New Treatment Options for Neuromuscular Disorders

Educational Objectives

The goal of this program is to improve use of new treatment options for neuromuscular disorders. After hearing and assimilating this program, the clinician will be better able to:

1. Optimize use of ocrelizumab in management of MS.

Summary

Disability progression: multiple sclerosis (MS) has >25 disease-modifying therapies (DMTs), but there are still many unmet needs; phase 3 results for glatiramer acetate (GA Depot) monthly intramuscular injection showed reduction of annualized relapse rates by 30%; the open-label extension trial suggests ocrelizumab is effective in reducing relapses and new magnetic resonance imaging (MRI) lesions; efficacy in reducing disability progression was low; the only drug approved for primary progressive MS; no drug approved for nonactive secondary progressive MS; 16% to 20% of patients with MS had confirmed disability progression; causes — meningeal ectopic lymphoid follicles outside the brain may cause additional inflammation; poor remyelination in MS causes progressive axonal loss; aging is a major driver of progressive disability; progressive ectopic lymphoid follicles are associated with cortical gray matter demyelination and neuronal loss; meningeal inflammation and follicles are resistant to B-cell depletion

Paths after demyelination: chronic inactive lesions are associated with failure of remyelination, variable axonal loss, and gliosis; chronic active lesions have microglia and macrophages concentrated at the lesion border; some are iron enriched; ongoing demyelination can slowly enlarge; chronic active lesions do not enhance on clinical MRI; present in both relapsing and progressive MS and very specific to MS

Strategies: ibudilast, and example of antimicrobial macrophage strategy, is a nonselective phosphodiesterase inhibitor; the SPRINT MS trial on ibudilast showed reduction in brain atrophy rate vs placebo; no differences in clinical outcomes; no effect on serum NfL levels; improving inflammation is another approach

Early high efficacy therapy vs escalation therapy: autologous bone marrow transplantation is the most aggressive; National Multiple Sclerosis Society in 2020 recommended not to use it in people >50 yr of age, those with MS for a short period of time, and those with highly active MS despite effective DMT; benefits — large upfront cost but potential long-term cost savings; large upfront risk but potential long-term risk reduction (≈80% of patients no longer need DMT); a 2019 study compared stem cell transplant with DMT (mostly low efficacy); 70% to 80% of patients remained relapse-free without DMT at 4 or 5 yr; another study showed 65% were progression-free at 4 yr; less effective in patients with secondary progressive MS; risks — treatment-related mortality; most of the patients who die are >50 yr of age and have more disability; secondary autoimmune diseases in 5% to 10% patients; more severe autoimmune diseases with autoimmune thyroid disease

Bruton tyrosine kinase (BTK) inhibitor: BTK is important in the proliferation, maturation, and antigen presenting capability of B-cells and cytokine production; important in the cascade of activation of myeloid cells; BTK activation produces inflammatory cytokines like tumor necrosis factor-α, interleukin (IL)-β, and IL-6; may lead to further organ damage and activate T and B cells; data suggest BTK inhibition may skew microglia more toward M2 phenotype (more noninflammatory and may promote repair and growth); some bind covalently and irreversibly (eg, evobrutinib), and some bind noncovalently and are more reversible (eg, tirabrutinib); molecules are small and can cross the blood brain barrier (BBB) and enter the CNS; safety — phase 2 trials showed evobrutinib and tolebrutinib were safe; the higher dose evobrutinib group had more adverse effects, all asymptomatic elevated liver enzymes

Remyelination: failure of cortical remyelination correlates with greater cortical atrophy; some lesions that remyelinate protect the brain from neurodegeneration; ongoing inflammation in chronic active lesions and behind the BBB may prevent microglia-macrophage dysfunction with impaired myelin debris clearance; laying down of scar tissue formation (gliosis) prevents remyelination; decreased production of growth factors and metabolic disturbance with aging can affect remyelination; a study showed intermittent fasting and metformin can improve remyelination in aged mice

Readings

Barkhof F, Kappos L, Wolinsky JS, et al. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Neurology. 2019 Nov 5;93(19):e1778–e1786; Fox RJ, Coffey CS, Conwit R, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med. 2018 Aug 30;379(9):846–855; Georges GE, Cohen JA, Griffith LM, et al. Best available therapy versus autologous hematopoietic stem cell transplantation for multiple sclerosis. Biology of Blood and Marrow Transplantation. 2020 March;26(3):S297; Naismith RT, Bermel RA, Coffey CS, et al. Effects of Ibudilast on MRI measures in the phase 2 SPRINT-MS study. Neurology. 2021 Jan 26;96(4):e491–e500; Tasso B, Spallarossa A, Russo E, et al. The development of BTK inhibitors: A five-year update. Molecules. 2021 Dec; 26(23): 7411; Zhukovsky C, Sandgren S, Silfverberg T, et al. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing–remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2021 Feb;92(2):189–194.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Sy receives grant/research support from Novartis AG and Roche. Members of the planning committee reported nothing relevant to disclose. Dr. Sy's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Sy was recorded at Latest Updates on Neurology: 7th Annual Conference for Healthcare Professionals and Patients, held online on December 3, 2022, and presented by Cedars-Sinai Medical Center. For information on future CME activities from this presenter, please visit https://cedars.cloud-cme.com/neuroimmunologycme. Audio Digest thanks the speakers and Cedars Sinai Medical Center for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

NE140503

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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