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Multiple Sclerosis
Challenges Facing Future Multiple Sclerosis Clinical Trials
a report by
Helmut Butzkueven, MBBS, PhD
1,2,3
and Anneke van der Walt, MBChB
1,3
1. MS Units, Box Hill and Royal Melbourne Hospitals; 2. MS Group, Howard Florey Institute, University of Melbourne;
3. The Centre for Neuroscience, University of Melbourne
This article will begin by reviewing the continuing success of clinical trials in mitoxantrone
1
and natalizumab
2
as second-line treatment options for severe
identifying new treatments for relapsing–remitting multiple sclerosis (RRMS). relapsing MS. In addition, recent CIS trials have proved the utility of
However, it is also important to note that this success has also led to a great treatment with interferon-beta (IFN-β)
3,4
and glatiramer acetate
5
for
challenge for the MS trial community: identifying the first disease-modifying subgroups of patients with high cerebral T2 lesion load on incident magnetic
treatment for progressive MS. Other important challenges also lie ahead. In resonance imaging (MRI). Further studies, including the largest study ever
the next decade, we will see the arrival of many new therapies for RRMS. conducted in RRMS,
6,7
have compared IFN-β and glatiramer acetate head-to-
These new medications will provide patients and doctors with more choice, head and confirmed clinical equivalence.
but they will also be associated with significant new side effects and
complications. Some of these complications may become apparent only Many phase II and phase III trial programs for RRMS and CIS are ongoing,
with prolonged exposure, well in excess of the time for which patients are with the oral cladribine versus placebo (CLARITY) and the fingolomid versus
observed in randomized clinical trials. It is also unlikely that many of these avonex (TRANSFORMS) studies likely to report their outcomes in the first
medications will be compared with each other in randomized head-to-head quarter of 2009.
8
The prospect of a safe oral medication for RRMS is greatly
studies, producing a very significant challenge in the development of anticipated by clinicians and patients alike. Additional candidates include
evidence-based treatment strategies. teriflunomide, laquinimod, and fumarate (BG12), all currently in extensive
phase III trial programs.
8
The monoclonal anti-CD52 antibody alemtuzumab
We believe that the worldwide web has the potential to underpin global, has also recently commenced its phase III trial program. If the superior
comprehensive, long-term safety and efficacy outcome registries, and that efficacy that this agent demonstrated in its phase II active comparator trial
emerging statistical tools will allow future treatment comparisons to be program (alemtuzumab versus rebif) is replicated, it will become a powerful
conducted using these registries, outside the randomized clinical trial new therapeutic option for severe RRMS.
8,9
framework. However, we must set the groundwork for these efforts now, so
that we can effectively and comprehensively capture the real-world What, If Any, Are the Key Challenges Facing
treatment experience for the many new therapies that will become available Future Multiple Sclerosis Trials?
to us in the near future. Undoubtedly, the greatest challenge is the identification of treatments for
progressive forms of MS. Paradoxically, the modest success of RRMS
The last decade has seen unprecedented clinical trial activity in the treatments to date and the prospect of a much brighter future for this
therapeutic areas of RRMS and clinically isolated syndromes (CIS). disease has accentuated the suffering, seemingly without significant
In many parts of the world, this trial activity has resulted in the addition of hope, of patients with progressive MS. Why are so few agents being tried
in secondary progressive MS in particular? It is probably easiest to answer
this question by first asking why so many trials in RRMS are being
Helmut Butzkueven, MBBs, PhD, is a multiple sclerosis (MS)
neurologist at the Royal Melbourne Hospital and the Box
conducted successfully.
Hill Hospital, both in Melbourne. He is also a Senior
Research Fellow at the Centre for Neuroscience and the
The key to this success is two-fold. First, we increasingly understand
Howard Florey Institute at the University of Melbourne,
and Chair of the MSBase Foundation (www.msbase.org),
potentially successful therapeutic mechanisms of action in CIS and
which is building a global physician-owned network of RRMS. Immunomodulatory and immunosuppressive therapeutic
collaborative epidemiological MS research.
strategies have repeatedly demonstrated efficacy in RRMS, as have
helmutb@hfi.unimelb.edu.au
more targeted approaches of interference with lymphocyte migration
Anneke van der Walt, MBChB, is enrolled in a PhD
into the central nervous system (CNS), exemplified by natalizumab
2
program at the University of Melbourne, supported by a and fingolomid.
10
Second, the pharmaceutical industry has come to
training fellowship of the Australian National Health and
rely on the results of six- to 12-month phase II studies using MRI lesion
Medical Research Council and the GSK Neurology
Fellowship. Her research focus is on multimodal
activity as a biomarker in order to select appropriate candidates for
assessment of the anterior visual system as a model for subsequent phase III programs, focusing on primary clinical end-points.
axonal degeneration in multiple sclerosis.
Phase III programs in RRMS have become company-defining
investments in that they now routinely involve separate studies of the
candidate therapy against both placebo and active comparators, are
6 © TOUCH BRIEFINGS 2008
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