Butzkueven_subbed.qxp 9/1/09 12:22 pm Page 7
Challenges Facing Future Multiple Sclerosis Clinical Trials
usually conducted at more than 100 multinational trial sites, and rather than the exception,
31
the selection of this CNS pathway may
typically recruit in excess of 1,000 patients. initially seem counterintuitive. However, retrobulbar lesions of the optic
nerve, such as optic neuritis, cause anterograde axonal (Wallerian)
Unfortunately, immunomodulatory and immunosuppressive agents have degeneration and, subsequently, also retrograde axonal degeneration,
generally not been successful in progressive forms of MS, and the list of the latter detectable in the retina. The first potential biomarker tool is
failed agents in this disease type now includes glatiramer acetate,
11
IFN-β,
12
once again MRI, because Wallerian degeneration results in optic nerve
alemtuzumab,
13
and rituximab.
14
Pulsed intravenous mitoxantrone
1
and atrophy measurable by optic nerve MRI,
32
and both diffusion tensor
cyclophosphamide
15
are of limited benefit in secondary progressive MS, imaging and magnetization transfer imaging have been shown to
particularly in younger patients with high relapse activity and rapid accurately measure axonal loss in the optic nerve.
33,34
MRI is unique in that
progression. However, and perhaps surprisingly, a lack of new potential it allows assessment of the distribution and extent of acute inflammation
therapeutic candidates is not the major impediment to future trials in and, in consequence, provides the possibility of interrogating injured
progressive MS. The last decade has witnessed a great expansion in our axonal tracts distal or proximal to the inflammatory lesion.
knowledge of MS neuropathology, and these studies have already
suggested a number of pathogenetic mechanisms in progressive MS that The second promising technique involves measurement of the retinal
could potentially represent therapeutic targets. First, slowly progressive nerve fibre layer (RNFL) thickness. The RNFL is the innermost layer of the
axonal injury, within both acute
16
and chronic
17
lesions, but also in the non- retina and consists of unmyelinated axons. The development of ocular
lesional white matter,
18
has been highlighted as the likely pathogenetic coherence tomography (OCT) to quantitate RNFL thickness has provided
mechanism for progressive MS. Second, increasing evidence points to the an ideal opportunity to study retrograde axonal degeneration,
innate immune system, namely microglial cells and macrophages, as independent of demyelination, in a discrete CNS structure.
35
Loss of RNFL
effectors of ongoing axonal injury, particularly in non-lesional white thickness is seen in MS patients with optic neuritis (25–33% loss
matter.
18,19
Third, we have begun to understand barriers to remyelination compared with healthy individuals), and the RNFL of the clinically
in longstanding MS. Although remyelination capacity generally decreases unaffected fellow eye is also frequently thinned (5–20% compared with
with advancing age, as demonstrated in animal models,
20
lack of healthy controls).
36,37
Furthermore, RNFL thickness inversely correlates
remyelination in chronic lesions may be due not to exhaustion of the with visual outcome, and a modest correlation with clinical disability in
oligodendrocyte progenitor pool but to a block of the remyelination MS has also been demonstrated.
37
What remains unclear is whether
program in appropriately positioned oligodendrocytes within lesions.
21
changes in RNFL thickness more generally correlate with CNS axonal loss
over time in MS patients. As a result of these promising studies, OCT is
Juxtaposed to this increased knowledge of human MS neuropathology, already being implemented as a secondary outcome measure in several
the explosion of genetically altered mouse models in the last decade has phase II and III trials in RRMS, even though the change in the RNFL in MS
also led to a substantial increase in our knowledge of endogenous patients without optic neuritis is likely to be modest.
38
molecular mechanisms that exacerbate or ameliorate MS-like CNS injury
in animal models. Examples include the identification of major factors The third promising paraclincial assessment tool is assessment of
promoting maturation, survival, and myelination of oligodendrocytes, for multifocal visual evoked responses (mfVEP), a relatively new technique
example insulin-like growth factor-1,
22,23
neurotrophin-3,
23
and inhibition that involves topographic analysis of optic nerve function using
of LINGO,
24
modulators of innate immune cell activation such as measurements of amplitude and latency from locally derived VEP in
minocycline
25
and growth-arrest specific gene-6,
26
and factors limiting numerous small areas of the visual field. Recent studies suggest that
neuronal damage after CNS insults, for example erythropoietin
27
and mfVEP is more sensitive than conventional VEP in detecting decreased
leukemia inhibitory factor.
28,29
Therefore, we could logically proceed to amplitude (reflecting axonal loss) and increased latency (due to
test agents that might afford neuronal or axonal protection, anti- demyelination) after optic neuritis.
39
Interestingly, a recent publication
inflammatory agents directed against innate immune cells, and, possibly, established a strong relationship between mfVEP measures and RNFL
therapies promoting the elaboration of myelin in oligodendroglia. thickness after optic neuritis.
40
Further studies assessing change in mfVEP
measures over time and attempts to correlate these with cerebral axonal
Given the great therapeutic need and the size of the potential commercial loss and change in disability in MS patients are necessary to validate
market, why are these trials not proceeding? The major reason is the lack mfVEP measures as biomarkers of demyelination and axonal injury.
of validated biomarkers for axonal injury and remyelination.
30
Such
biomarkers would avoid the need to first test candidates in large phase III Detailed prospective studies serially assessing the change in mfVEP, OCT,
trials, allowing the design of efficient and relatively inexpensive phase II optic nerve volume, and optic nerve diffusion parameters after an
trial programs. In due course, this would then lead to judicious agent episode of optic neuritis have commenced. Assessment of the
selection for phase III trials focusing on clinical end-points, replicating the relationship of these paraclinical markers with each other will clarify the
well-established paradigm for RRMS trials. individual and composite role of these putative biomarkers in assessing
acute and chronic axonal degeneration and their utility in predicting
In order to develop a validated biomarker tracking axonal injury, current subsequent clinical outcomes.
interest is increasingly focusing on the optic nerve. In particular, several
groups around the world are prospectively studying multimodal It now seems likely that the first paraclinical evidence for
assessment of axonal injury outcomes in acute optic neuritis. Given that neuroprotection will emerge from a successfully conducted phase II trial
clinical recovery of vision after an episode of optic neuritis is the rule of an immunomodulatory therapy in which one or several of the above
FUTURE DIRECTIONS IN NEUROLOGY 7
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32