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Cladribine is associated with stable or improved cognition over 4 years in RMS

A pooled analysis of data from the extension of the CLARIFY-MS and MAGNIFY-MS studies assessed the long-term effects of cladribine on cognitive function in patients with relapsing MS (RMS). Results showed that most participants had stable or improved cognitive function, with clinically meaningful improvements or stability in cognitive processing speed (CPS) observed over 4 years [1].

Cognitive decline is a highly prevalent and debilitating symptom of MS, often present even at early stages of the disease. The CLARIFY-MS (NCT03369665) and MAGNIFY-MS (NCT03364036) studies showed that short-course cladribine tablets can stabilise or improve cognitive function for up to 4 years, as measured by the Symbol Digit Modalities Test (SDMT) [2,3]. The pooled analysis included data from 499 patients: 280 participating in the CLARIFY-MS extension (NCT00641537) and 219 in the MAGNIFY-MS extension (NCT04783935). All participants received short-course cladribine (cumulative dose of 3.5 mg/kg) in years 1 and 2, followed by a treatment-free period in years 3 and 4.

At baseline, the mean age was 37.9 years, 68.7% were women, and the median SDMT was 53 points. After 48 months, the least-squares mean SDMT scores improved by 1.79 points (95% CI 1.05–2.54; P<0.0001) in the total population and by 2.22 points (95% CI 1.40–3.04; P<0.0001) in patients aged <50 years (n=434). SDMT in patients aged ≥50 years (n=65) improved by 0.81 points (95% CI -4.97 to 6.59; P=0.7806), which was not statistically significant.

Most participants had stable or improved SDMT scores after 48 months. Using a threshold of a ≥4-point change, 74.4% were stable or improved, and 25.2% worsened. A ≥8-point change threshold yielded proportions of 86.6% and 12.9%, respectively. Percentages of stable or improved patients were relatively high among patients aged ≥50 years and among those with low (<53) versus high (≥53) baseline SDMT scores.

Based on these findings, the authors suggested that cladribine tablets have long-term benefits beyond their effects on conventional disability measures, particularly when initiated at an early stage of MS. This complementary effect, the authors noted, supports early use to maximise benefit.

  1. Brochet B, et al. Cladribine tablets maintain or improve cognition over 4 years in people with relapsing multiple sclerosis: Pooled analyses of the CLARIFY-MS and MAGNIFY-MS Extension Studies. P117, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
  2. Selmaj K, et al. Sustained disease-activity-free (NEDA) status in patients with relapsing multiple sclerosis (RMS) treated with cladribine tablets: data from the CLARITY extension study. P846, ECTRIMS Congress 2024, 18–20 September, Copenhagen, Denmark.
  3. De Stefano N, et al. Long-term effectiveness of cladribine tablets over 4 years in relapsing multiple sclerosis: Results from the MAGNIFY-MS Extension study. P349, ECTRIMS Congress 2024, 18–20 September, Copenhagen, Denmark.

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New findings support ofatumumab as first-line therapy in early MS

A post-hoc analysis of the ASCLEPIOS I/II trials comparing ofatumumab with teriflunomide focused on newly diagnosed relapsing MS (RMS) patients with low disease activity. In this subgroup, ofatumumab was associated with >2-fold higher odds of remaining free of disease activity at 1 year and an 18-fold higher odds at 2 years [1].

The rationale for this post-hoc analysis was the well-documented evidence that early use of high-efficacy therapy is associated with less accrual of long-term disability [2–4]. In the phase 3 ASCLEPIOS I/II trials (NCT02792218/NCT02792231), the anti-CD20 monoclonal antibody ofatumumab demonstrated a favourable safety and superior efficacy versus teriflunomide in the overall RMS population, as well as in the recently diagnosed (≤3 years) and treatment-naïve subgroups [5,6]. Prof. Heinz Wiendl (University of Freiburg, Germany) presented the results from a subgroup analysis of 261 treatment-naïve patients with early MS and low disease activity, defined as no more than 1 relapse in the 2 years prior to enrolment. The primary efficacy endpoint was no evidence of disease activity (NEDA-3).

In year 1, the proportions achieving NEDA-3 were 43.9% with ofatumumab versus 28.9% with teriflunomide (OR 2.38). In year 2, these proportions were 89.9% versus 34.4%, respectively (OR 18.27).

Despite the low clinical disease activity, ofatumumab demonstrated a pronounced effect on MRI activity and neurofilament light (NfL) levels, and a trend toward a lower annualised relapse rate (ARR):

  • Adjusted number of gadolinium-enhancing (Gd+) T1 lesions: 0.02 versus 0.30 (RR 0.08; 95% CI 0.03–0.21; P<0.001).
  • Adjusted number of new or newly enlarging T2 lesions: 0.62 versus 3.59 (RR 0.17; 95% CI 0.12–0.26; P<0.001).
  • ARR: 0.07 versus 0.10 (RR 0.63; 95% CI 0.32–1.26; P=0.192).
  • Serum NfL levels: a relative reduction with ofatumumab of 20.4% in year 1 (P=0.258) and 15.2% in year 2 (P<0.001).

The safety of ofatumumab was consistent with that observed in the overall ASCLEPIOS I/II population. Adverse events occurred in 86.7% of patients in the ofatumumab group and 88.7% in the teriflunomide group. Rates of serious adverse events and serious infections were similar between groups (5.8% versus 7.1%).

Prof. Wiendl and colleagues concluded that these findings support the early use of ofatumumab as first-line therapy in RMS patients, even in the presence of low disease activity.

  1. Wiendl H, et al. Efficacy and safety of ofatumumab in treatment-naive people with early RMS and low clinical disease activity. P134, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
  2. Kappos L, et al. JAMA Neurol. 2020;77(9):1132–1140.
  3. Lublin FD, et al. Brain. 2022;145(9):3147–3161.
  4. He A, et al. Lancet Neurol. 2020;19(4):307–316.
  5. Hauser SL, et al. N Engl J Med. 2020;383(6):546–557.
  6. Gärtner J, et al. Mult Scler. 2022;28(10):1562–1575.

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NEDA sustained for up to 10 years with ocrelizumab in treatment-naïve RMS

In approximately 9 of 10 treatment-naïve (TN) patients with relapsing MS (RMS) treated with ocrelizumab, either intravenous (IV) or subcutaneous (SC), no evidence of disease activity (NEDA-3) was maintained in any given year. Long-term safety data were reassuring, with infection rates decreasing over time and serious infection rates remaining low and stable [1].

These findings derive from long-term follow-up of the phase 3 OPERA I/II (NCT01247324/NCT01412333) [2], with up to 10 years of follow-up, and the phase 3 OCARINA II study (NCT05232825) [3], with 2 years of follow-up. Both studies enrolled TN patients with early RMS. In OPERA I/II, 603 participants were randomised to IV ocrelizumab, of whom 375 had been diagnosed with MS within the previous 2 years. In OCARINA II, 46 participants were randomised to SC ocrelizumab.

The primary efficacy endpoint was NEDA-3, defined as the absence of protocol-defined relapses, no 48-week confirmed disability progression (CDP48), and no MRI activity (no gadolinium-enhancing T1 lesions (Gd+ T1) and no new or enlarging T2 lesions. Event rates over the entire study period and safety were also evaluated.

Across both studies, approximately 9 of 10 participants achieved NEDA-3 in any given year. Efficacy appeared comparable between IV and SC formulations. Most participants remained free of relapses, CDP48, and MRI activity throughout the ocrelizumab treatment.

Over the entire follow-up period, corresponding to 4,547.8 patient-years in the IV group (10 years) and 95.8 patient-years in the SC group (2 years), the proportions of patients achieving key outcomes were as follows:

  • NEDA-3: 60.9% (IV) and 90.6% (SC);
  • No relapse: 75.0% (IV) and 97.8% (SC);
  • No CDP48: 83.4% (IV) and 98.1% (SC);
  • No Gd+ T1 lesions: 97.8% (IV) and 98.6% (SC);
  • No new or enlarging T2 lesions: 89.2% (IV) and 89.5% (SC).

Regarding safety, infection rates declined over time, while serious infections remained low and stable in both groups. In the IV group, infection rates per 100 patient-years were 90.5 at year 1, 68.0 at year 5, and 44.1 at year 10. Corresponding rates of serious infections were 0.68, 1.72 and 1.3 per 100 patient-years, respectively. In the SC group, infection rates decreased from 83.1 per 100 patient-years at year 1 to 38.0 at year 3; no serious infections were reported in this cohort.

Overall, these long-term data support sustained high efficacy and favourable safety profile of both IV and SC ocrelizumab in treatment-naïve patients with early RMS.

  1. Newsome SD, et al. No Evidence of Disease Activity in treatment-naive people with relapsing multiple sclerosis treated with intravenous or subcutaneous ocrelizumab: Findings of the OPERA (10 Years) and OCARINA II (2 Years) studies. P125, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
  2. Hauser SL, et al. N Engl J Med. 2017;376(3):221-234.
  3. Newsome SD, et al. Neurology. 2025;104(9):e213574.

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