SPECIAL REPORT

Intensive therapy vs. escalation
Long-term data
B cell depletion and EBV
New formulation
Treatment discontinuation

Intensive therapy vs. escalation
The year 2024 saw an increasing preference for high-efficacy disease-modifying therapies (DMT) as first-choice agents for the treatment of relapsing multiple sclerosis, a recognition of the superior outcomes that may be achieved with early, more effective interventions (Oreja-Guevara et al. Ther Adv Neurol Disord 2024;17:17562864241284372).

This strategy was supported by an analysis of the Austrian MS Registry (N=970), which compared patients on modest-efficacy DMTs (dimethyl fumarate or teriflunomide) who were escalated to a higher-efficacy agent versus patients initiating treatment with a higher-efficacy agent (monoclonal antibody, S1PR receptor modulator or cladribine) (Guger et al. J Neurol 2024;271:3142-3152). First-line higher-efficacy treatment was associated with a significant 78-83% lower probability of relapse and a significant 45% lower risk of 12-week EDSS progression.

A separate study compared outcomes in the OPERA trials of ocrelizumab (n=611) with data from the German NeuroTransdata MS registry (n=7141) (Muros-Le Rouzic et al. J Cent Nerv Syst Dis 2024;16:11795735241260563). There was a significantly lower risk of relapse (hazard ratio 0.30-0.54) and disability progression (HR 0.51-0.67) with ocrelizumab at 5.5 years compared to other therapies.

In addition, two indirect comparisons examined the relative efficacy of ofatumumab versus oral DMTs (fingolimod, ozanimod, cladribine) (Riley et al. Ther Adv Neurol Disord 2024;17:17562864241239453). In the propensity-score analysis, ofatumumab was superior to fingolimod with respect to annualized relapse rate (ARR) and three-month confirmed disability progression (CDP), but not for six-month CDP. In the simulated treatment comparison, ofatumumab was superior to fingolimod, ozanimod and cladribine with respect to ARR and proportion of patients with three-month CDP; and superior to fingolimod and ozanimod in decreasing the proportion of patients with six-month CDP.

Long-term data
Long-term efficacy and safety data for anti-CD20 agents were presented at this year’s ECTRIMS meeting. The ALITHIOS open-label extension study (n=1367) compared first-line treatment with ofatumumab at six years versus delayed high-efficacy therapy in the teriflunomide/ofatumumab switch group (Bar-Or et al. ECTRIMS 2024;P058). Continuous ofatumumab was associated with a non-significant lower rate of six-month CDP (21.1% vs. 24.8%), and six-month progression independent of relapse activity (PIRA) (15.4% vs. 16. 6%). A larger treatment effect was seen in the recently diagnosed/treatment naïve subgroup for six-month CDP (16.6% vs 23.7%) and six-month PIRA (11.1% vs 16.7%).

A long-term safety analysis of ofatumumab (cumulative exposure 8042 patient-years) reported that the rate of serious infections remained stable (5.8%) during the six-year observation period (Wiendl et al. ECTRIMS 2024;P392). The most common infections were COVID-19 (2.49%), urinary tract infection (UTI; 0.81%) and respiratory tract infection (RTI; 0.81%).

Similar safety data were presented for ocrelizumab (Hauser et al. ECTRIMS 2024;P300). Over an 11-year period (cumulative exposure 30,396 PY), the overall rate of serious adverse events was 5.9% for relapsing MS and 10.8% for progressive MS. The most common serious infections were UTI (0.3/100 PY for RMS, 1.4/100 PY for PMS), lower RTI (0.5/100 PY for RMS, 0.8/100 PY for PMS) and gastrointestinal tract infections (0.3/100 PY for RMS, 0.5 /100 PY for PMS). The rate of malignancies was 0.51/100 PY.

B cell depletion and EBV
A recent study reported that Epstein-Barr viral load is significantly higher in blood and CSF in MS compared to other neurological conditions or healthy controls (Thebault et al. ECTRIMS 2024;O007), and there has been some speculation whether anti-CD20 agents act, in part, via depletion of EBV-infected memory B cells (Berger & Kakara. Mult Scler Relat Disord 2022;59:103678).

Preliminary data examining this question are conflicting. One study reported that MS is characterized by an aberrant MHC-I-restricted T cell response directed at EBV, which was modified by treatment with ocrelizumab, teriflunomide or dimethyl fumarate (Schneider-Hohendorf et al. Brain 2024; epublished July 18, 2024). However, a separate study found that ocrelizumab did not appear to lower EBV viral load or reduce the expression of EBV or human endogenous retrovirus (HERV) (Tarlinton et al. Mult Scler Relat Disord 2024;86:105597). The authors concluded that while EBV/HERV are linked to MS onset, high levels of viral expression do not appear to be part of the disease process.

New formulation
Also noteworthy this year was the FDA approval of subcutaneous ocrelizumab (Zunovo) for the treatment of CIS/RMS, active SPMS and PPMS. Animal models have suggested that subcutaneous administration of anti-CD20 agents increases drug penetration into lymph nodes, decreases B and T cell infiltration in lesions and decreases glial cell activation to a greater extent than IV administration (Torres et al. Front Immunol 2022:13:814064).

For the new formulation, subcutaneous abdominal injections (920 mg ocrelizumab + 23,000 units of hyaluronidase) must be administered by a healthcare professional. Injections take about 10 minutes and are given every six months. Pretreatment with a corticosteroid and an antihistamine is recommended 30 minutes prior to ocrelizumab administration. Patients should be monitored for one hour after the first dose and for 15 minutes for subsequent doses. Approval was based on the results of the phase III OCARINA II study, which showed similar levels of B cell depletion with ocrelizumab 920 mg SC and 600 mg IV (Newsome SD. ECTRIMS-ACTRIMS 2023;P370). Results from OCARINA I were published this year (Newsome et al. Ann Clin Transl Neurol 2024; epublished October 26, 2024). Subcutaneous ocrelizumab is reportedly not expected to be submitted to Health Canada for approval.

Treatment discontinuation
Several studies reported this year on whether high-efficacy DMTs can be safely discontinued. The largest published analysis involved patients aged >50 years in the French MS database (N=1620) (Jouvenot et al. JAMA Neurol 2024;81:490-498). All patients had RMS with no relapses or new MRI activity for at least two years. In the propensity score-matched comparison (mean age 57.7 years, mean 5.6 years since last inflammatory activity), the time to first relapse was significantly reduced in patients who stopped treatment compared to those who continued on high-efficacy therapy (hazard ratio 4.1). The relapse risk was higher in patients discontinuing natalizumab (HR 7.2) or fingolimod (HR 4.5) but not for those stopping anti-CD20 therapy (HR 1.1). The results suggest that caution may be advised when stopping an anti-trafficking agent associated with a risk of rebound disease activity. These patients may benefit from bridging to an alternative DMT prior to discontinuation. Additional studies are required to determine the most appropriate candidates and optimal approach for discontinuation.