By Clinical Content Hub

Jacqueline T. Bernard, MD, FAAN
Oregon Health & Science University
Portland, Oregon

Although the American Academy of Neurology (AAN) conducted its 2021 Annual Meeting virtually from April 17 to April 22, the science was as rigorous as ever. The sessions presented exciting developments in the diagnosis and treatment of multiple sclerosis (MS) and related diseases.

Neurology Advisor asked Jacqueline T. Bernard, MD, FAAN, associate professor, quality chief, and clinical vice-chair of neurology in the School of Medicine at Oregon Health & Science University, and a presenter at the meeting, to share key takeaways from this meeting for clinicians who treat patients with MS and neuromyelitis optica spectrum disorders (NMOSDs).

Data on some of the newest therapies for MS were presented at the AAN 2021 Virtual Annual Meeting. How are these therapies looking?

A poster presented 5-year data from the phase 3 EXPAND core study (ClinicalTrials.gov Identifier: NCT01665144) that showed significant improvement in magnetic resonance imaging (MRI) parameters in patients who were switched from placebo to siponimod, both at the time of the switch and through the extension period.1
 
Brain-tissue atrophy remained low in the continuous siponimod group through the trial.  Brain atrophy recovered following treatment in patients switched from placebo to siponimod for the extension period, and complete suppression of cortical gray matter atrophy was maintained without any increase in T2-lesion volume within 12 months after starting treatment.
 
When the phase 3 EXPAND trial was designed, it was hoped it would show neurodegenerative benefit in patients with secondary progressive MS, for whom neurodegeneration might be a more significant concern. This study was able to demonstrate that siponimod is effective in suppressing inflammation and neurodegeneration.[DD1] 
 
In addition, a poster on ozanimod by Vermersch and colleagues described rapid onset of action.2 The RADIANCE study (ClinicalTrials.gov Identifier: NCT01628393) showed efficacy as early as week 8 after the start of therapy, which is pretty remarkable and much faster than we would have imagined.

Many presentations at this year’s AAN Annual Meeting examined developments in NMOSDs. How is this important to the management of MS?

I think it’s important to examine MS and NMOSDs together because, as clinicians, that’s where we all live. NMOSDs have had a lack of recognition and lack of treatment.

Now that we have the ability to clearly distinguish NMOSDs from MS on MRI, and we have a good existing treatment and potential new therapies, things have improved vastly for people with an NMOSD. We are also getting much closer to global agreement about imaging criteria, and we have many more choices and promising therapies for these patients than ever before.

What new information was presented on treatments for NMOSDs?

We’ve had good data for eculizumab, which is an already-approved treatment.3 A long-term study (ClinicalTrials.gov Identifier: NCT02003144) showed 192 weeks of being relapse free with eculizumab in patients who had experienced 1 or 2 relapses over the year before the study.3
Another poster showed a prediction model for response to eculizumab over a 20-year period compared with placebo. Treatment with eculizumab was associated with 3.9 fewer relapses, an additional 7.6 life-years and 14.1 relapse-free years, and 4.4 fewer years spent with long-term disability.4

At the same time, we see promising new options in satralizumab-mwge and inebilizumab.
A poster reviewing the SAkura studies (SAkuraSky, ClinicalTrials.gov Identifier: NCT02028884; and SAkuraStar, ClinicalTrials.gov Identifier: NCT02073279) showed good efficacy and safety with satralizumab-mwge in patients with concomitant autoimmune disease; these results were comparable to what was seen in the general study populations.5

Inebilizumab is the other drug in development that offers hope for patients with severe NMOSD. One of several posters from the N-MOmentum study group (ClinicalTrials.gov Identifier:
NCT02200770), led by Bruce Cree, MD, PhD, MAS, demonstrated the superiority of inebilizumab over placebo in preventing attacks; 87.7% of patients receiving inebilizumab remained free of attacks compared with 60.7% of patients receiving placebo.6

We have good global agreement about how we diagnose NMOSDs and good evidence that the treatments we have are safe and efficacious. We also have promising new treatments about to become available. It’s a hopeful time for those of us who treat NMOSDs, because we can do so much more for our patients.

When the phase 3 EXPAND trial was designed, it was hoped it would show neurodegenerative benefit in patients with secondary progressive MS, for whom neurodegeneration might be a more significant concern. This study was able to demonstrate that siponimod is effective in suppressing inflammation and neurodegeneration.

You’ve emphasized a unified approach to autoimmune disorders. Were there sessions this year that offered new information?

We’ve become sophisticated in our biomarker approaches to autoimmune disorders. In the AAN 2021 Annual Meeting course on autoimmune neurology, taught by Stacy L. Clardy, MD, PhD, FAAN, she looked at how far we’ve come. Autoimmune disorders aren’t just a swirling mass of antibodies and brain-on-fire any longer, because now we have more data and we’ve identified more synaptic, as well as nuclear and cytoplasmic, targets. Treatment principles for these diseases continue to expand, while becoming more specific. We now have a range of empiric first-line immunotherapies and experience in their management.
 
Every year, autoimmune neurology is one of the more popular courses at the AAN Annual Meeting, and every year the course gets better. Why am I talking about it? Because people who treat MS and NMOSDs are also those into whose hands these autoimmune cases are placed. From my standpoint, I think MS, NMOSDs, and autoimmune neurology are all conditions that we handle and have to be comfortable with. It’s especially important, in the time of the coronavirus disease 2019 (COVID-19) pandemic, to look at how we think about all these things.

Are there reliable biomarkers that might make a difference in MS?

A few abstracts at the AAN 2021 Annual Meeting explored the serum level of neurofilament light chain (NfL), which, I think, is going to be interesting because we all would like to have a crystal ball when it comes to MS. Kuhle et al reported in a poster that a high baseline serum level of NfL is directly associated with the likelihood of conversion to clinical MS within 2 years of a first demyelinating event, when measured by the 2005 revision of the McDonald Criteria.7
 
We know that early diagnosis and treatment correlate with better outcomes. Use of serum NfL level as a biomarker might become an important adjunct to help us determine in which patients we should start therapy early. NfL seems like it’s becoming an increasingly important part of our clinical dashboard for MS.

The COVID-19 pandemic had a major impact on the delivery of care for MS and caused great concern over the challenges of the overlap of MS and NMOSDs in the same patient. What information was presented at the AAN 2021 Annual Meeting that helped with clinical understanding of the implications?

The NYU Langone COVID-MS database collected information on MS patients who had COVID-19 and reviewed them by age, Expanded Disability Status Scale score, and disease-modifying treatment (DMT) at the time of their infection. Overall, mortality is 8% in this group; for them, vaccination is safe and important.8 These are real-world data that we need right now, when our patients ask whether they should change to another DMT or withhold DMT if they become infected with COVID-19. The authors show that the most significant variables are younger age, insurance status, and Hispanic ethnicity.
 
There were several posters from our colleagues representing registries in Italy, Germany, the United Kingdom, and Canada. I’m a member of the International Women in MS group, and many of these registries reported results at our meetings in real time. When the COVID-19 pandemic and subsequent lockdown started, we continued having our meetings virtually, sharing our data every other week. Doing so was critical because, as clinicians, we didn’t know what to do: Should we stop therapy for our patients or increase the interval between treatments? And, we didn’t know who was at highest risk of severe COVID-19.
 
We had no guidelines on how to manage DMT in our patients initially during the pandemic, so data coming from the NYU Langone registry on patients in New York and the international registries have been helpful. We saw firsthand how important it was to share these data. The NYU Langone registry, for instance, reported that we shouldn’t panic and switch or stop DMT; rather, we need to continue patients on their DMT and look at these other variables instead. We need data to guide us, and I’m appreciative that data were available to us.

Key Takeaways

  • There are new choices of therapy for MS. The most recent data on siponimod show that the drug is effective for longer and onset of action is fast (within 8 weeks of initiation).
  • MRI data have been helpful in distinguishing MS from other diseases, particularly NMOSDs. We are also getting much closer to global agreement about imaging criteria, and we have more, and more promising, therapies for patients with NMOSD than ever before. 
  • Identification of new biomarkers, such as serum NfL, helps predict disease patterns in a way that enhances the effectiveness of treatment and helps determine the best treatment choices for individual patients.
  • There is good global agreement about how we diagnose NMOSD and good evidence about the treatments we have. Eculizumab is safe and efficacious, and promising treatments — such as satralizumab and inebilizumab — are about to become available for clinical use. This is a hopeful time for clinicians who treat NMOSD because we can do much more for our patients now than we once could.
  • Extensive sharing of information between providers and reports from several registries have provided a global network of reliable information throughout the COVID-19 pandemic.

The Q&A was edited for clarity and length.

Disclosure

Jacqueline T. Bernard, MD, FAAN, reported affiliations with Alexion Pharmaceuticals Inc., Biogen, and Genentech, Inc.

References

1. Arnold DL, Kappos L, Vermersch P, et al. Long-term effect of siponimod on MRI outcomes in SPMS: analyses from the EXPAND study up to 5 years (2217). Neurology. 2021;96(15 Suppl). Abstract 2217.

2. Vermersch P, Arnold DL, Cohen J, et al. Onset of action of ozanimod for MRI outcomes in patients with relapsing multiple sclerosis (4265). Neurology. 2021;96(15 Suppl). Abstract 4265.

3. Pittock S, Fujihara K, Palace J, et al. Long-term efficacy and safety of eculizumab monotherapy in AQP4+ neuromyelitis optica spectrum disorder (1578). Neurology. 2021;96(15 Suppl). Abstract 1578.

4. Kielhorn A, Thomas S, Sabatella G, Johnston K. The potential impact of long-term relapse reduction: a disease model of eculizumab in neuromyelitis optica spectrum disorder (1188). Neurology. 2021;96(15 Suppl). Abstract 1188.

5. Traboulsee A, Yeaman MR, Weinshenker BG, et al. Satralizumab in patients with neuromyelitis optica spectrum disorder and concomitant autoimmune disease (4118). Neurology. 2021;96(15 Suppl). Abstract 4118.

6. Cree B, Bennett J, Weinshenker B, et al. Long term safety outcomes with inebilizumab treatment in NMOSD: the N-MOmentum Trial (2283). Neurology. 2021;96(15 Suppl). Abstract 2283.

7. Kuhle J, Leppert D, Comi G, et al. Baseline serum neurofilament light chain levels predict conversion to McDonald 2005 multiple sclerosis (MS) within 2 years of a first clinical demyelinating event in patients with MS (1908). Neurology. 2021;96(15 Suppl). Abstract 1908.

8. Parrotta E, Kister I, Charvet L, et al. COVID-19 outcomes in MS: observational study of early experience from NYU Multiple Sclerosis Comprehensive Care Center. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e835. doi:10.1212/NXI.0000000000000835
 
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Reviewed May 2021