Best Practices
The Multiple Sclerosis Centers of Excellence: A Model of Excellence in the VA
The MS Centers of Excellence at the VA improves the consistency and quality of care for veterans with MS.
Therapies in Development
DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.20 Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.
Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.21 It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.22 It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.23 A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.24 A follow-up multicenter trial is ongoing.
Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.25 Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.26
Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.27 A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.28 Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.29 A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.30 These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.
Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.31,32
Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.33 Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.34 A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.
Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.35 In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.36 A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.