Recapping Research From 2023 ACTRIMS


As a recap from ACTRIMS 2023, get caught up on some of the latest news in multiple sclerosis as the NeurologyLive® team shares some of our data updates.

In recent months, the NeurologyLive® team has been covering the news and conducting interviews with experts on the latest updates in the clinical care of individuals with multiple sclerosis (MS), including those with relapsing-remitting MS and other related autoimmune disorders such as neuromyelitis optica spectrum disorder (NMOSD).

To recap the 2023 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 23-25, in San Diego, California, the team has culminated some of the biggest pieces of news to offer updates on new developments in literature about MS to spread awareness on the prevention and treatment of the condition.

Click here for more coverage of the ACTRIMS 2023.

Latest Literature

Metabolic Changes, Cognitive Improvements in Multiple Sclerosis Observed Through Intermittent Calorie Restriction

Findings from a short-term, 12-week study of patients with MS indicated that intermittent calorie restriction (iCR) is a safe and effective method for this patient population, with several positive metabolic, immunologic, and cognitive changes observed.1 Forty-two patients were randomly assigned to either iCR or unrestricted diet (Ctr) for 12 weeks. Those in the iCR group ate 1-2 salads with non-starchy vegetables with a light dressing, totaling 400-500 calories, for 2 days of the week, with the remaining 5 eating normally. Participants had a diagnosis of relapsing MS, had Expanded Disability Status Scale scores less than 6, had body mass index (BMI) between 22 and 38, and were stable for 1 year.

At the 12-week follow-up, 17 of the 22 from the iCR group and 17 of the 20 from controls completed the study. Compared with baseline, those randomly assigned to iCR demonstrated significant decreases in weight, BMI, and waist circumference over time at both the 6- and 12-week observed time points. Specifically, investigators recorded a mean decrease of 2.2 kg in total body fat at the conclusion of the analysis in the iCR group.

At the 6- and 12-week time points, patients in the iCR group showed significantly lower leptin serum levels (week 6: P = .04; week 12: P = .03) and significantly increased adiponectin levels relative to controls (P = .01). T-cell subsets were also modulated by 12-week iCR, as represented by significantly lower counts of effector memory CD4+ T-cells at both time points, and significantly increases in naïve CD4+ T-cells at the conclusion of the study. Notably, there were statistically significant differences in the increase in regulatory T-cells as well.

Changes in cognition were also observed in the iCR group, as demonstrated by increases in Symbol Digit Modalities Test (SDMT) scores at 6 (mean increase, 3.5; 95% CI, 0.6-6.3; P = .01) and 12 (mean increase, 6.2; 95% CI, 3.4-9.5; P = .00004) weeks.

Favorable Safety Outcomes Observed in Ozanimod Over Diroximel Fumarate

Data from a matching-adjusted indirect comparison (MAIC) of ozanimod (Zeposia; Bristol Myers Squibb) and diroximel fumarate (Vumerity) in patients with relapsing-remitting multiple sclerosis (MS) indicated that the 2 disease-modifying therapies (DMTs) have comparable efficacy; however, ozanimod displayed a superior safety profile, with significantly lower risks of key safety outcomes.2

The MAIC was informed by a targeted literature review (TLR) that comprised of the phase 3 EVOLVE-MS-1 trial (NCT02634307) of diroximel fumarate and the phase 3 SUNBEAM (NCT0229408) and RADIANCE (NCT02047734) trials of ozanimod. Individual patient data from SUNBEAM and RADIANCE were weighted to match baseline patient characteristics of EVOLVE-MS-1, including Expanded Disability Status Scale (EDSS) score, prior relapse, gadolinium-enhancing lesions, prior DMT use, age, sex, and weight.

There were significant baseline differences between the studies, as EVOLVE-MS-1 trial patients (n = 696) had a mean age of 41.9 years. Patients in that study had mean weight of 74.9 kg, 72.6% were female, and 65% had prior DMT use. In comparison, the pooled ozanimod trials (n = 880) had mean age of 35.4 years, mean weight of 70.3 kg, with 65.5% of patients female, and 28.5% with prior DMT use.

In terms of safety, there were reduced odds of adverse events with ozanimod (OR, 0.877; 95% CI, 0.583-1.320); however, these were not statistically significant. There were several differences in safety outcomes, including a significantly lower odds of discontinuation (OR, 0.089; 95% CI, 0.030-0.268) and serious AEs (OR, 0.290; 95% CI, 0.114-0.737) with ozanimod.

Long-term Ozanimod Treatment in Relapsing Multiple Sclerosis Associated With Stable or Improved Disease Activity and Safety

Findings of an ad hoc analysis of data from the phase 3 SUNBEAM (NCT02294058) and RADIANCE (NCT02047734) clinical trials, as well as the open-label extension DAYBREAK (NCT02576717), suggest that regardless of age, patients with relapsing multiple sclerosis (MS) who were treated with ozanimod (Zeposia; BMS) reported stable or improved clinical and radiologic measures of disease activity over a 6- to 7-year treatment period.3 Additionally, these patients reported no new adverse events (AEs), confirming that long-term treatment is safe and well-tolerated.4

Regardless of patient age group, the adjusted annualized relapse rate (ARR) in the phase 3 trials was less than 0.2, and it remained similarly low in the DAYBREAK extension trial. Additionally, the adjusted mean number of Gadolinium-enhancing lesions per scan remained stable, or decreased, regardless of age category. The adjusted mean number of new/enlarging T2 lesions per scan relative to the DAYBREAK baseline also either remained stable or decreased among those treated with continuous ozanimod, regardless of age.3

In SUNBEAM and RADIANCE, adults with relapsing MS received oral ozanimod 0.46 mg or 0.92 mg per day or intramuscular interferon beta-1a 30 µg per week for at least 12 months (in SUNBEAM) or 24 months (in RADIANCE). Upon entering the open-label DAYBREAK trial, patients received ozanimod 0.92 mg per day.

Satralizumab Shows Long-term Efficacy and Safety in AQP4-IgG-Seropositive NMOSD

Findings from the roll-over, open-label SAkuraMoon study (NCT04660539) showed a high proportion of adult patients with aquaporin-4 immunoglobulin seropositive (AQP4-IgG+) NMOSD who remained free of relapse with a consistently low annualized relapse rate (ARR) over 4.6 years of satralizumab (Enspryng; Genentech) exposure.5 The agent, a humanized monoclonal antibody medication, was approved in 2020 by the FDA for the treatment of NMOSD.

Satralizumab-treated patients had an overall ARR of 0.09 (95% CI, 0.06-0.12). Notably, the ARR did not increase with additional years of treatment (year 1, 0.16 [95% CI, 0.09-0.27]; year 2, 0.10 [95% CI, 0.05-0.20]; year 3, 0.05 [95% CI, 0.01-0.15]; year 4, 0.07 [95% CI, 0.02-0.26]). After 4.6 years, 72% (95% CI, 62-80%) of satralizumab-treated patients were free from investigator-determined protocol-defined relapse (iPDR). At the same time, 91% (95% CI, 84-96) of patients were free from severe iPDR, and 85% (95% CI, 75-91%) had no sustained Expanded Disability Status Scale (EDSS) worsening.

Overall, the median duration of satralizumab exposure was 5.0 years (range, 0.1-7.9). Rates of AEs and serious AEs in the overall satralizumab treatment period were comparable with the DBPs (AEs, 332.6 per 100 PY [95% CI, 316.7-349.1]; serious AEs: 10.5 per 100 PY [95% CI, 7.8-13.8]). Rates of infections (92.9 per 100 PY; 95% CI, 84.6-101.8) and serious infections (2.4 per 100 PY; 95% CI, 1.3-4.2) in the overall treatment period were comparable with the DBP, with no increases being observed over time. No deaths, anaphylactic reactions related to satralizumab, or injection-related reactions occurred that led to changes in study treatment.

Ocrelizumab and Rituximab Demonstrate Similar Safety, Efficacy in Treatment of Multiple Sclerosis

In a comparative study of middle-aged patients with multiple sclerosis (MS) on rituximab (Rituxan; Genentech) and ocrelizumab (Ocrevus; Genentech), findings showed similar safety and efficacy over a 2-year period.6 The odds of experienced disease activity was similar between ocrelizumab and rituximab, before (P = .063) and after adjustments (P = .249). Over a 2-year period, 20.8% and 24.7% of patients on ocrelizumab and rituximab, respectively, discontinued treatment.

Randomly selected patients treated with ocrelizumab (n = 245) and rituximab (n = 182), and observed outcomes such as lab data, relapse history, adverse events (AEs), MRI outcomes, disease history, and patient characteristics. Descriptive statistics and logistic regression adjusting for age disease duration, MS type, sex and enhancement on baseline MRI were used to describe and compare the sample groups.

Both rituximab and ocrelizumab have similar mechanisms of action that target CD20, resulting in B-cell depletion. Rituximab, first approved in 1997, is also indicated for patients with non-Hodgkin’s lymphoma, chronic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris. In 2017, Ocrelizumab was approved as a treatment for adults with relapsing or primary progressive forms of MS. It represented the first product approved for primary progressive MS.

BTK Inhibitor Evobrutinib Displays Superior Efficacy Compared With Anti-CD20 Treatment for MS

New data from a preclinical assessment onevobrutinib (EMD Serono), a highly selective central nervous system (CNS)-penetrant Bruton tyrosine kinase (BTK) inhibitor, demonstrated superior efficacy compared with anti-CD20 treatment for targeting compartmentalized neuroinflammation in multiple sclerosis (MS).7 The findings support the BTK inhibitor as a promising therapy for persistently targeting neuroinflammation and disease progression in MS.

Evobrutinib reduced both disease severity (65% reduction; P <.0001) and immunopathological parameters of disease (56% reduction; P <.01) in progressive-like experimental autoimmune encephalitis mice compared with anti-CD20 (clone: SA271G2) treatment. The favorable effects of evobrutinib paralleled with a significant gain in body weight and decrease in cumulative disease score in comparison with anti-CD20 treatment (54% disease score reduction; P <.001).

The BTK inhibitor significantly reduced the number and activation of lymphoid and myeloid cells, lessening neuroinflammation, Alvarez et al noted. In addition, evobrutinib significantly reduced the extent of submeningeal demyelination both in the brain (44% reduction; P <.01) and the spinal cord (42% reduction; P <.01).

Majority of Long-Term Immunotherapy-Treated Patients With MOGAD Sustain Relapses

A recent multicenter retrospective analysis of 70 patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) demonstrated that majority of patients sustained relapses on long-term immunotherapies, including rituximab (Rituxan, Genentech), mycophenolate mofetil (CellCept; Genentech), and intravenous immunoglobulins (IVIG).8 The findings provide evidence on the timing of relapses and immunotherapy efficacy for determining the most effective therapy regimens for preventing or reducing relapses.

Fifty-precent of patients with MOGAD remained relapse-free on rituximab (14 of 28) and mycophenolate mofetil (5 of 10), whereas 63.6% of patients treated with IVIG (7 of 11) remained relapse-free, with those in the IVIG group experiencing a slightly lower relapse rate.

In the first year, 73.9% of patients experienced their first relapse (n = 34 out of 46), and 17.4% of patients experienced their first relapse more than 4 years (4-15 years) after initial presentation (n = 8 out of 46). Eighty-seven percent of patients were initiated on long-term immunotherapy often after the first relapse (n = 40/46).

Glatiramer Acetate Depot Injection Shows T1 and T2 Lesion Reduction in Relapsing MS

xxxNews from the phase 3 multinational, double blind, placebo-controlled study (NCT04121221) in patients with relapsing forms of multiple sclerosis (MS) showed significant reductions of T1 and T2 lesion volume with treatment with Mapi Pharma’s glatiramer acetate depot (GA Depot).9 These findings were strengthened by the MRI end points and suggest GA Depot, a long-acting intramuscular injection of GA, can be an effective disease-modifying therapy for patients with MS.

In the primary analysis, a 30% statistically significant reduction of annualized relapse rate (ARR) was observed in the GA Depot arm compared with placebo (P = .0066).2 The first secondary end point of cumulative newly enhancing T1 lesions displayed a 28.5% reduction in the GA Depot arm (P = .0083), while the second secondary end point showed a 17.3% reduction of cumulative number of new or newly enlarging hyperintense T2 lesions displayed at week 52 in GA Depot-treated patients (P = .0305). The mean Expanded Disability Status Scale (EDSS) scores also demonstrated a consistent and statistically significant (P = .0193) reduction in the GA Depot arm.

Additionally, the treatment arm experienced an expected higher incidence to treatment emergent adverse events (TEAEs). The most common TEAEs were injection site reactions, though they were mostly mild. The compliance rate was approximately 99% for the total remaining patients in the study. Among those patients that completed RCT, 93.4% continued to the open-label period study.

Disability Progression Risk Lowered in Diverse Patients With Relapsing MS on Ocrelizumab

Post-hoc findings from the phase 3 OPERA I and II studies (NCT01247324; NCT01412333) showed that despite a more severe disease course for non-Hispanic Black (NHB) and Hispanic or Latino (HL) patients with relapsing multiple sclerosis (MS), the risk for disability progression was reduced in these populations while on ocrelizumab (Ocrevus; Genentech).10 In the analysis, 65 NHB, 213 HL, and 1350 non-Hispanic White (NHW) patients with relapsing MS were included, with a goal to understand differences in baseline disease burden, B-cell and B-cell subset levels, and risk for disability progression differs between groups.

Investigators examined several different measures, such as baseline demographics and clinical outcomes like Expanded Disability Status Scale (EDSS), 25-foot walk test (25FW), and 9-hole peg test (9HPT). Additionally, brain MRI outcomes including T2 lesion volume (T2LV) gadolinium and lesion count, and brain volume, as well as blood outcomes such as B-cells and subsets, T-, B-, and NK-cell counts, and immunoglobulin D panels, were assessed. In OPERA I and II, patients with relapsing MS received intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks.

Compared with NHW, HL patients with relapsing MS had higher 9HPT (HL, 23.8; NHW, 22.0 sec), higher 25FW (HL, 6.8; NHW, 5.4 sec) and greater BMI (HL, 25.9, NHW, 24.8 kg/m2); all P<0.05. NHB and HL groups had greater baseline CD19+ B cell counts (NHB, 273; HL, 272; NHW, 222 cells/µL), including mature naive (NHB, 177; HL, 170; NHW, 140 cells/µL), plasmablast-plasma (NHB, 5; HL, 5; NHW, 3 cells/µL) and double-negative memory B cells (NHB, 12; HL, 10; NHW, 7 cells/µL); all P<0.005. Risk of 24-week confirmed disability progression, a composite of EDSS, 9HPT, and 25FW, was significantly higher in the NHB (HR, 3.0; 95% CI, 1.4-6.5) and HL (HR, 2.3; 95% CI, 1.6-3.4; P <.0001) groups relative to NHW in the interferon beta-1a arm, but not the ocrelizumab arm.

Combination Treatment Approach to Fatigue in MS Nets Benefits

Results of a randomized study examining different interventions for multiple sclerosis (MS)-related fatigue showed that a combination approach of cognitive behavioral therapy (CBT) plus modafinil resulted in reduced fatigue impact and perceived benefits in people with MS.10

People with MS were randomly assigned 1:1:1 to receive telephone-delivered CBT (n = 114; 8 weekly sessions plus 2 booster sessions), modafinil (n = 114; 50 mg daily-200 mg BID), or both (n = 108) over 12 weeks. Effects were measured using the Modified Fatigue Impact Scale (MFIS) at baseline and at the end of the treatment period. Notably, Braley and colleagues also assessed different clinical features that could potentially have an effect on the intervention, including depression, anxiety, excessive daytime sleepiness, obstructive sleep apnea, sleep hygiene, MS subtype, and disability level.

Overall, 336 people with MS completed the study. At 12 weeks, all 3 interventions were associated with statistically significant and clinically meaningful reductions in the MFIS (CBT, 15.2; modafinil, 16.9; combination, 17.3), with nearly 60% of participants in each group experiencing at least a 10-point reduction in overall MFIS score. Notably, sleep hygiene did modify the effect of the interventions, as those with worse sleep hygiene were shown to experience a greater benefit on the MFIS score following CBT (P =.03). Overall sleepiness based on the Epworth Sleepiness Scale was also associated with changes on the MFIS but not effect modification.

1. Ghezzi L, Tosti V, Cantoni C, et al. Randomized clinical trial of intermittent calorie restriction in people with multiple sclerosis: effects on immunometabolic and cognitive measures. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, CA. Cutting Edge Developments.
2. McGinley M, Paul D, Branchcomb T, et al. A matching-adjusted indirect comparison of ozanimod to diroximel fumarate in patients with relapsing-remitting multiple sclerosis. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, CA. Abstract P0461.
3. Cree BA, Selmaj KW, Steinman L, et al. Long-term Efficacy of Ozanimod by Age Category in Patients With Relapsing Multiple Sclerosis in Two Phase 3 Trials and an Open-label Extension Trial. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, CA. Abstract P080.
4. Selmaj KW, Cohen JA, Steinman L, et al. Long-term Safety and Tolerability of Ozanimod by Age Category in Patients With Relapsing Multiple Sclerosis From Two Phase 3 Trials and an Open-Label Extension Study. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, CA. Abstract P081.
5. Bennett JL, Greenberg B, Weinshenker BG, et al. Long-term Efficacy and Safety of Satralizumab in Adults with AQP4-IgG-seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from the Roll-over, Open-label Study SAkuraMoon. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P324.
6. Vollmer B, Nair K, Sillau S, Corboy JR, Alvarez E. Comparison of ocrelizumab and rituximab over 2 years of treatment for multiple sclerosis. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, California. Abstract P159
7. Kebir H, Li C, May MJ, Church ME, Boschert U, Alvarez JI. The Bruton’s Tyrosine Kinase Inhibitor Evobrutinib Demonstrates Superior Efficacy in Targeting Compartmentalized Neuroinflammation Compared to Anti-CD20 Treatment. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P149.
8.Elfasi A, Alkabie S, Rodriguez E, et al. Treatment Response to Different Immunotherapies in Relapsing Myelin-Oligodendrocyte Glycoprotein Antibody - Associated Disease (MOGAD) Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P337.
9. Miller AE, Popper L, Berger JR, et al. Results of a Phase III, Multinational, Double Blind, Placebo-Controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P087.
10. Williams MJ, Boorgu DSSK, Cree BA, et al. Greater baseline disease burden and risk for disability progression in self-reported non-Hispanic Black and Hispanic or Latino individuals with relapsing multiple sclerosis: findings from OPERA I and II trials of ocrelizumab. Presented at: 2023 ACTRIMS Forum; February 23-25; San Diego, CA. Abstract P078.
11. Braley TJ, Alschuler KN, Ehde DM, et al. A Comparative Effectiveness Trial of Telephone-Delivered Cognitive Behavioral Therapy, Modafinil, and Combination Therapy of Both Interventions for Fatigue in Multiple Sclerosis: Primary Results From the COMBO-MS Trial. Presented at: 2023 ACTRIMS Forum. February 23-25, 2023; San Diego, CA.
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