Topic 1:
Treatment of Autoimmune Disease: The Evolution of Immunotherapy in Multiple Sclerosis
Speaker: Prof David Hafler
Multiple
sclerosis is the most common neurologic disease of young adults. It has gone
from a non-treatable disease with no clear cause to a highly treatable
autoimmune disease where the underlying genetic architecture has been
elucidated. The first era began in 1993 with approval of IFN-β to treat
relapsing forms of MS followed by the development of glatiramer acetate, a random
co-polymer of four amino acids. In placebo controlled and double-blind clinical
trials of thousands subjects lasting two years all these agents produced
slightly more than 30% reduction in annual relapse rate and magnetic resonance imaging (MRI) disease
activity was reduced by a comparable or greater degree. A follow-up study 21
years after the first clinical trial of IFN-β showed a survival benefit for
those receiving active drug during the trial as compared with those given
placebo.
The second phase of MS therapeutic development came
with the approval of natalizumab and of fingolimod in 2009. Natalizumab a mAb
to α4 leukocyte arose from preclinical studies using the experimental autoimmune
encephalomyelitis model. Given by monthly intravenous infusion, natalizumab
exerted impressive inhibitory effects for inflammatory aspects of MS, with
>65% reduction in relapses during two years of treatment and >90%
suppression of new inflammatory MRI lesions. However, it became clear that in
patients who had been exposed to the JC virus, a proportion of patients
developed a rare, often-fatal opportunistic brain infection termed progressive
multifocal leukoencephalopathy (PML) prompting development of a biomarker,
measurement of JC virus ab that proved highly predictive for PML
susceptibility. Fingolimod, a pro-drug converted in vivo to a sphingosine
1-phosphate (S1P) analog, down-regulates type 1 S1P receptors on leukocytes and
endothelium, trapping naïve and central memory T lymphocytes in lymph nodes and
suppressing MS disease activity with 55-60% reduction of relapse rate and
reduction of MRI disease activity. Fingolimod lacks target specificity,
including those on vascular endothelium, arterial smooth muscle cells, atrial
myocytes, bronchial smooth muscle and central nervous system astrocytes and oligodendrocytes.
The third stage of MS therapeutic development involves
the oral immunomodulatory medication dimethylfumarate (DMF), which induces the
NRF2 transcription factor while blocking NFkB. Alemtuzumab or anti-CD52, a
leukocyte depleting monoclonal antibody was recently approved that has
comparable immunotherapeutic efficacy to Natalizumab, but is curiously
associated with significant induction of other autoimmune diseases. Perhaps
most remarkably, Ocrelizumab (CD20) has shown major efficacy in double-blinded,
controlled MS treatment trials, with lowering the MRI exacerbation rate to
almost zero in one year after infusions 6 months apart. In conclusion, MS
has gone from a non-treatable to a highly treatable disease. The major question
remains as to whether early treatment of relapsing remitting disease will
prevent entry into the more disabling secondary progressive disease.