Canadian researchers have proposed six criteria that must be met for a disease-modifying therapy (DMT) to be effective in progressive multiple sclerosis (Yong & Yong. Nat Rev Neurol 2022;18:40-55). Over a dozen DMTs are currently available but they generally have limited effectiveness in slowing the neurodegeneration that underlies disability progression.
The authors stated that current or emerging therapies must meet several criteria to reduce the burden of disability in PMS. The criteria are:
1. Cross the blood-brain barrier (BBB). Candidates need to be small, lipophilic molecules to cross the BBB, which is relatively intact in PMS. Examples are teriflunomide and S1P receptor modulators (fingolimod, siponimod, ozanimod, ponesimod). Dimethyl fumarate may meet this criterion although its metabolite, monomethyl fumarate, is less lipophilic and less readily crosses the BBB. Cladribine is a small molecule that penetrates the CNS but may have little therapeutic effect in the CNS due to the brief period of drug exposure with intermittent dosing. Monoclonal antibodies (e.g. natalizumab, anti-CD20s, alemtuzumab) do not readily cross the BBB.
2. Neutralize compartmentalized lymphocytes. An effective treatment must be effective against compartmentalized inflammation to limit the direct and indirect cytotoxic effects of immune cells in the CNS. These effects comprise diffuse inflammation largely mediated by T cells, as well as T and B cell activity aggregated in meningeal follicle-like structures, which induce cortical damage through antibody deposition and the release of soluble factors. Most DMTs deplete lymphocytes in the CNS by various mechanisms, such as depletion of peripheral lymphocytes (e.g. anti-CD20s, alemtuzumab), lymphocyte sequestration (S1PR modulators) or by blocking migration across the BBB (natalizumab). The sole exception is glatiramer acetate, which does not substantially reduce lymphocytes.
3. Antagonize microglia. A key target in PMS is activated microglia, which can be pro-inflammatory, produce neurotoxic enzymes (e.g. proteases, matrix metalloproteinases) and promote oxidative stress. Most of the current DMTs have not demonstrated an effect on microglia. To date, only siponimod and cladribine have shown a beneficial effect on microglial activation in animal studies (Gentile et al. J Neuroinflammation 2016;13:207. Singh et al. J Neuroimmune Pharmacol 2012;7:939–950).
4. Ablate free radical stress and mitochondrial injury. Oxidative stress is more pronounced in PMS compared to other neurodegenerative diseases (Fischer et al. Brain 2013;136:1799-1815) and contributes to mitochondrial dysfunction and axonal degeneration (Dutta et al. Ann Neurol 2006;59:478-489). S1PR modulators have been shown to reduce oxidative stress and protect mitochondria in preclinical studies (Ward et al. JCI Insight 2020;5:e132522). Dimethyl fumarate has been shown to preserve axons by stabilizing the Nrf2 antioxidant pathway in one animal study (Linker et al. Brain 2011;134:678-692).
5. Promote remyelination. The authors note that an attainable goal is to rescue demyelinated axons before neurodegeneration occurs. This could involve the stimulation of oligodendrocyte precursor cells to differentiate and proliferate and/or the neutralization of the inhibitory microenvironment. To date, only one animal study has shown that siponimod induces remyelination via the S1P5 receptor (Mannioui et al. Mult Scler 2018;24:1421-1432).
6. Exert direct neuroprotective effects. The combined effect of CNS inflammation, oxidative stress and mitochondrial dysfunction leads to neuroaxonal loss, as evidenced by MRI measures of brain atrophy. Phase III trials have demonstrated a reduction in brain atrophy with the S1PR modulators fingolimod, siponimod, ozanimod and ponesimod (FREEDOMS, EXPAND, RADIANCE and OPTIMUM trials, respectively), although only siponimod has been shown to slow disability progression in PMS. While some monoclonal antibodies (e.g. natalizumab) have demonstrated a reduction in brain atrophy, this does not appear to be a direct neuroprotective effect due to limited migration of MAbs across the BBB (Alvarez et al. Mult Scler Relat Disord 2021;55:103170).
The authors concluded that siponimod is the only DMT currently available that meets all six criteria for effectiveness in PMS; clinical efficacy in SPMS was shown in the EXPAND trial (Kappos et al. Lancet 2018;391:1263-1273). They further speculated that a more profound reduction in physical or cognitive worsening might be achieved if siponimod were employed earlier in the disease course.
Applying these criteria to treatments in development, the most promising were metformin and statins, which met all six criteria. The combination of metformin and clemastine is currently being evaluated as add-on therapy in the phase II CCMR Two study; the primary endpoint is change in visual evoked potentials. A single-site phase I trial in PMS was recently announced. High-dose simvastatin reduced brain atrophy in the phase II MS-STAT study of SPMS (Chataway et al. Lancet 2014;383:2213-2221). However, a recent study found no effect of simvastatin on serum neurofilaments, suggesting the drug’s effect on atrophy is not due to a reduction in neuroaxonal injury (Williams et al. Neurol Neuroimmunol Neuroinflamm 2022;9:e1130).
The authors further noted that Bruton’s tyrosine kinase (BTK) inhibitors meet five of the six criteria. It is unclear at present if they will have direct neuroprotective effects. At least three BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib) are in late-phase testing for MS (the phase III EVOLUTION RMS, GEMINI 1 and FENtrepid trials, respectively).