Monoclonal antibodies, chimeric molecules, and other immunomodulating drugs and novel approaches hold real promise for effectively treating multiple sclerosis.
There are a variety of emerging therapies for multiple sclerosis (MS) currently being evaluated in clinical trials. At the 2013 Annual Meeting of the Consortium of Multiple Sclerosis Centers, Mitzi Joi Williams, MD, a neurologist with the Multiple Sclerosis Center in Atlanta, Georgia, who has treated over 1,200 MS patients reviewed promising research and reported on her experiences using some of these therapies in a presentation titled, “Emerging Therapies: Implications for the Future.”
There are 12 FDA-approved therapies that the physician may consider for treatment of MS. A variety of antibodies are being studied in clinical trials. Alemtuzumab, an antibody against CD52, causes a general suppression of all lymphocytes, halting their migration, and effectively stalling them in the lymph nodes. In the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II) clinical trial, patients with refractory relapsing-remitting multiple sclerosis treated with alemtuzumab experienced a 42% reduction in relapses after two years. Side effects included increased infectious disease, low lymphocyte counts, and potential cardiac events. Additional studies are currently ongoing for examining alemtuzumab for the treatment of relapsing-remitting MS (RRMS).
Antibodies that more specifically target only the activated lymphocytes by binding to CD25 are also being examined. In the SELECTION phase II clinical trial, patients with RRMS treated with daclizumab, a monoclonal antibody that binds to the CD25 receptor protein, experienced a 59% reduction in relapse rate, a 54% reduction in disability, a 74% reduction in detectable T2 lesions, and an 84% reduction in detectable gadolinium-enhancing T1 lesions. Side effects again included increased infections, but also diarrhea and swelling of extremities among others.
A series of monoclonal antibodies all uniquely targeting CD20, which is primarily on B-cells, are also under investigation. Rituximab has been previously used as a chemotherapeutic agent for treating B-cell malignancies. In a 24-week phase II clinical trial, patients with RRMS who were treated with rituximab experienced a 56% reduction in annualized relapse rates, along with an impressive 91% reduction in MRI detectable gadolinium-enhancing lesions. A more humanized form of rituximab named ocrelizumab is now under investigation as well. Ocrelizumab has been previously examined for the treatment of rheumatoid arthritis, another autoimmune disease. Ofatumumab is yet another CD20 antibody that Williams mentioned is on the investigational horizon. All of these antibodies are associated with an increased risk for infections, but the benefits may outweigh the risks, according to Williams.
Other outstanding drug approaches include targeting of the sphingosine-1-phosphate pathway or inhibition of mast cells with masitinib. Williams expressed strong conviction for greater consideration in using vitamin D as an adjunct with MS therapies based on the “overwhelming evidence” in support of its myriad of positive effects on the immune system as related to MS.
Williams commented on how chronic cerebrospinal venous insufficiency (CCSVI) is one of the most hotly contentious topics for MS neurologists. Generally speaking, this is the theory that MS pathology arises in large part due to poor venous CNS exiting circulation, where angioplasty stenting figures prominently in procedural attempts to improve blood flow. Williams pointed out that CCSVI is not an explanation for the cause of MS parthenogenesis, but she stresses that we currently do not know whether there may be some therapeutic benefit to this approach and so, in her opinion, it is worthy of further investigation.
Because “we have nothing that repairs the damage,” MS ultimately remains largely an irreversible disease, according to Williams. However, she noted that stem cells hold great promise and newer therapies are being examined that target a negative myelination pathway involving LINGO-1, a signaling protein that is a negative regulator of myelination. Several inhibitors of the LINGO-1 pathway are currently in phase II clinical trials to attempt to stimulate remyelination.
Lastly, Williams stressed how it is most important to be vigilant in monitoring patients as we do not know the long-term effects for many of these relatively recently FDA-approved MS therapeutics. Consideration of non-neurological effects should be an active part of the therapy.