Unlocking the Future of Multiple Sclerosis Treatment: Highlights From ECTRIMS-ACTRIMS 2023

Between October 11 and October 13, 2023, specialists in the field of MS gathered in Milan, Italy, for the 2023 9th joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis and the America’s Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS).
 
For over 30 years, MS has been at the forefront of neurotherapeutics, with constantly evolving and developing innovative therapies and mechanisms to further guide treatment strategies. ECTRIMS-ACTRIMS is the world’s largest meeting in MS, connecting professionals from across multiple disciplines, institutes, and countries to facilitate an understanding of emerging therapies.
 
Fred D. Lublin, MD, holds the position of Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City, where he also serves as the director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis. Dr Lublin shares his key takeaways from the latest research in treatment strategies for adults with relapsing MS presented at ECTRIMS-ACTRIMS 2023.

What implications do the interim results have for the use of ofatumumab in patients transitioning from IV anti-CD20 therapies from the OLIKOS study (ClinicalTrials.gov identifier: NCT04486716), and how might it affect treatment decisions?

The OLIKOS study is a comprehensive, 12-month investigation that explores the transition from IV anti-CD20 therapy to the SC form with ofatumumab.¹ While the 6-month results have been reported, it is important to note that the study is still ongoing, with a strong emphasis on safety and sustained efficacy. A notable challenge is the ethical concern of withholding effective treatment from patients, which makes it difficult to have a control group for assessing efficacy.
I have observed anti-CD20 therapies to be highly effective treatments over time. In my practice experience, IV administration has been the standard for several years, but the introduction of the SC route has brought potential benefits, such as improved patient comfort, reduced clinic time, and potentially lower healthcare costs.

At the 6-month milestone, the OLIKOS study has not revealed any new safety concerns or a decline in efficacy.¹ This is comforting because I have noticed that extended anti-CD20 therapy can result in decreased immunoglobulin levels. Although a direct comparison between the 2 medications is lacking in this study, the results align with the collective observations and experiences of the medical community, confirming the continued promise of anti-CD20 therapies in managing various autoimmune conditions.

As the study progresses, more comprehensive insights into the long-term effects and benefits of SC ofatumumab compared with traditional IV treatments are expected. These insights will likely guide future treatment decisions and protocols for autoimmune disorders. Further findings from the ongoing study will provide additional insights into this transition in treatment methods.

How does ofatumumab compare to other emerging treatment strategies in relapsing MS?

Ofatumumab, an approved anti-CD20 therapy for MS treatment in the United States, is a valuable addition to the armamentarium of MS therapies.² Alongside ocrelizumab and ublituximab, these 3 anti-CD20 agents are recognized for their high efficacy in managing MS, distinguishing them from several oral agents that operate through different mechanisms of action.
 
What sets ofatumumab apart from its counterparts is its route of administration. Ocrelizumab is administered through IV every 6 months, whereas ofatumumab offers a more convenient monthly SC dosing schedule that patients can administer themselves.^1,2 In my experience, this dosing convenience can significantly contribute to patient adherence and overall treatment outcomes. In addition to its convenient dosing, the SC administration of ofatumumab offers patients flexibility and potentially reduces the need for frequent clinic visits, which can be especially valuable for those with mobility challenges or in remote areas.
 
Over time, I have observed safety considerations playing a pivotal role in treatment decisions for MS. Oral agents, platform agents, and anti-CD20 therapies have distinct safety profiles that should be carefully evaluated when selecting the most suitable therapeutic approach for individual patients.
 
The increasing popularity of anti-CD20 therapies in MS management reflects their effectiveness and the growing confidence among myself and other experts in the field. Ongoing research and clinical experience continuously refine our understanding of these treatments, enabling us to tailor therapy to each patient’s unique needs and preferences. This progress offers new hope to those living with MS.

What do the findings from the KYRIOS study (ClinicalTrials.gov identifier: NCT04869358) suggest about the effectiveness of SARS-CoV-2 mRNA vaccines in MS patients on ofatumumab therapy, for both initial and booster vaccinations?

The KYRIOS study was a prospective, open-label, 2-cohort study comparing patients who received their initial or booster dose of the COVID-19 mRNA vaccine either before or 4 weeks after starting ofatumumab treatment. The primary endpoint of this study was the impact of ofatumumab on the development of SARS-CoV-2 reactive T cells as well as the assessment of neutralizing antibodies and immune responses.³
 
The mechanism of action of an anti-CD20 medication, such as ofatumumab, is to reduce the number of circulating B lymphocytes, also known as B cells. B cells play a crucial role in maturing into plasma cells, which produce antibodies.⁴ Therefore, there has been concern about individuals on anti-CD20 medications having limited immune responses to vaccination during the COVID-19 pandemic. However, the findings revealed that neutralizing antibodies increased in all patients as soon as week 1 after full vaccination. Although titers were lower compared to the control group, this study demonstrates that ofatumumab treated patients can mount specific immune responses towards SARS-CoV-2 mRNA vaccines, even if their first vaccination or their booster occurred during stable ofatumumab treatment.³  

Can you explain the key differences between divozilimab and teriflunomide explored in the phase 3 MIRANTIBUS trial (ClinicalTrials.gov identifier: NCT05385744) and how these medications work in treating relapsing MS?

The MIRANTIBUS study was a significant clinical investigation conducted in Russia, aimed to assess the effectiveness of a novel anti-CD20 therapy called divozilimab in treating relapsing MS. This study holds particular relevance, as we previously discussed approved anti-CD20 therapies; divozilimab shares a similar mechanism of action by targeting anti-CD20 to deplete B cells, like its predecessors.⁵
 
Spanning over a duration of 2 years, this phase 3 trial involved 338 patients with relapsing MS. Participants were randomly assigned in a 1:1 ratio to receive either divozilimab at a dose of 500 mg every 24 weeks or teriflunomide at 14 mg daily, which served as an active comparator.⁵ This trial design aligns with previous studies investigating approved relapsing MS treatments, often employing active comparators to establish the efficacy and safety of new therapeutic agents.
 
The primary endpoint of the MIRANTIBUS trial was the annualized relapse rate (ARR) after 48 weeks of therapy. While the trial extended for a total of 2 years, the ARR remains the most commonly used primary outcome measure in relapsing MS research. Secondary endpoints included critical measures, such as proportion of relapse-free patients, time to the occurrence of the first relapse, and the observation of gadolinium-enhancing T1 lesions and combined unique active lesions.⁵
 
The MIRANTIBUS study indicated that at the end of 48 weeks, the divozilimab group had a significantly lower ARR compared with the teriflunomide group. It is worth noting that both groups had very low ARRs. Additionally, the study revealed that the proportion of relapse-free patients was higher in the divozilimab group compared with the teriflunomide control, indicating a reduced risk of relapses. The hazard ratio (HR) for time to first relapse was reported as HR=0.48, which is considered quite favorable. By week 48, the divozilimab-treated group showed no presence of gadolinium-enhancing T1 lesions, while approximately 20.7% of the teriflunomide group had these lesions.⁵
 
These results suggest that divozilimab is a successful therapeutic agent, as expected for a novel anti-CD20 therapy. The safety profile reported in the study appears to be similar, with infusion-related reactions reported in only 9.5% of individuals, which is lower than what has been observed in other anti-CD20 studies. Based on the 48 weeks of treatment, divozilimab demonstrates superior effectiveness compared with teriflunomide, while maintaining an acceptable safety profile.⁵

Can you explain the significance of targeting BTK as a novel mechanism for MS treatment?

BTK inhibition is a novel approach being investigated using various molecules, all of which target BTK. However, the mechanisms of inhibition differ slightly among them. Some of these molecules have the ability to penetrate the CNS,⁶ which is of utmost importance.
 
By inhibiting BTK, the B cells are targeted, but unlike anti-CD20 therapies, they are not depleted. Instead, B cells remain present and functional. It is not only the impact on B cells that is significant, but also the effect of BTK inhibitors on macrophages and microglia. These cells play crucial roles in the innate immune system, and we believe that it is the innate immunity mechanism working within the CNS, rather than the B cell effects from outside the CNS, that drives progressive disease. Therefore, my current understanding suggests the need to engage the innate immune system and develop agents that can enter the CNS to target macrophages and microglia. Fortunately, some BTK inhibitors can cross the blood-brain barrier and reach the CNS.⁶ This theoretically allows them to have effects on more progressive disease and its associated markers.
 
While most studies are currently focused on relapsing MS, there are a few studies exploring primary progressive or secondary progressive MS as well. If BTK inhibitors can have a positive impact on both types of MS, it would represent a significant advancement. Currently, our therapies for progressive disease are only moderately effective at best, and there is a pressing need for better treatment options in the field of MS therapeutics.

What makes evobrutinib unique as a BTK inhibitor and how does its mechanism of action potentially affect neuroinflammation, demyelination, and disability progression in patients with MS?

In the realm of MS research and treatment, the emergence of BTK inhibitors has sparked hope for improved therapeutic options. A particularly promising candidate is evobrutinib, which has shown notable progress in managing relapsing forms of MS. Encouraging outcomes from its phase 2 study (Clinicaltrials.gov identifier: NCT02975349) have generated optimism and paved the way for advancing to phase 3 trials. The 2 pivotal phase 3 studies, known as evolutionRMS 1 (ClinicalTrials.gov identifier: NCT04338022) and evolutionRMS 2 (ClinicalTrials.gov identifier: NCT04338061), are actively underway, poised to illuminate the potential of evobrutinib.⁷ Myself and other experts in the field are eagerly awaiting results from these studies, which are expected to be reported soon. If successful, evobrutinib may be considered for licensing as a viable treatment option for individuals living with relapsing forms of MS, potentially expanding the range of available therapies for this patient population.
 
While the effectiveness of evobrutinib in progressive forms of MS remains untested, the importance of further investigating its effects within the CNS cannot be overstated. Beyond evobrutinib, there are other BTK inhibitors in various stages of development, offering promising new approaches to MS treatment. Reports on their effectiveness in relapsing MS are expected to emerge, fueling anticipation for future research into their potential application in progressive forms of the disease.

What potential implications do the results of the abstracts discussed have for the treatment of patients with relapsing MS? How do you envision them affecting treatment strategies and recommendations?

In the ever-evolving landscape of MS treatment, the anticipation of advancements continues to foster optimism among patients, healthcare providers, and researchers alike. The quest for highly effective and safer therapeutic agents, which can be comfortably administered over an extended period of time, remains a shared goal. Fortunately, the research and development pipeline holds a diverse range of agents with varying mechanisms of action, offering promising prospects for the MS community.
 
While some upcoming molecules fall into familiar categories, such as anti-CD20 therapies that build upon the success of existing treatments, the real excitement lies in the emergence of entirely new classes like BTK inhibitors. As discussed previously, these agents set themselves apart by exerting their effects through cellular function modification rather than cell lysis, potentially allowing for reversibility.⁶ This unique quality opens the door to a spectrum of safety profiles, paving the way for more individualized treatment approaches that can address specific safety concerns and minimize the need for prolonged exposure to a single mechanism of action.
 
In my opinion, the concept of sequencing therapies, particularly in the context of relapsing remitting MS, holds promise for optimizing patient care. As researchers delve deeper into these diverse agents, there is also hope that they may uncover more effective treatments for progressive forms of the disease. A significant therapeutic breakthrough would be the discovery of a single agent capable of effectively addressing both relapsing and progressive forms of MS, potentially transforming the treatment landscape and enhancing the quality of life for countless individuals living with this complex condition.

This Q&A was edited for clarity and length.

References

1. Hua L, Brown B, Camacho E, et al. OLIKOS study: 6-month interim efficacy and safety in patients with relapsing multiple sclerosis who switched to subcutaneous ofatumumab from intravenous anti-CD20 therapies. Abstract presented at: European Committee for Treatment and Research in Multiple Sclerosis and the America’s Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2023 Meeting on MS; October 11-13, 2023; Milan, Italy. Abstract 3057/P784.
 
2. FDA approves Novartis Kesimpta^® (ofatumumab), the first and only self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis. Novartis Pharmaceuticals Corporation. Published August 20, 2020. Accessed November 6, 2023. https://www.novartis.com/news/media-releases/fda-approves-novartis-kesimpta-ofatumumab-first-and-only-self-administered-targeted-b-cell-therapy-patients-relapsing-multiple-sclerosis
 
3. Ziemssen T, Schlegel E, Winkelmann V, Leist L, Bopp T. Immune response to SARS-CoV-2 mRNA booster vaccinations in relapsing multiple sclerosis patients treated with ofatumumab s.c. – final results from the open-label multicenter KYRIOS trial. Abstract presented at: European Committee for Treatment and Research in Multiple Sclerosis and the America’s Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2023 Meeting on MS; October 11-13, 2023; Milan, Italy. Abstract 126/ P316.
 
4. de Sèze J, Maillart E, Gueguen A, et al. Anti-CD20 therapies in multiple sclerosis: from pathology to the clinic. Front Immunol. 2023;14:1004795. doi:10.3389/fimmu.2023.1004795
 
5. Boyko A, Linkova Y, Zinkina-Orikhan A, Porozova A. Phase III MIRANTIBUS trial: results of 48 weeks treatment with divozilimab versus teriflunomide in relapsing multiple sclerosis. Abstract presented at: European Committee for Treatment and Research in Multiple Sclerosis and the America’s Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2023 Meeting on MS; October 11-13, 2023; Milan, Italy. Abstract 1267/P276.
 
6. Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. 2023;19(5):289-304. doi:10.1038/s41582-023-00800-7
 
7. Montalban X, Vermersch P, Arnold D-L, et al. Design and baseline characteristics of phase 3, double-blind, randomised trials evaluating the efficacy and safety of evobrutinib versus teriflunomide in relapsing multiple sclerosis (evolutionRMS 1 and 2). Abstract presented at: European Committee for Treatment and Research in Multiple Sclerosis and the America’s Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2023 Meeting on MS; October 11-13, 2023; Milan, Italy. Abstract 1177/ P696.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.