1. health and fitness
2. disease

YEXNR-10556; No. of pages: 6; 4C:
Experimental Neurology xxx (2010) xxx–xxx
Contents lists available at ScienceDirect
Experimental Neurology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / yex n r
Review
New treatment strategies in multiple sclerosis
Joanne L. Jones ⁎, Alasdair J. Coles
Dept. of Clinical Neurosciences, Box 165 Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK
a r t i c l e
i n f o
Article history:
Received 8 March 2010
Revised 27 May 2010
Accepted 7 June 2010
Available online xxxx
a b s t r a c t
Multiple sclerosis is the most common, non-traumatic, disabling neurological disease of young adults,
affecting an estimated two million people worldwide. At onset multiple sclerosis can be categorised clinically
into relapsing remitting MS (RRMS — 85–90% of patients) or primary progressive MS (PPMS). Relapses
typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks
before they gradually dissipate. At first full recovery is the norm, later patients accumulate deficits and
ultimately most convert to a secondary progressive phase (SPMS), characterised by deficits that increase in
the absence of further relapses. The clinical picture reflects the complex interplay of focal inflammation,
demyelination and axonal degeneration occurring within the central nervous system.
Since the introduction of a genuine disease-modifying drug, interferon-beta1b in 1993, there has been a
growing interest from academia and pharmaceutical companies alike in multiple sclerosis therapy. In part
this effort has focused on investigating the “window of therapeutic opportunity” within the natural history of
the disease: it is becoming increasingly clear that immunotherapies are not useful in the secondary phase of
the disease but may offer long-term benefit if given early in the relapsing–remitting phase. In part, attention
is being paid to the details of dosing and administration of the various licensed therapies, but there is also a
significant research effort to explore new ways to treat the disease. In this review, we first sketch the
landscape of novel therapies in multiple sclerosis and then discuss in detail approaches which are likely to
emerge over the next few years.
© 2010 Elsevier Inc. All rights reserved.
Contents
The landscape of novel therapies in multiple sclerosis
New and emerging therapies and the rationale behind
Lymphocyte migration . . . . . . . . . . . . .
Natalizumab . . . . . . . . . . . . . . . . . .
Fingolimod (FTY720) . . . . . . . . . . . . . . . .
Targeting T cells . . . . . . . . . . . . . . . . . .
Daclizumab . . . . . . . . . . . . . . . . . .
Targeting B cells . . . . . . . . . . . . . . . . . .
Rituximab . . . . . . . . . . . . . . . . . . . . .
Mixed targets . . . . . . . . . . . . . . . . . . .
Alemtuzumab . . . . . . . . . . . . . . . . .
Cladribine . . . . . . . . . . . . . . . . . . .
In conclusion . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . .
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The landscape of novel therapies in multiple sclerosis
Broadly speaking, novel therapies of multiple sclerosis aim to
either disable a component of the immune system or to prevent
neurodegeneration, as seen in progressive forms of the disease.
⁎ Corresponding author.
E-mail address: [email protected] (J.L. Jones).
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Disabling the immune system can be achieved in a number of
ways, including: i) targeting whole populations of immune cells
believed to be involved in disease pathogenesis (e.g. daclizumab
neutralising the CD25 molecule on all T cells), ii) blocking the
migration of peripheral lymphocytes in to the CNS (natalizumab and
fingolimod) or iii) “resetting the immune system” by wiping out the
existing immune repertoire, including pathogenic myelin reactive
clones, then allowing a pool of new and healthy immune cells to
0014-4886/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.expneurol.2010.06.003
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003
2
J.L. Jones, A.J. Coles / Experimental Neurology xxx (2010) xxx–xxx
regenerate, either from residual, non-depleted haematopoietic precursor cells (rituximab for B cells, alemtuzumab for all lymphocytes)
or from autologous haematopoietic stem cells transplanted back into
the patient following chemotherapy (autologous stem cells transplantation). Whilst a number of these approaches have been shown to
be efficacious, a fundamental problem is that they deplete or
functionally inhibit “normal immune cells” as well as pathogenic
cells, potentially compromising immune protection. Ideally MS
therapy would be more directed, selectively targeting disease-specific
autoreactive cells, whilst leaving the rest of the immune system
competent to respond to infections. To date targeted approaches have
included peptide-specific therapies, in which MBP peptides, solubilised MHC–peptide complexes, or altered peptide ligands (APL) of
MBP peptides are administered orally, intravenously or transnasally
with the intent of re-establishing peripheral tolerance by engaging
the T cell receptor complex without co-stimulatory signals, so
inducing a) anergy, b) clonal deletion of myelin reactive cells or c)
bystander suppression by the induction of regulatory T cells or
tolerant antigen presenting cells. A fundamental problem with this
approach is that the primary target antigen in multiple sclerosis
remains unknown. Several targets are likely to be involved and
epitope spreading, that is the emergence of immune reactivity against
an expanding array of myelin targets, is likely to occur during the
course of the disease. Injecting plasmids, that encode multiple
peptides or the entire myelin basic protein, may be a way of circumventing this problem. Other directed therapies include vaccination
with attenuated autologous peripheral or CSF myelin specific T cells,
or with synthetic TCR peptides similar to those expressed by
encephalitogenic T cells, with the aim of specifically depleting myelin
reactive cells.
Despite success in animal studies these more directed, and in many
ways immunologically more sophisticated approaches have proved
disappointing when used in humans. Perhaps a fundamental problem
with trying to employ such a targeted approach is that we know
surprisingly little about the immunology of MS, for example only
recently has it become evident that there are extranodal lymphoid
follicles with the meninges of patients with multiple sclerosis (Serafini
et al., 2004). Surprisingly, a few years ago, it became apparent that
neutralising the cytokine TNFa increased multiple sclerosis disease
activity (etanercept and infliximab) (van Oosten et al., 1996). More
recently, and again unexpectedly, it has become clear that blocking the B
cell cytokines BAFF and APRIL, with the TACI receptor fusion protein
atacicept, leads to similar problems (ClinicalTrials.gov website, identifier NCT00642902, accessed 20 October 2009).
If little is known about the immunology of MS, then even less is
known about mechanisms driving neurodegeneration. Ken Smith, Steve
Waxman and others have proposed a model of neurodegeneration by
“energy failure”, as the metabolic load on the demyelinated axon
becomes unbearable. In theory, and in the animal laboratory, this is
ameliorated by sodium channel blockade, a strategy which so far has
been disappointing in humans: a trial of lamotrigine in progressive
multiple sclerosis has proved negative (presented at MS Frontiers,
London 2009). A number of other agents appear to have neuroprotective
effects in the laboratory. Broadly these agents either inhibit toxic
pathways (in particular glutamate), and/or activate trophic pathways.
Examples include the glutamate antagonists riluzole and memantadine
and low dose cannabinoids, which are believed to exert protective
effects by reducing glutamate excitotoxicity, inhibiting cell death
pathways and reducing the influx of calcium ions (Croxford et al.,
2008). It remains to be seen if any of these therapies will deliver tangible
results in the clinical setting. CUPID (cannabinoid use in progressive
inflammatory brain disease) a trial comparing oral dronabinol (an FDAapproved cannabinoids with an indication for appetite stimulation)
with placebo in progressive forms of the disease is underway. Statins,
also known as 3-hydroxy-3-methylgutaryl co-enzyme A (HMG-COA)
reductase inhibitors, have also been shown to have some neuroprotec-
tive effects in the laboratory (Miron et al., 2007; Paintlia et al., 2005,
2006). Statins may also have immunomodulatory functions (Kuipers
and van den Elsen, 2007), although results from early trials in RRMS
have produced variable results (Birnbaum et al., 2008; Markovic-Plese
et al., 2008; Paul et al., 2008; Vollmer et al., 2004).
A major question, yet to be resolved, is the relationship between
neurodegeneration and inflammation. It is now clear that strategies
aimed at disabling the immune system fail to prevent or reverse
disability once patients have entered the progressive phase of the
disease. This has led some to suggest that the inflammatory and
degenerative phases of the disease are entirely independent. We and
others disagree. Our position is that neurodegeneration occurs
predominantly through non-inflammatory mechanisms, but that
these mechanisms are set up by, and depend upon, prior inflammation.
If this is so, neurodegeneration may be best prevented by hitting the
inflammatory phase of the disease hard by effective immunotherapies.
New and emerging therapies and the rationale behind their use
Lymphocyte migration
Dysregulation of the blood–brain barrier and migration of
encephalitogenic inflammatory cells into the central nervous system
are key events in the immunopathogenesis of multiple sclerosis and,
as such, are strategic targets for MS therapies.
Natalizumab
The migration of inflammatory cells across the blood brain barrier
depends on the interaction of adhesion molecules such as VLA-4 (very
late antigen-4) expressed on activated lymphocytes and monocytes,
with its ligand VCAM-1 (vascular cell adhesion molecule-1) expressed
on cerebrovascular endothelial cells (Elices et al., 1990). Natalizumab
(Tysabri, Biogen Idec) is a humanised IgG4 monoclonal antibody that
binds to VLA-4. Like other human IgG4 antibodies, natalizumab does
not activate complement and thus does not lyse its target cell. Rather,
natalizumab is thought to exert its effect by physically preventing the
interaction of VLA-4 with VCAM-1, so impairing the trafficking of
inflammatory cells into the CNS. In keeping with this notion,
natalizumab has been shown to reduce the number of lymphocytes,
particularly CD4 + T cells, within the cerebrospinal fluid; an effect that
persists for at least 6 months following cessation of treatment (Stuve
et al., 2006a,b).
Natalizumab, given as a monthly intravenous infusion, has been
evaluated as a treatment of relapsing remitting multiple sclerosis in two
phase III clinical trials [the AFFIRM monotherapy trial, and the SENTINEL
add-on trial with interferon beta-1a (Avonex)]. AFFIRM demonstrated
that, compared to placebo, natalizumab reduced the risk of relapse by
68%, and the risk of sustained accumulation of disability by 42% at
2 years (Polman et al., 2006). On the SENTINEL trial, the addition of
natalizumab to interferon beta-1a (Avonex), led to a 56% reduction in
relapse rate, and to a 24% reduction in the risk of sustained accumulation
of disability when compared to Avonex monotherapy, again over two
years (Rudick et al., 2006). Both trials demonstrated comparable
reductions in MRI lesion activity (Polman et al., 2006; Rudick et al.,
2006). Based on these encouraging findings, natalizumab was approved
for the treatment of RRMS in November 2004. Surprisingly, only three
months later, Biogen Idec announced its voluntary withdrawal after two
patients with RRMS and one patient with Crohn's disease developed
progressive multifocal leukoencephalopathy (PML) following treatment. Two of the cases were fatal; all occurred in the context of
concomitant immunotherapies. Following a review of safety and
efficacy by the FDA and EMEA, natalizumab was re-introduced into
the market in 2006 as a monotherapy for patients with particularly
aggressive or treatment-resistant RRMS. Since this time, up until August
2009, a further 13 cases of PML have occurred in approximately 43,000
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003
J.L. Jones, A.J. Coles / Experimental Neurology xxx (2010) xxx–xxx
patients receiving natalizumab. There is some suggestion that rapid
removal of natalizumab by plasma exchange can reduce the mortality
associated with PML, although useful neurological recovery remains
very rare (source: Hans Peter Hartung, ECTRIMS). Additional adverse
effects have included allergic reactions (type I, but also type III) in up to
4% of patients, in many cases linked to the formation of neutralising
antibodies (Krumbholz et al., 2007; Leussink et al., 2008), and deranged
liver function tests with clinically significant liver damage in a small
number of cases (US Food and Drug Administration, 2009).
The cause of PML post-natalizumab is debated; for example, it has
been suggested that natalizumab leads to PML by mobilising JCVinfected cells, particularly B cell precursors, from bone marrow stores
{Bonig et al., 2008; Krumbholz et al., 2008; Ransohoff, 2005)Alternatively, or additionally, PML may occur due to reduced CNS immunosurveillance by lymphocytes. If reduced immunosurveillance alone is
sufficient to cause PML, the strategy of targeting lymphocyte trafficking
must be called into question.
Fingolimod (FTY720)
Fingolimod is an oral immunosuppressant under evaluation as a
treatment of MS. It is thought to exert its effect by sequestering
lymphocytes in secondary lymphoid tissue, so preventing the migration
of lymphocytes into the CNS. Fingolimod achieves its effect by acting as a
super-agonist to the sphingosine-1-phosphate receptor, which is
predominantly expressed on lymphocytes and regulates their migration
from lymphoid tissue. Excessive stimulation of the receptor leads to its
internalisation, so depriving these cells of crucial migration signals.
Interestingly, experimental evidence suggests that fingolimod differentially affects the sequestration of T regulatory cells and enhances their
suppressive function (Daniel et al., 2007; Sawicka et al., 2005).
In a proof-of-concept trial, daily oral fingolimod was shown to
reduce the number of new gadolinium-enhanced lesions on MRI and the
annualised relapse rate, compared with placebo (from 0.77 to: 0.35 on
1.25 mg fingolimod, and to 0.36 on 5 mg fingolimod) (Kappos et al.,
2006)This benefit was sustained during the 24 month extension study
(O'Connor et al., 2009). Based on these promising efficacy results
Novartis initiated a phase III study programme to evaluate fingolimod
vs. placebo (FREEDOMS study) or interferon beta-1a (TRANSFORMS
study) in patients with RRMS. In addition, the role of this drug in PPMS
will also be assessed in a Phase III trial comparing high dose Fingolimod
with placebo (INFORMS study).
In May 2009 data from TRANSFORMS were presented at the
American Academy of Neurology (AAN), showing a 52% reduction in
relapse rate on high dose fingolimod and a 38% reduction on low dose
fingolimod. However, whilst its efficacy appears promising, there are
increasing concerns about its safety profile. Although usually well
tolerated (nasopharyngitis, headache and flu-like symptoms are the
most common side effects), more serious adverse events have
included: 3 cases of herpes viral infections (2 of which were fatalTRANSFORMS, also see Leypoldt et al., 2009) 1 case of posterior
leukencephalopathy (Kappos et al., 2006), and an increase risk of local
skin malignancy (TRANSFORMS) (Kappos et al., 2006; O'Connor et al.,
2009).
An effective, orally available, well tolerated drug would be a
landmark in MS therapy, however, these side effects call into question
the validity of interfering with lymphocyte homing and migration.
Further analyses from all three phase III studies will be important in
clarifying the long-term safety of this drug.
Targeting T cells
T cells are believed to be pivotal in the pathogenesis of multiple
sclerosis, and as such are obvious therapeutic targets.
3
Daclizumab
IL-2 is a critical growth factor for the expansion and maturation of
activated T cells. Daclizumab is a humanised IgG1 monoclonal that
binds to the IL-2 receptor-α chain (CD25), expressed on activated but
not resting T cells, blocking IL-2 binding without triggering cytolysis.
Daclizumab is licensed for the treatment of renal-transplant rejection,
and has been used “off label” with some success as a treatment of
haematological malignancies and in a number of T cell mediated
autoimmune diseases (Waldmann, 2007).
With the intent of specifically targeting activated, autoreactive T
cells, daclizumab has been trialled as a treatment in multiple sclerosis.
In a phase II, open-label, baseline-versus-treatment study of 10 MS
patients with an incomplete therapeutic response to IFN-β, the
addition of daclizumab led to a 78% reduction in new gadoliniumenhancing lesions (Bielekova et al., 2004). Preliminary results from
CHOICE, a phase II randomised, double-blind, placebo-controlled,
add-on trial of 230 patients with active relapsing remitting multiple
sclerosis are also encouraging; showing a 72% reduction in new
contrast-enhancing lesions at 24 weeks for those receiving high dose
daclizumab in addition to concurrent IFN-β therapy (Montalban X,
2007).
To date, daclizumab appears to be well tolerated. Side effects seen in
the CHOICE study include: a higher rate of urinary tract infections (17%
vs. 13%), transient photosensitivity-type rashes, mouth ulcers, transient
headaches, and transient elevations of bilirubin, liver transaminases and
autoantibodies. Two cases of generalised lymphadenopathy have been
reported. In one case lymph node biopsy revealed non-specific reactive
changes. Both cases resolved after stopping the drug.
In contrast to predictions from in vitro studies (Goebel et al., 2000;
Tkaczuk et al., 2001) daclizumab appears to have little effect on T cell
function in vivo: peripheral CD4+ and CD8+ T cell counts are only
slightly reduced following treatment, CD4+ T cell proliferation is
reduced by just 20%, CD8+ T cell proliferation is unaffected, and T cell
mediated cytokine production is unchanged (Bielekova et al., 2006).
However, daclizumab expands a subset of NK cells expressing high
levels of the NK cell marker CD56 (CD56bright NK cells). The size of
this population correlates with reduced MRI disease activity,
supporting a role for these cells in the therapeutic effect of daclizumab
(Bielekova et al., 2006). Besides their well known antiviral and antitumour properties, CD56bright NK cells have been shown to have
immunoregulatory properties, including inhibiting the survival of
activated T cells in a contact-dependent manner (Bielekova et al.,
2006; Smeltz et al., 1999).
Long-term efficacy and safety data does not yet exist for
daclizumab treatment of multiple sclerosis and further trials are
needed. However, given the expansion of NK cells seen after
daclizumab, it seems unlikely that this treatment will be complicated
by the reactivation of latent viruses such as herpes viruses and the JC
virus.
Targeting B cells
MS is characterised by the intrathecal production of oligoclonal
IgG. In addition, clonally expanded activated B cells and plasma cells
accumulate in MS lesions (Baranzini et al., 2000; Owens et al., 1998)
and in the spinal fluid of patients with MS (Colombo et al., 2000; Qin
et al., 1998; Monson et al., 2005), suggesting local antigen-driven B
cell activation rather than a bystander response. B cells may
contribute to MS pathology in a number of ways; either directly by
the production of anti-myelin autoantibodies (Berger et al., 2003;
Genain et al., 1996), or indirectly by regulating T cell responses via
antigen presentation, cytokine release and via the induction of
regulatory T cells (Sfikakis et al., 2007). Depleting B cells is, therefore,
a reasonable therapeutic strategy in MS.
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003
4
J.L. Jones, A.J. Coles / Experimental Neurology xxx (2010) xxx–xxx
Rituximab
Rituximab is a chimeric murine/human IgG1k mAb directed against
CD20, a protein present on the surface of pre-B cells and mature B cells
(but not plasma cells, or bone marrow progenitor cells), triggering
cytolysis. In a recent Phase II, randomised, double-blind, placebocontrolled trial (Hauser et al., 2008), patients with RRMS were given two
rituximab infusions (or placebo infusions), two weeks apart. Compared
to placebo-treated patients, those receiving rituximab had significantly
(91%) fewer gadolinium-enhancing T1 brain lesions on MRI at weeks 12,
16, 20 and 24. A 58% relative reduction in the proportion of patients who
experienced a relapse was noted after 24 weeks of therapy and patients
in the rituximab group, compared with those in the placebo group, had a
lower annualised relapse rate at 24 weeks (0.37 vs. 0.84, p = 0.04),
unfortunately this was not sustained to 48 weeks. On the whole,
rituximab was well tolerated. Mild to moderate infusion reactions due to
cytokine release during B cell lysis were common and consistent with
those reported in patients with receiving rituximab for rheumatoid
arthritis (Cohen et al., 2006). Despite the rapid and complete depletion
of peripheral B cells, there was no higher risk of infection (Hauser et al.,
2008). However, as the authors point out, this trial was not designed to
assess long-term safety, or to detect uncommon adverse events.
Opportunistic infections, such as JC virus resulting in progressive
multifocal leukoencephalopathy, have been reported in other patient
populations treated with rituximab (Carson et al., 2009a; Molloy and
Calabrese, 2008), with an estimated risk of 1:4000, associated with 90%
mortality (Carson et al., 2009b).
Critically, the results from this study support the idea that B cells
play an important role in the pathogenesis of MS. It also lends weight
to the therapeutic strategy of targeting B cells. As plasma cells are not
depleted by rituximab, and antibody body levels are not significantly
affected, it is unlikely that rituximab exerts its effect through the
reduction of pathogenic autoantibodies, but rather by modulating
antigen presentation and pro-inflammatory B cell cytokine production (Bar-Or et al., 2008). Further trials with rituximab are unlikely,
but its humanised successor, ocrelizumab, has been taken to a phase 3
trial.
Mixed targets
Alemtuzumab
Alemtuzumab (formally known as Campath-1H) is a humanised
monoclonal antibody directed against CD52, a protein on the surface of
lymphocytes and monocytes with unknown function. Treatment rapidly
produces a profound lymphopenia. Lymphocytes regenerate, but the
speed and degree of recovery varies between cell types: CD4+ T cells
are particularly slow to recover, taking five years to reach pre-treatment
levels (Coles et al., 2006). Alemtuzumab is licensed for the treatment of
chronic lymphocytic leukaemia (Robak, 2005), and has been used
successfully in a variety of autoimmune diseases (Hale and Waldmann,
1996; Isaacs et al., 1992, 1995, 1996; Killick et al., 1997; Lim et al., 1993;
Lockwood et al., 1996), as well as in renal transplantation (Watson et al.,
2005) and non-myeloablative conditioning prior to stem cell therapy
(Maloney et al., 2002).
In 1991, studies of alemtuzumab in the treatment of SPMS revealed
efficacy in the suppression of relapses, but not in preventing the
continued progression of disability. In contrast, open-label studies in
RRMS showed that alemtuzumab stabilised and even improved existing
deficits. These findings led to the hypothesis that the progressive phase
of the disease is due to post-inflammatory neurodegeneration and that
immunosuppression would influence long-term disability only if given
early in the disease course. These concepts informed the design of
CAMMS-223; a phase II randomised trial comparing alemtuzumab with
subcutaneous interferon beta-1a (Rebif) in the treatment of patients
with early active RRMS. CAMMS-223 demonstrated alemtuzumab to be
highly effective in the treatment of RRMS, reducing the risk of relapse
and risk of sustained accumulation of disability by N70% when
compared to Rebif. In addition, in line with early studies, mean disability
scores improved among those receiving alemtuzumab, but worsened
among those on Rebif. This was paralleled by an increase in brain
volume on T1 MRI between months 12 and 36, whereas brain atrophy
continued among patients on Rebif. This positive effect on disability is
unprecedented in trials of MS.
The principal adverse effect of alemtuzumab is autoimmunity,
arising months to years after treatment in the setting of lymphopenia.
Typically, this is directed against the thyroid gland with 20–30% of
patients developing some form of thyroid autoimmunity (most
commonly hyperthyroidism) following treatment. In addition, in
CAMMS-223 6 patients (2.8%) receiving alemtuzumab, and one patient
(0.9%) receiving Rebif developed idiopathic thrombocytopenia purpura
(ITP), an immune mediated condition directed against blood platelets.
The index patient suffered a fatal brain haemorrhage before diagnosis.
All subsequent cases were identified by the risk management
programme. Of those treated with alemtuzumab, remission of ITP
occurred without treatment in one patient, after corticosteroid therapy
in two patients, and after rituximab therapy in two patients (Coles et al.,
2008). All are currently off treatment and have platelet counts within
the normal range. In addition to ITP and thyroid autoimmunity, we have
also observed two cases of Goodpasture's disease (one in the Cambridge
cohort, and one on the phase 3 programme) and single cases of
autoimmune neutropenia (Coles et al., 2006) and autoimmune
haemolytic anaemia (unpublished observation). We have shown that
autoimmunity arises in those patients with greater T cell apoptosis and
cell cycling in response to lymphopenia, driven by genetically
determined higher levels of IL-21 (Jones et al., 2009), i.e., autoimmunity
arises, not due to lymphocyte depletion per se, but rather as a result of
the homeostatic response it induces. Importantly, serum IL-21 levels
measured before alemtuzumab can predict, with 70% accuracy, whether
or not someone will develop an autoimmune complication of treatment.
If confirmed, this will allow for improved counselling of patients
considering alemtuzumab treatment, as an individualised risk of
autoimmunity can be given, it will also permit focused surveillance of
high-risk individuals.
In the CAMMS-223 trial, three cancers (non-EBV-associated
Burkitt's lymphoma, breast cancer and cervical carcinoma in situ)
were reported in patients in the alemtuzumab group, with onset
ranging from 22 to 64 months after the first annual cycle; one patient
treated with Rebif developed colon cancer at 36 months (Coles et al.,
2008). Whilst cancers were not statistically more frequent after
alemtuzumab (1.4% of patients vs. 0.9%) we speculate that the case of
non-EBV associated Burkitt's lymphoma may have been caused by
treatment with alemtuzumab. Infections were more common following alemtuzumab; however, this was largely due to an increase in
mild-to-moderate respiratory tract infections. To date, no cases of
PML have been seen.
The rationale behind using alemtuzumab as a treatment of MS was to
disable the aberrant immune response by simply removing lymphocytes. This is now known to be an oversimplified view of its mechanism
of action; indeed the composition of lymphocyte pool is radically altered
following alemtuzumab. B cell numbers recover rapidly (Thompson
et al., 2010) whereas T cells take up to 5 years to reach pre-treatment
levels. Memory T cells dominate the depleted T cell pool, and for the first
6 months there is a predominance of cells with a regulatory phenotype
(CD4+ CD25hi FoxP3+), with very reduced constitutive cytokine
expression (Cox et al., 2005), providing a tolerogenic environment for
newly generated lymphocytes to emerge.
Two phase III trials; Care-MS I trial comparing low dose
alemtuzumab with Rebif in the treatment of RRMS, and Care-MS II
trial comparing two doses of alemtuzumab with Rebif in patients with
RRMS who have continued to relapse whilst on one of the licensed
disease-modifying therapies are underway.
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003
J.L. Jones, A.J. Coles / Experimental Neurology xxx (2010) xxx–xxx
Cladribine
Cladribine (2-chlorodeoxyadenosine; 2-CdA) is an adenosine deaminase-resistant nucleoside analogue with selective lymphotoxicity.
As an analogue of ATP, cladribine triphosphate is incorporated into the
DNA of dividing cells, resulting in DNA damage and eventual cell death.
Cladribine was first tested in multiple sclerosis on patients with
progressive forms of the disease (Beutler et al., 1996; Rice et al., 2000;
Sipe et al., 1994). Despite suppressing new gadolinium-enhancing
lesions, patients treated with cladribine continued to slowly progress
(Rice et al., 2000). In 1999, Romine et al. published a small, 18 month,
placebo-controlled, double-blind study, of 52 patients with relapsing–
remitting multiple sclerosis treated with either subcutaneous cladribine (or placebo) for 5 consecutive days per month. Those treated
with cladribine had a 60% reduction in their annualised relapse rate
compared to those receiving placebo, with a comparable reduction in
contrast-enhancing MRI lesions (Romine et al., 1999).
Data from CLARITY, a phase III randomised, double-blind, placebocontrolled trial of oral cladribine in relapsing remitting multiple sclerosis
were presented at the 19th ENS meeting in June 2009. Cladribine tablets
were administered in two dosage arms. One arm (low dose) consisted of
two courses for the first and second year; the other arm (high dose)
consisted of four courses for the first year and two courses for the second.
Each course consisted of once daily tablets for four to five consecutive
days. Both treatment arms significantly reduced the annualised relapse
rate when compared to placebo (by 58% in the low dose group and by
55% in the high dose group). This effect was sustained over the course of
the study and was accompanied by a significant reduction in T1
gadolinium-enhancing lesions. The effects of cladribine on clinical and
MRI measures were associated with a rapid and sustained reduction in T
cell numbers. The effect on B cell numbers was transient.
To date cladribine has been well tolerated, but there remain concerns
over the long-term risk of malignancy. Herpes zoster infections were
reported in 2.3% of patients treated with cladribine. These were localised
to the skin and responded appropriately to treatment. Two further
studies of oral cladribine are underway: the ORACLE MS study (oral
cladribine in early MS) and the ONWARD trial (oral cladribine add-on to
rebif in patients with relapsing remitting MS).
In conclusion
The future of multiple sclerosis therapy looks bright, but
increasingly complex. As our therapeutic armamentarium grows,
the challenge will be finding the balance between effective immunosuppression and the risk of adverse effects.
To date, no drug, immunomodulating or otherwise, has been shown
to prevent or reverse disability once patients have entered the secondary
progressive phase of the disease. Some interpret this as evidence that the
inflammatory and degenerative phases are independent. We believe
that neurodegeneration occurs through non-inflammatory mechanisms,
but that these mechanisms are set up by, and depend upon, prior
inflammation. If this is the case, then anti-inflammatory therapies will
best prevent the progression of disability if given early in the course of
the disease, before the cascade of events that leads to axon degeneration
has been irretrievably established. This raises the difficult prospect of
exposing well non-disabled young adults to potentially toxic treatments;
a decision made all the more complex by the unpredictable nature of
multiple sclerosis. Finally, these drugs continue to inform basic science,
revealing aspects of the pathogenesis of multiple sclerosis and reminding
us of the complexity of the human immune system.
References
Baranzini, S.E., Elfstrom, C., Chang, S.Y., et al., 2000. Transcriptional analysis of multiple
sclerosis brain lesions reveals a complex pattern of cytokine expression. J.
Immunol. 165, 6576–6582.
5
Bar-Or, A., Calabresi, P.A., Arnold, D., et al., 2008. Rituximab in relapsing-remitting
multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 63, 395–400.
Berger, T., Rubner, P., Schautzer, F., et al., 2003. Antimyelin antibodies as a predictor of
clinically definite multiple sclerosis after a first demyelinating event. N. Engl. J.
Med. 349, 139–145.
Beutler, E., Sipe, J.C., Romine, J.S., Koziol, J.A., McMillan, R., Zyroff, J., 1996. The treatment
of chronic progressive multiple sclerosis with cladribine. Proc. Natl. Acad. Sci. U. S.
A. 93, 1716–1720.
Bielekova, B., Richert, N., Howard, T., et al., 2004. Humanized anti-CD25 (daclizumab)
inhibits disease activity in multiple sclerosis patients failing to respond to
interferon beta. Proc. Natl. Acad. Sci. U. S. A. 101, 8705–8708.
Bielekova, B., Catalfamo, M., Reichert-Scrivner, S., et al., 2006. Regulatory CD56(bright)
natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted
therapy (daclizumab) in multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 103,
5941–5946.
Birnbaum, G., Cree, B., Altafullah, I., Zinser, M., Reder, A.T., 2008. Combining beta
interferon and atorvastatin may increase disease activity in multiple sclerosis.
Neurology 71, 1390–1395.
Bonig, H., Wundes, A., Chang, K.H., Lucas, S., Papayannopoulou, T., 2008. Increased
numbers of circulating hematopoietic stem/progenitor cells are chronically
maintained in patients treated with the CD49d blocking antibody natalizumab.
Blood 111, 3439–3441.
Carson, K.R., Evens, A.M., Richey, E.A., et al., 2009a. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases
from the Research on Adverse Drug Events and Reports project. Blood 113,
4834–4840.
Carson, K.R., Focosi, D., Major, E.O., et al., 2009b. Monoclonal antibody-associated
progressive multifocal leucoencephalopathy in patients treated with rituximab,
natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events
and Reports (RADAR) Project. Lancet Oncol. 10, 816–824.
Cohen, S.B., Emery, P., Greenwald, M.W., et al., 2006. Rituximab for rheumatoid arthritis
refractory to anti-tumor necrosis factor therapy: results of a multicenter,
randomized, double-blind, placebo-controlled, phase III trial evaluating primary
efficacy and safety at twenty-four weeks. Arthritis Rheum. 54, 2793–2806.
Coles, A., Cox, A., Le Page, E., et al., 2006. The window of therapeutic opportunity in
multiple sclerosis. J. Neurol. 253, 98–108.
Coles, A.J., Compston, D.A., Selmaj, K.W., et al., 2008. Alemtuzumab vs. interferon beta1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801.
Colombo, M., Dono, M., Gazzola, P., et al., 2000. Accumulation of clonally related B
lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J. Immunol.
164, 2782–2789.
Cox, A.L., Thompson, S.A., Jones, J.L., et al., 2005. Lymphocyte homeostasis following
therapeutic lymphocyte depletion in multiple sclerosis. Eur. J. Immunol. 35,
3332–3342.
Croxford, J.L., Pryce, G., Jackson, S.J., et al., 2008. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J.
Neuroimmunol. 193, 120–129.
Daniel, C., Sartory, N., Zahn, N., Geisslinger, G., Radeke, H.H., Stein, J.M., 2007. FTY720
ameliorates Th1-mediated colitis in mice by directly affecting the functional
activity of CD4+CD25+ regulatory T cells. J. Immunol. 178, 2458–2468.
Elices, M.J., Osborn, L., Takada, Y., et al., 1990. VCAM-1 on activated endothelium
interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/
fibronectin binding site. Cell 60, 577–584.
Genain, C.P., Abel, K., Belmar, N., et al., 1996. Late complications of immune deviation
therapy in a nonhuman primate. Science 274, 2054–2057.
Goebel, J., Stevens, E., Forrest, K., Roszman, T.L., 2000. Daclizumab (Zenapax) inhibits
early interleukin-2 receptor signal transduction events. Transpl. Immunol. 8,
153–159.
Hale, G., Waldmann, H., 1996. Recent results using CAMPATH-1 antibodies to control
GVHD and graft rejection. Bone Marrow Transplant. 17, 305–308.
Hauser, S.L., Waubant, E., Arnold, D.L., et al., 2008. B-cell depletion with rituximab in
relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688.
Isaacs, J.D., Watts, R.A., Hazleman, B.L., et al., 1992. Humanised monoclonal antibody
therapy for rheumatoid arthritis. Lancet 340, 748–752.
Isaacs, J.D., Hale, G., Waldmann, H., et al., 1995. Monoclonal antibody therapy of chronic
intraocular inflammation using Campath-1H. Br. J. Ophthalmol. 79, 1054–1055.
Isaacs, J.D., Manna, V.K., Rapson, N., et al., 1996. CAMPATH-1H in rheumatoid arthritis—
an intravenous dose-ranging study. Br. J. Rheumatol. 35, 231–240.
Jones, J.L., Phuah, C.L., Cox, A.L., et al., 2009. IL-21 drives secondary autoimmunity in
patients with multiple sclerosis, following therapeutic lymphocyte depletion with
alemtuzumab (Campath-1H). J. Clin. Invest. 119, 2052–2061.
Kappos, L., Antel, J., Comi, G., et al., 2006. Oral fingolimod (FTY720) for relapsing
multiple sclerosis. N. Engl. J. Med. 355, 1124–1140.
Killick, S.B., Marsh, J.C., Hale, G., Waldmann, H., Kelly, S.J., Gordon-Smith, E.C., 1997.
Sustained remission of severe resistant autoimmune neutropenia with Campath1H. Br. J. Haematol. 97, 306–308.
Krumbholz, M., Pellkofer, H., Gold, R., Hoffmann, L.A., Hohlfeld, R., Kumpfel, T., 2007.
Delayed allergic reaction to natalizumab associated with early formation of
neutralizing antibodies. Arch. Neurol. 64, 1331–1333.
Krumbholz, M., Meinl, I., Kumpfel, T., Hohlfeld, R., Meinl, E., 2008. Natalizumab
disproportionately increases circulating pre-B and B cells in multiple sclerosis.
Neurology 71, 1350–1354.
Kuipers, H.F., van den Elsen, P.J., 2007. Immunomodulation by statins: inhibition of
cholesterol vs. isoprenoid biosynthesis. Biomed. Pharmacother. 61, 400–407.
Leussink, V.I., Lehmann, H.C., Hartung, H.P., Gold, R., Kieseier, B.C., 2008. Type III
systemic allergic reaction to natalizumab. Arch. Neurol. 65, 851–852.
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003
6
J.L. Jones, A.J. Coles / Experimental Neurology xxx (2010) xxx–xxx
Leypoldt, F., Munchau, A., Moeller, F., Bester, M., Gerloff, C., Heesen, C., 2009.
Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case
report. Neurology 72, 1022–1024.
Lim, S.H., Hale, G., Marcus, R.E., Waldmann, H., Baglin, T.P., 1993. CAMPATH-1
monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic
purpura. Br. J. Haematol. 84, 542–544.
Lockwood, C.M., Thiru, S., Stewart, S., et al., 1996. Treatment of refractory Wegener's
granulomatosis with humanized monoclonal antibodies. QJM 89, 903–912.
Maloney, D.G., Sandmaier, B.M., Mackinnon, S., Shizuru, J.A., 2002. Non-myeloablative
transplantation. Hematology (Am. Soc. Hematol. Educ. Program) 392–421.
Markovic-Plese, S., Singh, A.K., Singh, I., 2008. Therapeutic potential of statins in
multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future
Neurol. 3, 153–167.
Miron, V.E., Rajasekharan, S., Jarjour, A.A., Zamvil, S.S., Kennedy, T.E., Antel, J.P., 2007.
Simvastatin regulates oligodendroglial process dynamics and survival. Glia 55 (2),
130–143.
Molloy, E.S., Calabrese, L.H., 2008. Progressive multifocal leukoencephalopathy in
patients with rheumatic diseases: are patients with systemic lupus erythematosus
at particular risk? Autoimmun. Rev. 8, 144–146.
Monson, N.L., Brezinschek, H.P., Brezinschek, R.I., et al., 2005. Receptor revision and
atypical mutational characteristics in clonally expanded B cells from the
cerebrospinal fluid of recently diagnosed multiple sclerosis patients. J. Neuroimmunol. 158, 170–181.
Montalban X WDKMWMFA. Preliminary CHOICE results: a phase 2, randomised,
placebocontrolled multicentre study of subcutaneous daclizumab in patients with
active, relapsing forms of multiple sclerosis on interferon beta. 2007. p. A50.
O'Connor, P., Comi, G., Montalban, X., et al., 2009. Oral fingolimod (FTY720) in multiple
sclerosis: two-year results of a phase II extension study. Neurology 72, 73–79.
Owens, G.P., Kraus, H., Burgoon, M.P., Smith-Jensen, T., Devlin, M.E., Gilden, D.H., 1998.
Restricted use of VH4 germline segments in an acute multiple sclerosis brain. Ann.
Neurol. 43, 236–243.
Paintlia, A.S., Paintlia, M.K., Khan, M., Vollmer, T., Singh, A.K., Singh, I., 2005. HMG-CoA
reductase inhibitor augments survival and differentiation of oligodendrocyte
progenitors in animal model of multiple sclerosis. FASEB J. 19, 1407–1421.
Paintlia, A.S., Paintlia, M.K., Singh, I., Singh, A.K., 2006. Immunomodulatory effect of
combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune
encephalomyelitis. Am. J. Pathol. 169, 1012–1025.
Paul, F., Waiczies, S., Wuerfel, J., et al., 2008. Oral high-dose atorvastatin treatment in
relapsing-remitting multiple sclerosis. PLoS ONE 3 e1928.
Polman, C.H., O'Connor, P.W., Havrdova, E., et al., 2006. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354,
899–910.
Qin, Y., Duquette, P., Zhang, Y., Talbot, P., Poole, R., Antel, J., 1998. Clonal expansion and
somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple
sclerosis. J. Clin. Invest. 102, 1045–1050.
Ransohoff, R.M., 2005. Natalizumab and PML. Nat. Neurosci. 8, 1275.
Rice, G.P., Filippi, M., Comi, G., 2000. Cladribine and progressive MS: clinical and MRI
outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology
54, 1145–1155.
Robak, T., 2005. Alemtuzumab in the treatment of chronic lymphocytic leukemia.
BioDrugs 19, 9–22.
Romine, J.S., Sipe, J.C., Koziol, J.A., Zyroff, J., Beutler, E., 1999. A double-blind, placebocontrolled, randomized trial of cladribine in relapsing-remitting multiple sclerosis.
Proc. Assoc. Am. Phys. 111, 35–44.
Rudick, R.A., Stuart, W.H., Calabresi, P.A., et al., 2006. Natalizumab plus interferon beta1a for relapsing multiple sclerosis. N. Engl. J. Med. 354, 911–923.
Sawicka, E., Dubois, G., Jarai, G., et al., 2005. The sphingosine 1-phosphate receptor
agonist FTY720 differentially affects the sequestration of CD4+/CD25+ Tregulatory cells and enhances their functional activity. J. Immunol. 175,
7973–7980.
Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E., Aloisi, F., 2004. Detection of ectopic
B-cell follicles with germinal centers in the meninges of patients with secondary
progressive multiple sclerosis. Brain Pathol. 14, 164–174.
Sfikakis, P.P., Souliotis, V.L., Fragiadaki, K.G., Moutsopoulos, H.M., Boletis, J.N.,
Theofilopoulos, A.N., 2007. Increased expression of the FoxP3 functional marker
of regulatory T cells following B cell depletion with rituximab in patients with lupus
nephritis. Clin. Immunol. 123, 66–73.
Sipe, J.C., Romine, J.S., Koziol, J.A., McMillan, R., Zyroff, J., Beutler, E., 1994. Cladribine in
treatment of chronic progressive multiple sclerosis. Lancet 344, 9–13.
Smeltz, R.B., Wolf, N.A., Swanborg, R.H., 1999. Inhibition of autoimmune T cell
responses in the DA rat by bone marrow-derived NK cells in vitro: implications for
autoimmunity. J. Immunol. 163, 1390–1397.
Stuve, O., Marra, C.M., Bar-Or, A., et al., 2006a. Altered CD4+/CD8+ T-cell ratios in
cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch.
Neurol. 63, 1383–1387.
Stuve, O., Marra, C.M., Jerome, K.R., et al., 2006b. Immune surveillance in multiple
sclerosis patients treated with natalizumab. Ann. Neurol. 59, 743–747.
Thompson, S.A., Jones, J.L., Cox, A.L., Compston, D.A., Coles, A.J., 2010. B-Cell
reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple
sclerosis. J. Clin. Immunol. 30 (1), 99–105.
Tkaczuk, J., Milford, E., Yu, C., et al., 2001. Intracellular signaling consequences of antiIL-2Ralpha blockade by daclizumab. Transplant. Proc. 33, 212–213.
van Oosten, B.W., Barkhof, F., Truyen, L., et al., 1996. Increased MRI activity and immune
activation in two multiple sclerosis patients treated with the monoclonal antitumor necrosis factor antibody cA2. Neurology 47, 1531–1534.
Vollmer, T., Key, L., Durkalski, V., et al., 2004. Oral simvastatin treatment in relapsingremitting multiple sclerosis. Lancet 363, 1607–1608.
Waldmann, T.A., 2007. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia,
autoimmune diseases, and in the prevention of allograft rejection: a 25-year
personal odyssey. J. Clin. Immunol. 27, 1–18.
Watson, C.J., Bradley, J.A., Friend, P.J., et al., 2005. Alemtuzumab (CAMPATH 1H)
induction therapy in cadaveric kidney transplantation—efficacy and safety at five
years. Am. J. Transplant. 5, 1347–1353.
Please cite this article as: Jones, J.L., Coles, A.J., New treatment strategies in multiple sclerosis, Exp. Neurol. (2010), doi:10.1016/j.
expneurol.2010.06.003