Multiple Sclerosis (MS)


Many disease-modifying treatments have been approved by the US Food and Drug Administration (FDA) for multiple sclerosis (MS).1 Most of these medications are approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) but are not effective in treating the progressive forms of the disease.

Research is ongoing to develop new treatments that could benefit patients with progressive MS. The following article highlights current experimental therapies for multiple sclerosis.

Experimental Treatments for RRMS

Clemastine fumarate, an oral over-the-counter antihistamine, was tested to assess if it was able to promote remyelination by acting on oligodendrocytes.2 Results of a phase 2 clinical trial showed there was a 1.7-ms reduction per eye in P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. No serious adverse events were reported during the trial.3

Research has shown that the oral antibiotic minocycline may reduce the risk of transitioning from clinically isolated syndrome (CIS) to MS.4 A phase 3 clinical trial that aims to confirm the potential benefits of minocycline in MS is recruiting participants in Canada.5

Experimental Treatments for Progressive MS

Masitinib, simvastatin, ibudilast, and lipoic acid are currently being tested in clinical trials as potential therapies for progressive forms of MS.6    

Masitinib

Masitinib is an oral immunomodulator tested in phase 2 and 3 clinical trials as a potential treatment for primary progressive multiple sclerosis (PPMS) or relapse-free secondary progressive multiple sclerosis (SPMS).7 Masitinib inhibits the inflammatory process by acting on tyrosine kinases targeting mast cells and macrophages.

Results of a phase 2a trial showed that 32% of patients treated with masitinib responded to treatment, as measured by an improvement in Multiple Sclerosis Functional Composite Scores (MSFC) compared to baseline.8 The most common adverse events associated with masitinib treatment were asthenia, rash, nausea, edema, and diarrhea.

In a phase 2b/3 clinical trial, masitinib was shown to slow down disease progression as measured by change on the Expanded Disability Status Scale (EDSS). Moreover, masitinib treatment significantly reduced the risk of patients reaching a level of disability severe enough to require a wheelchair. These results were presented at the 8th Joint Meeting of the European (ECTRIMS) and American Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS).9

Simvastatin

Simvastatin is a cholesterol-lowering treatment used for the treatment of vascular disease.10 It is being tested in clinical trials as a potential treatment for progressive MS. It is thought that simvastatin has anti-inflammatory effects and may protect nerves from damage by interfering with the activation and entry of T lymphocytes into the central nervous system.11

Results of a phase 2 trial showed that simvastatin had a beneficial effect on brain atrophy and disability in people with SPMS.12 A follow-up study found a positive correlation between simvastatin treatment and improved frontal lobe function and patient-reported physical quality of life.13

A phase 2 trial is recruiting participants to test the ability of simvastatin to slow down disease progression in patients with SPMS.14 Another trial, in phase 3, is recruiting participants to test whether simvastatin can slow the rate of disability progression in patients with SPMS.15

Ibudilast

Ibudilast, a phosphodiesterase inhibitor thought to have neuroprotective effects, is emerging as a potential treatment for PPMS and SPMS.16 It works by suppressing IL-1β, TNF-α, and IL-6. Ibudilast may also have neuroprotective effects and reduce inflammation by acting on anti-inflammatory cytokines. 

A placebo-controlled phase 2 clinical trial tested the safety and efficacy of ibudilast in patients with PPMS and SPMS. It showed that patients who received ibudilast had a 48% reduction in brain atrophy compared with those who received placebo. Ibudilast was safe and well tolerated with adverse effects being nausea, diarrhea, abdominal pain, fatigue, and depression.16

Lipoic Acid

Lipoic acid is an oral antioxidant that could benefit patients with SPMS. It was shown to reduce inflammation and disability in experiments using animals with disease states similar to MS.17 

In clinical trials, lipoic acid decreased brain atrophy compared to placebo.18 A phase 2 clinical trial is currently recruiting participants for a 2-year study to determine whether daily oral lipoic acid can reduce brain injury and maintain mobility in patients with progressive MS.19

Stem Cell Therapies

There are also several clinical trials investigating the therapeutic potential of stem cells in MS. However, this approach is still in its infancy.20

References

  1. Medications. National Multiple Sclerosis Society. Accessed June 9, 2021.
  2. Clemastine fumarate. MS Society. Accessed June 9, 2021.
  3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489. doi:10.1016/S0140-6736(17)32346-2
  4. Metz LM, Li DKB, Traboulsee AL, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376(22):2122-2133. doi:10.1056/NEJMoa1608889
  5. Minocycline in MS: confirmation of benefit (MS). ClinicalTrials.gov. March 2, 2020. Accessed June 9, 2021.
  6. Treatments in development. MS Society. Accessed June 9, 2021.
  7. Masitinib. MS Society. Accessed June 9, 2021.
  8. Vermersch P, Benrabah R, Schmidt N, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. Published online June 12, 2012. doi:10.1186/1471-2377-12-36
  9. Vermersch P, Hermine O. FC04.01 – Masitinib in primary progressive (PPMS) and non-active secondary progressive (nSPMS) multiple sclerosis: Results from phase 3 study AB07002. 8th Joint ACTRIMS/ECTRIMS Meeting, September 11-12, 2020.
  10. Simvastatin. MedlinePlus. Accessed June 9, 2021.
  11. Simvastatin. MS Society. Accessed June 9, 2021.
  12. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383(9936):2213-2221. doi:10.1016/S0140-6736(13)62242-4
  13. Chan D, Binks S, Nicholas JM, et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol. 2017;16(8):591-600. doi:10.1016/S1474-4422(17)30113-8
  14. Simvastatin in secondary progressive multiple sclerosis (MS-OPT). ClinicalTrials.gov. March 29, 2019. Updated March 30, 2020. Accessed June 9, 2021.
  15. Multiple sclerosis-simvastatin trial 2 (MS-STAT2). ClinicalTrials.gov. January 2, 2018. Updated October 18, 2018. Accessed June 9, 2021.
  16. Ibudilast. MS Connect. Accessed June 9, 2021.
  17. Lipoic acid. MS Society. Accessed June 9, 2021.
  18. Spain R, Powers K, Murchison C, et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e374. doi:10.1212/NXI.0000000000000374
  19. Lipoic acid for progressive multiple sclerosis (MS) (LAPMS). ClinicalTrials.gov. May 9, 2017. Updated April 12, 2021. Accessed June 9, 2021.
  20. Cuascut FX, Hutton GJ. Stem cell-based therapies for multiple sclerosis: current perspectives. Biomedicines. 2019;7(2):26. doi:10.3390/biomedicines7020026

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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