As the most common non-traumatic cause of disability in young people in the industrialized world, multiple sclerosis affects more than 2.5 million people globally. Those who suffer with the disease are categorized into two types of multiple sclerosis patients: those with relapsing-remitting multiple sclerosis (RRMS) make up the majority of patients (~85%) and those with progressive multiple sclerosis can be further subcategorized into primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS). The disease state of approximately 80% of RRMS patients will transition into SPMS.
A variety of risk factors are associated with developing one of the forms of multiple sclerosis. According to “Risk Factors Associated with the Onset of Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Systematic Review,” which was published in BioMed Research International, more risk factor-related research has been conducted for RRMS than for PPMS. Findings show that although Epstein-Barr virus (EBV) exposure is highly associated with developing RRMS, an association with PPMS is much less clear. Higher titers of EBV exist in RRMS patients than in PPMS, and some SPMS patients also display high EBV titers. Other viruses, such as human herpesvirus-6 (HHV-6), have also been studied as risk factors, but there seems to be no difference among patients and healthy controls. Other risk factors such as Chlamydia pneumonia infection, antibiotic exposure, oral contraceptive use, and smoking status show an insignificant relationship with developing multiple sclerosis, but it is noted that progressive multiple sclerosis typically presents later in life.
Despite the large population of individuals with either PPMS or SPMS, there are no drug therapies approved by the FDA specifically to treat these patients. Instead, some patients are prescribed treatments indicated for RRMS, while others (such as in Australia and New Zealand) must cope with the disease without treatment. According to “Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis,” which was published in PLOS One, barriers to developing treatments for progressive multiple sclerosis include incomplete understanding of the complex disease, a lack of predictive value in animal models, declining resources and increasing costs for clinical trials, and a lack of established clinical trial methodologies.
Certainly the lack is not a function of neglect. “As a person living with SPMS and leaders in the multiple sclerosis patient advocacy community, we are familiar with the hopes and frustrations of people living with progressive multiple sclerosis,” wrote the authors of “Overcoming Barriers in Progressive Multiple Sclerosis Research,” an article published in the journal The Lancet Neurology. “An urgent need exists to solve the challenges of progressive multiple sclerosis. Only the collective engagement of people living with the disease, researchers, patient advocates, medical professionals, funders, governments, and industry can address the collective frustration felt by all stakeholders and offer the confidence that we will soon see a transformation in the treatment and care of people with progressive multiple sclerosis.”
To fix the disparity in treatment and avoid some of the barriers to successful drug development, some research groups are investigating the efficacy of repurposed oral neuroprotective drugs to treat progressive multiple sclerosis. This strategy of drug development accelerates the drug discovery and testing process. There are at least 52 drug candidates that have been identified for rescue and repurpose trials in SPMS. Seven of these were considered by the authors of “Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis” to be promising for further clinical evaluation.
To highlight a few of these treatments, ibudilast, a treatment for asthma sold in Japan and South Korea, may help SPMS patients due to its attenuation of pro-inflammatory signals and promotion of neuroprotective signals. Riluzole, which is sold as Rilutek from Covis Pharmaceuticals for amyotrophic lateral sclerosis, may benefit SPMS patients by reducing glutamate release and antagonizing voltage dependent sodium channels. Amiloride, a diruetic and acid sensing ion channel blocker, has myelo- and neuroprotective effects. Fluoxetine, an anti-depression medication from Edgemont Pharmaceuticals, stimulates production of brain-derived neurotrophic factor and improves axonal energy metabolism.
Yet there is no lack of “normal” clinical trials testing new compounds in patients with progressive multiple sclerosis. As reported by “Treatment of Progressive Multiple Sclerosis: What Works, What Does Not, and What Is Needed,” which was published with two other articles in a series in The Lancet Neurology, the goal of many of these trials is to manage and minimize symptoms and improve function, as trials with intentions to modify the disease often times fail in the case of progressive multiple sclerosis. These trials are necessary because without proper treatment, progressive multiple sclerosis patients must cope with debilitating symptoms. As many as 90% of patients experience spasticity, and approximately 80% of patients experience mobility impairment, ataxia, fatigue, balance impairment, bladder dysfunction, pain, and cognitive dysfunction.
A wide variety Phase 2 and 3 clinical trials are identified in “Clinical Trials in Progressive Multiple Sclerosis: Lessons Learned and Future Perspectives,” which was published in The Lancet Neurology article series. Some trials focus solely on one of the two forms of progressive multiple sclerosis, while others focus on either form and also include RRMS.
Innate’s Experimental SPMS Therapy Progressing Through Clinical Trials in Australia
One treatment actively being studied in patients with SPMS is MIS416, from Innate Immunotherapeutics. MIS416, a novel immune modulator, which was first tested by patients with SPMS under compassionate use and is currently in Phase 2B clinical trials with 90 SPMS patients in Australia and New Zealand to test safety and efficacy of treatment. Earlier trial results identify benefits of treatment for SPMS patients. At the conclusion of the Phase 2A trial for MIS416, 80% of SPMS patients had at least a 30% improvement of clinical status in at least one measure of multiple sclerosis.
MIS416 is derived from gram-positive, LPS-negative P. acnes bacteria. It displays two ligands to inflammatory cells and leads to an increase in anti-inflammatory mediators and a decrease in inflammatory mediators. Compared to baseline, patients showed an increase in plasma levels of vascular endothelial factor, erythropoietin, insulin growth factor-1, and hepatocyte growth factor.
At this point in time, “Steady progress is being made enrolling patients into the Company’s Phase 2B safety and efficacy trial of MIS416 in patients suffering from SPMS,” indicated an update from Innate Immunotherapeutics. Results for the Phase 2B trial are expected in 2016.
“Making such clinical trials available in Australia is particularly exciting and provides Australians with multiple sclerosis with early access to promising new treatments,” wrote Dr. Matthew Miles, Chief Executive Officer of Multiple Sclerosis Research Australia, in a letter of support for Innate’s clinical trials. “This is an area of unmet need for people with multiple sclerosis world-wide.”
With therapies such as MIS416 under evaluation to treat SPMS, the future is bright for progressive multiple sclerosis patients. “Momentum is gathering apace, but perseverance, focus, and funding will be needed to ensure that this initiative is successful,” noted Dr. Alan J. Thompson, author of “A Much-needed Focus on Progression in Multiple Sclerosis,” published in The Lancet Neurology article series.
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