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.