Download Researchers Expand Focus on Progressive Forms Of Multiple

Researchers Expand Focus on Progressive Forms
Of Multiple Sclerosis
Efforts to Pinpoint the Beginning of Disease May Yield Clues to Treatment
Susan Worley
A
fter more than a century of impressive research, multiple
sclerosis (MS)—a complex inflammatory, demyelinating neurodegenerative disorder—continues to have no
known cause and no known cure. Important achievements in
recent decades have included the development of more than
a dozen disease-modifying treatments (Figure 1) for patients
with relapsing and remitting forms of MS (RRMS).1 These
drugs have been proven to reduce disability and likely delay
progression in patients with RRMS; however, because the most
effective among them pose risks for serious adverse events,
the search for more tolerable agents for RRMS continues.
Meanwhile, despite a lack of head-to-head clinical trials, efforts
to establish a rational ordering of current treatments have led
to early-stage treatment algorithms and efficacy rankings.2
RRMS, which is characterized by episodic inflammatory
attacks on the central nervous system (CNS) and followed by
spontaneous recovery of varying degrees, represents only one
of several recognized categories of the disease.3 It is estimated
that approximately 10% of patients have a primary progressive
form of MS (PPMS), characterized by a gradual, irreversible
progression of clinical disability, and more than 50% of patients
who present with RRMS will eventually transition to secondary
progressive MS (SPMS). Drugs used to treat RRMS have so far
demonstrated little efficacy in the treatment of progressive MS
and are not currently approved to treat PPMS or SPMS. The
absence of treatments for progressive disease has become an
increasingly important focus of an international community of
researchers.
“A treatment for progressive MS is unquestionably the most
important unmet need today, in part because progressive disease
is the most significant source of disability,” says Philip De Jager,
MD, PhD, Associate Professor of Neurology at Brigham and
Women’s Hospital and Harvard Medical School. “ Recently MS
organizations around the world have launched a collaborative
effort to tackle progressive MS, which will likely lead to some
breakthroughs. Genetic studies and other research have taught
us that if we join together rather than compete with one another
on big questions such as this one, we stand a chance of being
successful. We are at the point now where small studies of
progressive disease led by individual investigators are unlikely
to provide us with an answer.”
Some of the current research on progressive disease involves
delving deeper into its biology and pathophysiology. Homing in
on the elusive beginnings of the disease, investigators believe,
Susan Worley is a freelance medical writer who resides in Pennsylvania.
Figure 1 Timeline of Approvals of Major MS Medications1
IFNB-1b (Betaseron)
IFNB-1a (Avonex)
Glatiramer acetate
(Copaxone)
Mitoxantrone (Novantrone)
IFNB-1a (Rebif)
Natalizumab (Tysabri)
Teriflunomide (Aubagio)
Alemtuzumab (Lemtrada)
Compound timeline
Dalfampridine (Ampyra)
FDA approval
Fingolimod (Gilenya)
Dimethyl fumarate (Tecfidera)
IFNB-1a (Plegridy)
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
2010
2012
2014
This timeline shows milestones in the development of 12 available MS treatments, all of which are disease-modifying except
for dalfampridine (Ampyra). It begins with the first patient visit of the oldest clinical trial, provides the FDA approval date, and
ends with the last patient visit of the most recently completed and published clinical trial. It includes FDA-approved compounds
and completed phase 2 and 3 trials, but it excludes unapproved compounds, ongoing trials, pilot studies, and phase 4 trials.
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Researchers Expand Focus on Progressive Forms of Multiple Sclerosis
may provide insight into causes and potential treatments for
all forms of MS.
“We are basically at an inflection point in terms of understanding the onset of the disease,” Dr. De Jager says. “As with
Alzheimer’s disease, MS develops over many years before
symptoms appear, and so far we have not had an opportunity to
observe the transition from health to MS; we’ve only observed
patients already diagnosed with the disease.
However, we now have detailed maps of the
genes involved in the onset of MS, and we are
on the road to discovering others. We also are
zeroing in on environmental risk factors. As
we gain a greater understanding of the biology
that leads to MS, we eventually will be able
to investigate primary prevention—strategies
that will prevent the disease from starting in
the first place.”
of natalizumab has attested to a major role of the immune
system; whether this represents ‘autoimmunity’ or ‘immunity
to an infectious agent’ or both remains an enigma. We need to
remain humble until we understand what causes the disease,
and until we can cure it.”
To arrive at a better characterization of the disease and identify opportunities for earlier treatment, more MS researchers are
engaging in or proposing prospective studies
that allow a closer examination of disease trajectories over time. One such study, led by
Dr. De Jager and colleagues at Brigham and
Women’s Hospital and the National Institute of
Neurological Disorders and Stroke (NINDS),
including Dr. Daniel Reich (see Frontiers of
MS Imaging later in this article), is designed
to examine the transition from health to MS by
following a unique cohort of first-degree relatives of individuals with MS.6 The Genes and
Genes and Environment:
the Environment in MS (GEMS) study, which
The Search for a Trigger
was launched in 2011, has enrolled nearly 3,000
The complex pathophysiology of MS, which
individuals who have provided detailed family
Philip De Jager, MD, PhD
is not yet completely understood, begins with
and medical histories and saliva samples for
neural inflammation that leads to the destruction of myelin in
extraction of DNA. Participants commit to completing periodic
the brain and spinal cord of patients. Inflammation of the brain
questionnaires—and, in some cases, undergoing imaging and
endothelium compromises the blood–brain barrier, allowing the
other testing—over a period of 20 years.
entry of immune cells into the brain. The mechanism of action
Building on the work of previously conducted genome-wide
for natalizumab (Tysabri, Biogen) (Figure 2), which is widely
association studies and published studies of environmental
considered the most effective treatment for MS, has provided
risk factors, Dr. De Jager and colleagues developed a risk
researchers with greater insight into the disease.4,5 While
algorithm that is used to generate a weighted Genetic and
some experts are inclined to think of MS as an autoimmune
Environment Risk Score (GERS) for each subject. The study’s
disorder, others are willing only to recognize an autoimmune
risk algorithm can be updated to incorporate new risk factors
component, and they remain in search of a “triggering event”
and significant relationships among risk factors as these are
that may or may not have autoimmune features.
confirmed. Selected patients with high risk scores undergo
“It does appear that, at least what we call relapsing–remitting
imaging and other testing, generating data that eventually
disease, can be highly attenuated by inhibiting the entry of the
should enable investigators to map the intricate sequence of
events that leads to MS.
immune system into the brain,” says Lawrence Steinman, MD,
Professor of Neurology at Stanford University. “The success
“First-degree relatives of people with MS are an impor-
Figure 2 Natalizumab blocks lymphocyte entry into central nervous system: (A) Alpha-4 integrin binds to vascular
cell adhesion molecule 1 (VCAM1) and to osteopontin (not depicted) on inflamed brain endothelium. This interaction
gives lymphocytes access to the central nervous system. The presence of immune cells in the brain is a prominent
feature of MS. (B) Natalizumab, a humanized antibody to alpha-4 integrin, blocks binding of lymphocytes to VCAM and
osteopontin on inflamed brain endothelium, thereby preventing lymphocyte entry into the central nervous system.
©2012 Steinman. The Journal of Cell Biology.5 199:413–416. doi: 0.1083/jcb.201207175
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Researchers Expand Focus on Progressive Forms of Multiple Sclerosis
tant population because their risk for developing the disease
is approximately 30 times greater than that of the general
population,” Dr. De Jager says. “However, the absolute risk
for each of these individuals is still rather small—only 2% to
3% will develop MS over their lifetime. By examining not only
genetic risk factors but also environmental risk factors, such
as a history of smoking or mononucleosis, our risk score seeks
to identify the members of this population who are at greatest
risk for developing the disease. We also expect to discover
critical relationships among risk factors over time.”
According to Dr. De Jager, plans are under way to expand
the study to sites in more countries with the intention of
making GEMS an international resource and eventually a
platform for clinical trials that focus on primary
prevention. As the study continues, members
of the International Multiple Sclerosis Genetics
Consortium and other researchers continue to
identify new gene variants that may play a role
in MS.7 A deeper exploration of environmental
factors, including immune responses to the
Epstein–Barr virus (EBV)8 and the influence
of gender,9,10 also continue to yield valuable
information about the disease.
These are distinctly different from the nonspecific white-matter
changes or bright spots that are seen in the majority of cases
by neurologists, which are not consistent with MS.”
More recently, Dr. Okuda and colleagues reported on data
from 451 individuals in five countries who were retrospectively
identified as having MRI anomalies suggestive of demyelinating disease.12 After following these individuals for five years,
the authors identified risk factors—such as age (younger than
37 years), male gender, spinal cord involvement, and combinations of these—that were the most meaningful predictors of
eventual symptom onset.
Data from this study also identified a presymptomatic
phase in individuals who went on to fulfill criteria for PPMS.
An examination of clinical outcomes enabled
investigators to identify characteristics that
separated individuals who developed RRMS
from those who developed progressive disease.
Characteristics of the group with PPMS
included a more advanced age range, a tendency to have an abnormal cerebral spinal
fluid profile, a longer period of time to first
clinical event, and a much higher lesion load
within the spinal cord. To date, Dr. Okuda and
colleagues have collected data on more than 14
RIS: The Value of Incidental Findings
individuals with RIS who went on to develop
progressive disease.
Among individuals already diagnosed with
MS, it has been estimated that approximately
“One of our goals is to determine whether we
Darin T. Okuda, MD
80% initially showed symptoms after the disease
can use imaging early on in the disease course,
had already been present for a decade or longer.4 This estimate
prior to the emergence of symptoms, to forecast what clinical
has long posed an intriguing question to researchers in the
subtype of MS an individual will ultimately have. Although we
field—among them, the lead investigator of another unique
currently do not have any approved therapies for progressive
prospective study of patients with MS.
disease, we hope to determine whether we can intervene in
“Figures representing the estimated incidence of MS and
some way to prevent disability in patients on a progressive
the estimated number of patients who are diagnosed each year
trajectory,” Dr. Okuda says.
have remained relatively stable during the past few years,”
Dr. Okuda, members of the Radiologically Isolated Syndrome
says Darin T. Okuda, MD, Associate Professor of Neurology
Consortium (RISC), and colleagues at the University of Texas
Southwestern have formed a strategic research alliance with
at the University of Texas Southwestern. “So an important
question is: How many people do we think are unknowingly in
Biogen to investigate, in a separate study, whether treatment has
some early stage of the disease? Unless we screen the general
the potential to delay the emergence of symptoms in individuals with RIS. This year, the alliance will launch ARISE, the first
population, which is not currently feasible, or until we discover
novel methods of identifying these individuals, we don’t really
randomized, placebo-controlled trial in the U.S. to examine the
know the prevalence of undiagnosed disease. However, we
efficacy of dimethyl fumarate (Tecfidera, Biogen) in extending
can learn a great deal from MRI anomalies that are suggestive
the time to a first neurological symptom associated with CNS
of MS, and that are found incidentally during evaluations for
demyelination.13 According to Dr. Okuda, the trial, which will
symptoms unrelated to demyelinating disease.”
involve approximately 200 subjects who fulfill RIS criteria at
In 2009, Dr. Okuda and colleagues published findings from
more than 20 sites in the U.S., is not seeking a new indication
for the drug but rather the answer to scientific questions.
a study of 44 asymptomatic patients with abnormalities on
MRI (magnetic resonance imaging) that were discovered
Dimethyl fumarate received FDA approval in 2013 for the
treatment of patients with RRMS. In April 2015, noteworthy
incidentally when these patients underwent MRI evaluation
post-hoc analyses supporting its efficacy in specific types of
for conditions such as head injury or migraine.11 The paper
introduced the term radiologically isolated syndrome (RIS),
patients were presented at the annual meeting of the American
a presymptomatic category of MS, and presented formal criAcademy of Neurology (AAN).14,15
teria to improve diagnostic specificity and ensure accurate
classification.
Frontiers of MS Imaging
“RIS only applies to structural radiologic anomalies that are
MRI is an indispensable tool for monitoring MS, which until
highly typical for demyelinating plaques,” Dr. Okuda says.
now has largely involved tracking the presence of focal, demy“These lesions on imaging are not only of a specific size,
elinated white-matter lesions—widely recognized pathological
containing key morphological characteristics, but also are
hallmarks of the disease. However, experts have long been
located in specific areas within the central nervous system.
aware that current imaging techniques relay only a partial
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Researchers Expand Focus on Progressive Forms of Multiple Sclerosis
story: The number and volume of white-matter lesions do not
that are expected to accelerate lesion recovery. In 2015, this
correlate strongly with clinical manifestations of MS. An MRI
method of assessing treatment efficacy will be used for the
series may, for example, suggest extensive disease activity in a
first time in early-stage testing of guanabenz (see Research
Highlights below).
patient who reports relatively mild symptoms. This imperfect
correlation, known in the field as the clinical/
“If successful, our new trial design will allow
radiological paradox, is a persistent source of
the early testing of agents that might protect
frustration for clinicians and patients.
brain tissue, or promote its repair, to be conducted more quickly and with fewer patients,
The degree to which MRI can track the
compared with current paradigms,” Dr. Reich
efficacy of treatments is also limited, in part
because it is often impossible to distinguish
says. “This should allow the early testing of
between the efficacy of a drug and the spontamore agents at a lower cost, hopefully hastenneous remission of disease.
ing the day when such treatments will reach
our patients.”
As a result, a major goal in imaging is to identify previously uncaptured or poorly captured
processes in new regions of the brain and spinal
Current Clinical Challenges
cord that may provide relevant information
Despite a wide range of treatment options for
about disease activity. In 2014, progress toward
patients with RRMS, clinicians face significant
this goal was reflected in published reports of
challenges in their efforts to tailor use of these
Daniel Reich, MD, PhD
significant relationships between gray-matter
therapies to individuals. While experts agree
abnormalities and disability in RRMS16,17 and in
that early identification of the most effective
SPMS.18 More recently, researchers reported success in using
drug for each patient with MS is critical, pharmacogenetic
a novel technique to capture leptomeningeal inflammation in
information that might help guide treatment selection is lacking.
individuals with MS,19 a process previously detected during
Utilization management programs used by some insurers and
autopsies and biopsies but never before captured in vivo. Now
the need to observe risk-management strategies for many
on the road to being validated as a new, noninvasive marker of
medications also can complicate the decision-making process.
inflammation, imaging of this pathology may eventually be used
Lily Jung Henson, MD, a fellow of the American Academy
to test treatments designed to reduce this inflammation and
of Neurology and Chief of Neurology for the Piedmont Health
may point to a new avenue of investigation for progressive MS.
System in Atlanta, says that although natalizumab is widely
“This marker likely can be made more sensitive,” says Daniel
regarded as the most effective treatment for MS, it is not
Reich, MD, PhD, Chief of the Translational Neuroradiology
commonly used as first-line therapy for a variety of reasons.
Unit at NINDS and lead investigator of this study. “And further
“Natalizumab tends to be used as first-line therapy primarily
investigation may help us discover other similar and perhaps
in patients with very aggressive disease, in situations where
more useful markers. Once we find these, we
neurologists believe that if we don’t slow down
can ask questions about the disease such as:
the disease quickly, the patient may end up
When does meningeal inflammation start? How
having a lot of damage,” Dr. Jung Henson says.
does it accumulate over time? Does it respond
“For most newly diagnosed patients, we tend
to recommend either injectables or the orals.
to current therapies or potential new therapies,
and if so, can that help us better understand
The injectables make sense for patients who are
the clinical course of the disease? Perhaps
more conservative in terms of their willingness
most significantly, answers to these questions
to tolerate risks of adverse events. Patients can
may eventually improve our understanding of
be reluctant to begin taking some of the oral
progressive MS.”
drugs initially because they are relatively new,
Another critical goal in imaging is the estaband we are still gathering information about
lishment of clear and widely agreed-upon
their side effects. However, if a patient is very
definitions of response to treatment. Even for
needle-phobic, an oral medication may be a
well-established treatments, such as interferon
more reasonable choice.”
Lily Jung Henson, MD
therapy, experts continue to explore better
While Dr. Jung Henson and many of her U.S.
methods for separating responders from nonresponders during
colleagues generally support an efficacy ranking of current
clinical trials.20
treatments published this year by Ransohoff and colleagues,2
For newer categories of drugs, including tissue-protective
utilization management or “step therapy” programs developed
and putative remyelinating agents, there has been an absence
by insurers frequently lead to delays in effective treatment. To
of sensitive markers for documenting efficacy. A further comaddress this problem, the American Academy of Neurology
plication is that most of these newer agents will be tested in
published a position statement in February 2015 that urges
appropriate access to treatment.22
patients concurrently receiving approved immunomodulatory
therapies; however, Dr. Reich and colleagues reported this year
“Not long ago,” Dr. Jung Henson says, “I wanted to prescribe
on a unique measure of lesion recovery that addresses this
natalizumab for a patient with very aggressive disease; however,
problem.21 The documentation of changes to individual lesions
her insurer insisted that we try an injectable and an oral agent
over time, these researchers demonstrated, can be used as a
first. I wasted about three months watching her go downhill while
powerful outcome measure in proof-of-concept trials for agents
she failed therapy. Although I predicted that she would indeed
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Researchers Expand Focus on Progressive Forms of Multiple Sclerosis
Table 1 Emerging Treatments for Multiple Sclerosis
Agent
Manufacturer or sponsor
Description / Mechanism of Action
Indication
Name
of Trial
Status
Monoclonal antibody that modulates interleukin
2 signaling; given once monthly by SC injection
RRMS
DECIDE
BLA filed in
April 2015
Antibody that targets CD-20 and mediates
destruction of B cells; given by IV infusion
RRMS
OPERA
Phase 3
PPMS
ORATORIO
Phase 3
Orally administered sphingosine-1-phosphate
receptor binder that prevents lymphocytes
from exiting lymphatic tissue
SPMS
EXPAND
Phase 3
Masitinib
AB Science
Orally administered tyrosine kinase inhibitor that
targets mast cells and macrophages, important
cells for immunity, by inhibiting a limited number
of kinases
PPMS, SPMS
Anti-LINGO-1
Biogen
Monoclonal antibody (BIIB033) that significantly
improved recovery of optic nerve latency in
phase 2 RENEW study; given by IV infusion
RRMS, SPMS
SYNERGY
Phase 2; results
expected in 2016
Used to treat vascular disease; has immunomodulatory and neuroprotective properties;
administered orally
SPMS
MS–TAT
Phase 2
(phase 3 trial
planned)
Sphingosine 1-phosphate 1,5 receptor modulator
(new version of fingolimod); administered orally
RRMS
Monoclonal antibody against CD-20 protein on
B cells; administered orally
RRMS
CONCERTO
Phase 3
PPMS
ARPEGGIO
Phase 2
Zinbryta (daclizumab high-yield process)
Biogen/AbbVie
Ocrelizumab
Roche
Siponimod (BAF312)
Novartis
Simvastatin
Imperial College London (with funding
from Moulton Foundation and others)
RPC1063
Receptos, Inc.
Laquinimod
Teva
Phenytoin
NMSS, MSS, Novartis (unrestricted grant)
Used to treat epilepsy; blocks passage of sodium
into axons; administered orally
Guanabenz acetate
NINDS, MRF, University of Chicago
Protects myelin-producing oligodendrocytes to
reduce demyelination; administered orally
Phase 2b/3
Phase 3
Phase 2
RRMS
Phase 1
BLA = biologics license application; IV = intravenous; MRF = Myelin Repair Foundation; MSS = Multiple Sclerosis Society of Great Britain and Northern Ireland;
NMSS = National Multiple Sclerosis Society; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SC = subcutaneous;
SPMS = secondary progressive multiple sclerosis
Additional information available at ClinicalTrials.gov
fail, we had no choice but to follow this path. These situations
are frustrating and wrong—particularly when we know that
they may lead to irreversible damage. We can’t take a cookiecutter approach to treating patients, because disease activity
and severity and response to treatment often vary considerably.”
Dr. Jung Henson adds that clinicians also must consider
patient lifestyles, dosing preferences, and tolerance for risk
when making treatment decisions. Indeed, these important
factors have prompted considerable research geared toward
improving patient convenience23 and safety24 for currently
approved treatments.
Ascertaining a patient’s tolerance for risk is particularly
important because the most effective treatments for RRMS
tend to have less favorable risk–benefit ratios. For example,
natalizumab25 (and, in a handful of recent cases, two other MS
drugs26,27) have been associated with a risk for developing
progressive multifocal leukoencephalopathy, a rare but serious
brain infection. Other drugs associated with potentially serious
adverse events that require patient enrollment in risk evaluation
and mitigation strategy (REMS) programs include fingolimod
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(Gilenya, Novartis), which poses cardiovascular and other
risks;28 and alemtuzumab (Lemtrada, Genzyme), which poses
a range of risks associated with prolonged immunosuppression.29 As efforts to develop more tolerable agents for RRMS
continue, risk-management strategies for currently approved
drugs are expected to undergo further refinement.30
Research Highlights: New Uses for Old Drugs
A growing number of agents currently under investigation
for the treatment of MS (Table 1)— particularly for progressive forms of the disease—are drugs that have already been
approved for use in other therapeutic areas. In the past, new
indications for older drugs were frequently discovered by
chance, but researchers are now taking a more systematic
approach to repurposing drugs and to leveraging their wealth
of safety profile and post-marketing data.
Simvastatin, a well-known, relatively safe, and well-tolerated
cholesterol-lowering drug, for example, showed promise in
a phase 2 clinical trial for slowing the progression of MS.31
Phenytoin, commonly used to prevent epileptic seizures, is
Researchers Expand Focus on Progressive Forms of Multiple Sclerosis
undergoing testing as a neuroprotective drug and may be
useful in treating acute optic neuritis; results of a phase 2
randomized controlled trial were presented at the AAN annual
meeting in April 2015.32
More recently the Myelin Repair Foundation (MRF), in
collaboration with NINDS and researchers at the University
of Chicago, announced the launch of a phase 1 study of guanabenz, an FDA-approved drug used to treat high blood pressure.
Researchers funded by the MRF (which has since announced
its shutdown, although this is not expected to affect the ongoing
study) reported in March 2015 that guanabenz prevents the
loss of myelin and reduces symptoms of MS in animal models.33
Phase 1 clinical studies are assessing the safety and tolerability
of the drug at doses used to treat MS.
As will likely be the case in trials of other new neuro­
protective agents, patients participating in the phase 1 clinical trial of guanabenz will also be receiving an FDA-approved
anti-­inflammatory treatment for RRMS. Since many experts
believe that treatment of progressive MS ultimately will require
a mix of anti-inflammatory, regenerative, and neuroprotective
strategies,34 such trials may be seen as harbingers of a new
era of combination treatment.
“Combination therapies already are standard in the treatment of disorders such as cancer and HIV/AIDS,” says Tassie
Collins, PhD, Vice President of Translational Medicine at
the MRF, “but a combination treatment approach to MS has
not been possible until now. Ideally, this new generation of
MS drugs, which are designed to protect tissue or to restore
damaged tissue, will be coupled with approved drugs that
target the autoimmune response. Combination therapy makes
sense—it’s important not only to halt further damage, but also
to help damaged tissue heal.”
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