Therapeutic Strategies for Treating Adults With Relapsing-Remitting MS: Highlights From AAN 2023

The 75th Annual Meeting of the American Academy of Neurology (AAN) convened from April 22 to April 27, 2023, in Boston, Massachusetts. The meeting featured presentations of cutting-edge research that extends the boundaries of current therapies and explores new avenues for the diagnosis and treatment of MS. Advances in disease-modifying therapies (DMTs) have led to new MS treatment strategies, as well as better diagnostic and prognostic indicators. In this article, Dean M. Wingerchuk, MD, director of the Mayo Clinic Division of Multiple Sclerosis and Autoimmune Neurology in Scottsdale, Arizona, provides insights into advancements for the treatment of MS and explains several ways in which treatment approaches are expanding.

An entire afternoon session at this year’s AAN meeting was devoted to current investigations of biomarkers for MS outcomes, such as serum neurofilament light chain (sNfL), cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP), and telomere length. How effective are these biomarkers for predicting outcomes, and what are the limitations of these approaches? How might the use of these biomarkers influence treatment decisions?

In clinical practice, MS disease activity is currently assessed via clinical examination and MRI-based detection of new and active lesions. Conventional MRI approaches assess inflammatory activity, but there is considerable interest in biomarkers that reflect neuroaxonal injury, particularly if those biomarkers are easy to access and can serve as prognostic indicators of future disease activity, course, and clinical outcomes. The current leading candidate is sNfL — increases in its serum and CSF levels have been associated with relapses, lesion activity on MRI, and brain atrophy.
 
Research presented at the 2023 AAN meeting extended published observations regarding the utility of sNfL. Satyanarayan and colleagues presented data showing that sNfL measurement early in relapsing-remitting MS was associated with worsening disability, measured by Expanded Disability Status Scale (EDSS) scores after controlling for clinical and MRI disease activity; this suggests that sNfL could be used to identify patients at risk for disability progression, independent of activity in early stages of disease.¹ If the findings are validated, sNfL measurements may be useful in early therapeutic decisions. Silverman and colleagues showed that menopause was associated with an increase in sNfL and a decline in function, measured by MS Functional Composite scores.² Thus, sNfL may contribute insights regarding endogenous and external factors that influence the course of MS. However, sNfL currently has limited utility as an actionable biomarker for routine clinical practice. Extensive work is needed to determine its prognostic value, including efforts to control for or consider other variables that influence sNfL levels (eg, neurological and non-neurological comorbidities).
 
The astrocytic cytoskeletal protein GFAP, which can be measured in CSF and serum, has been associated with MS activity and progression. Meier et al found that, compared with serum sNfL, serum GFAP had a stronger association with what they regarded as “pure progression” (ie, no evidence of disease activity or inflammation); this finding suggests that serum GFAP is a more specific marker for MS progression.³ In a study of 60 patients with MS, Thebault and colleagues assessed the prognostic value of paired serum and CSF samples of both neurofilament light chain and GFAP; they reported that age-adjusted sNfL and CSF GFAP were the strongest predictors of disease progression.⁴ Piedrabuena and colleagues showed that leukocyte telomere length, a marker of aging, was associated with disability and brain lesion volume in people with MS aged 50 years or older, but not in people with MS aged 18 to 35 years; their findings raise questions about how researchers might explain the effects of aging in people with progressive MS.⁵ These studies demonstrate the potential for additional biomarkers beyond sNfL; they also indicate the enhanced predictive value that may arise from models comprising combinations of biomarkers focused on different aspects of disease pathology. For eventual use in routine practice, serum testing will be feasible, but CSF testing will not. Accordingly, additional correlative studies involving clinical components, MRI examinations, and serum and CSF biomarkers are expected; there is hope that the data will converge toward a validated set of accessible predictive and therapeutic biomarkers.

A retrospective analysis conducted using the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network revealed a significantly greater degree of disability in Latinx people with MS compared with White people.⁶ What are the implications of this finding for the diagnosis and treatment of people in the Latinx community?

There is increasing interest in understanding the natural history of MS and responses to MS treatment in non-White people. This reasonably large study showed that, compared with White people who had MS, Latinx people with MS displayed greater physical disability and worse cognitive function despite their younger age and shorter clinical disease duration. Additionally, MRI markers, such as lesion burden and deep and cortical gray matter atrophy, were more advanced in the Latinx group.⁶ These results are similar to findings in studies of African American people with MS.⁷ As the science of clinical course prediction evolves, awareness of distinct disease features in specific groups of patients (eg, patients with non-White backgrounds) may facilitate early DMT decisions, surveillance strategies, and the development of clinical trials that address the needs of these patients.

A study of various MRI protocols in people with RIS revealed new evidence concerning progression to a diagnosis of MS.⁸ Does this new evidence suggest that diagnoses of MS can be made earlier? What influence might this knowledge have on MRI-based management strategies in early disease?

A diagnosis of RIS relies entirely on the interpretation of MRI abnormalities and requires the absence of clinical events suggestive of MS. Variables associated with future MS development include MRI findings such as higher T2 lesion load and the presence of cortical or juxtacortical lesions.⁹ Novel MRI biomarkers could further enhance this predictive value. Oh et al reported that paramagnetic rim lesions, which indicate chronic active demyelination, were the strongest predictor of future MS development over a median follow-up period of 6.3 years.⁸ This important early observation suggests that, by identifying imaging patterns associated with immunopathological findings in people with confirmed clinical MS, prognostic ability at the time of RIS detection can be enhanced; this new knowledge could enrich clinical trials, inform MRI and clinical surveillance strategies, and eventually enable confident decisions regarding early preclinical DMT.

Research presented in poster sessions was focused on the identification of MS subtypes. The CLIMB study specifically analyzed patterns of transition between phenotypes.¹⁰ What are researchers learning about these transitions overall, and how does that knowledge contribute to clinical management? What do the findings of these studies suggest about the current understanding of MS phenotypes?

Although the current classification of MS disease course as relapsing or progressive is clinically useful, it does not reflect the notion that biological processes underlying clinical progression are active from an early stage of disease in many patients, and further studies are required; there is also a need for further exploration of transitions from a relapsing phenotype to a progressive phenotype. Bose et al reported the results of a retrospective study in which patients were followed up for more than 10 years after diagnosis to determine whether they displayed a relapsing-remitting phenotype or a progressive phenotype. Among the nearly 17% of patients who transitioned to secondary progressive MS (SPMS) during follow-up, most (58.9%) progressed to non-relapsing SPMS (nrSPMS); the remaining 41%, who displayed active SPMS (aSPMS), were younger and more likely to have a history of DMT escalation.¹⁰ These results suggest that it is possible to define and identify distinct groups of patients with different prognoses and responses to current therapies. These definitions may also provide opportunities to validate biomarkers that predict disease progression independent of inflammatory activity.

The potential long-term benefits and effects of anti-CD20 therapies continue to be investigated. Can you discuss any interesting new data that were presented this year regarding drugs such as ocrelizumab and ofatumumab?

Studies continue to demonstrate the sustained long-term effectiveness of anti-CD20 therapies. Subgroup follow-up analyses of ocrelizumab for patients with early relapsing MS, who had been enrolled in the OPERA studies (ClinicalTrials.gov identifiers: NCT01412333 and NCT01247324), demonstrated significant and sustained benefit in extension studies with a duration of more than 9 years, showing that fewer patients reached early disability milestones.¹¹ Ofatumumab extension studies showed a sustained benefit in terms of minimizing disease activity and enabling most patients to remain progression-free; better outcomes were achieved in patients who had begun treatment earlier.¹² Questions remain regarding specific mechanisms of long-term benefits and effects on relapse-independent disease progression, as well as treatment duration and safety.

Updates on clinical trials of the BTK inhibitor drugs evobrutinib, tolebrutinib, and remibrutinib were presented at AAN 2023.^13-15 What are the particular benefits and risks of this class of drugs, and what roles might they play in future treatment protocols for MS?

BTK inhibitors influence B cell receptor and Fc receptor signaling. Oral BTK inhibitors have demonstrated efficacy in the treatment of relapsing MS. Unlike current DMTs, which reduce MS activity through peripheral mechanisms, some BTK inhibitor drugs cross the blood-brain barrier and could influence the chronic compartmentalized central nervous system inflammation that may underlie disease progression.^13-17 Therefore, BTK inhibitors have potential uses in the treatment of both relapsing and progressive forms of MS.

This Q&A was edited for clarity and length.

References

1. Satyanarayan S, Sand IK, Sumowski J. Serum neurofilament light chain association with progression independent of activity in people with early RRMS. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S9.005.
 
2. Silverman H, Bostrom A, Lazar A, et al. Accelerated worsening in serum neurofilament light chain levels and multiple sclerosis functional composite in women with MS after menopause. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S9.009.
 
3. Meier S, Benkert P, Maceski AM, et al. Serum glial fibrillary acidic protein compared with neurofilament light chain as biomarker for multiple sclerosis disease progression.
Poster presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Poster P5.3-016.
 
4. Thebault S, Fereshtehnejad SM, Bergman H, Bose G, Freedman M. Serum neurofilament light chain (NfL) and CSF glial fibrillary acidic protein (GFAP) together improve the prediction of long-term clinical outcomes in multiple sclerosis. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S9.001.
 
5. Piedrabuena M, Correale J, Farez M, Fiol M, Marrodan M, Ysrraelit C. Telomere length as a biomarker in multiple sclerosis. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S9.002.
 
6. Ontaneda D, McGinley M, Harvey T, et al. Latinx with multiple sclerosis have greater disability and loss of deep and cortical gray matter. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S31.003.
 
7. Gray-Roncal K, Fitzgerald KC, Ryerson LZ, et al. Association of disease severity and socioeconomic status in Black and White Americans with multiple sclerosis. Neurology. 2021;97(9):e881-e889. doi:10.1212/WNL.0000000000012362
 
8. Oh J, Lim T, Suthiphosuwan S, et al. Paramagnetic rim lesions predict the development of clinical MS in radiologically isolated syndrome: results from a prospective cohort study. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S27.003.
 
9. De Stefano N, Giorgio A, Tintoré M, et al; MAGNIMS study group. Radiologically isolated syndrome or subclinical multiple sclerosis: MAGNIMS consensus recommendations. Mult Scler. 2018;24(2):214-221. doi:10.1177/1352458517717808
 
10. Bose G, Greene N, Healy BC, et al. Patterns and predictors of multiple sclerosis phenotype transitions: a longitudinal analysis using the CLIMB study. Poster presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Poster P5.3-018.
 
11. Cerqueira J, Berthele A, Cree B, et al. Long-term treatment with first-line ocrelizumab in patients with early RMS: 9-year OPERA subgroup analysis. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S46.002.
 
12. Cohen J, Hauser S, Zielman R, et al. Effect of longer-term ofatumumab treatment on disability progression and brain volume change. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S16.009.
 
13. Montalban X, Wolinsky JS, Arnold DL, et al. Efficacy and safety of the Bruton’s tyrosine kinase inhibitor evobrutinib for relapsing multiple sclerosis over 3.5 years of treatment: an ongoing phase II open-label extension. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S16.008.
 
14. Oh J, Syed S, Li T, Salloum N, Turner TJ, Fox RJ. Safety and clinical efficacy outcomes from the long-term extension study of tolebrutinib in participants with relapsing multiple sclerosis: 2.5-year results. Abstract presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Abstract S16.010.
 
15. Kieseier B, Cenni B, Pulz R, Angst D, Eichlisberger D, Ziehn M. Remibrutinib, a novel Bruton’s tyrosine kinase inhibitor, exhibits improved target selectivity and potency in vitro. Poster presented at: 2023 American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA. Poster P8.3-003.
 
16. Baskaran AB, Grebenciucova E, Shoemaker T, Graham EL. Current updates on the diagnosis and management of multiple sclerosis for the general neurologist. J Clin Neurol. 2023;19(3):217-229. doi:10.3988/jcn.2022.0208
 
17. Zuroff LR, Benjamins JA, Bar-Or A, Lisak RP. Inflammatory mechanisms underlying cortical injury in progressive multiple sclerosis. Neuroimmunol Neuroinflamm. 2021; 8:111. doi:10.20517/2347-8659.2020.35

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