Long-term treatment of multiple sclerosis with anti-CD20 therapies is associated with sustained efficacy and a favourable safety profile, according to new data presented at the American Academy of Neurology (AAN) annual meeting, held April 22-27 in Boston. The following summarizes some of the key data that were presented.
Following the publication of the five-year data for ocrelizumab (Hauser et al. Neurology 2020;95:e1854-1867), long-term analyses of ocrelizumab have largely focused on the subgroup of previously untreated MS patients. Seven-year results were presented at ECTRIMS 2022 (Cerqueira et al. ECTRIMS 2022;P723); nine-year results were presented this year (Cerqueira et al. AAN 2023;S46.002). Overall, 67% of ocrelizumab patients remained on treatment. The proportion of patients with no evidence of disease activity (NEDA; MRI rebaselined at 24 weeks) was 48% during the trial + extension phase and 79% had no 6-month confirmed disability progression (CDP).
About 9.3% had IgG < lower limit of normal (LLN) according to the seven-year data. A total of 1.8% had serious infections when IgG < LLN. A pooled analysis of phase III studies previously reported that IgG levels decline about 3-4% per year over the first six years of ocrelizumab exposure. The rate of serious infections was 5.48/100 patient-years (PY) with IgG < LLN vs. 2.14 with IgG >LLN (Derfuss et al. ECTRIMS 2019;65. Full presentation at https://medically.roche.com/content/dam/pdmahub/non-restricted/neurology/ectrims-2019/ECTRIMS_2019_OPERA_ORATORIO_Derfuss.pdf). The most common infections were urinary tract infections, cellulitis and pneumonia.
Ofatumumab long-term safety was analysed from the ALITHIOS study (N=1969), which comprised patients previously enrolled in four clinical trials (ASCLEPIOS I/II, APOLITOS and APLIOS). Four-year data were presented at the European Academy of Neurology meeting (Kappos et al. EAN 2022; EPR-161) and have now been updated (Cohen et al. AAN 2023;P8.004). The exposure-adjusted incidence rate (EAIR) for infections declined from 51.1/100 patient-years during the core study to 40.9/100 patient-years at five years. EAIR for serious infections (excluding COVID-19) also declined from 1.55/100 PY to 0.93/100 PY at year 5. The infection recovery rate was 95% and <5% discontinued ofatumumab. There was one death due to pneumonia and septic shock.
The most common serious infection was COVID-19 (646 confirmed/suspected cases, 38% of cohort) with 93.9% of cases being mild or moderate in severity. There were five COVID-related deaths (3 in unvaccinated individuals). A total of 98.6% of patients with COVID-19 were recovered/recovering at data cut-off. Risk factors for serious COVID-19 were male sex (hazard ratio 1.89) and high body-mass index (HR 1.98).
Mean IgG levels remained stable over the five-year period (10.35 g/L at baseline, 9.96 at week 264) during continuous ofatumumab. IgG remained >LLN in 98% of patients. Mean IgM levels declined from 1.34 to 0.72 g/L, although IgM remained >LLN in 69.4% of patients. There was no association between a reduction in Ig levels and the risk of serious infections. This finding was consistent with the conclusions of a recent systematic review, which found that ofatumumab may have a more favourable effect on IgG compared to other B cell-depleting agents (Saidha et al. Neurol Sci 2023;44:1515–1532. Free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC9843103/pdf/10072_2022_Article_6582.pdf). The authors hypothesized that differing effects on IgG may be due to dosing, route of administration and/or epitope binding.
The rate of malignancy in ALITHIOS at four years was unchanged at 0.32/100 PY. The most common malignancies were breast/nipple neoplasms (9 cases) and skin neoplasms excluding melanomas (4 cases).
A separate analysis examined the effect of treatment on serum neurofilament-light (NfL) levels (Alvarez et al. AAN 2023;S6.013). In ALITHIOS, sNfL levels remained stable in the continuous ofatumumab group from baseline (month 24, mean 8.5 pg/mL) to month 48 (mean 8.38 pg/mL). In months 24-36 of continuous ofatumumab, 87.6% of patients achieved NEDA; in months 36-48, the NEDA rate was 92.8%.
During long-term use, the annual rate of whole-brain volume change was -0.27%/year with continuous ofatumumab (Cohen et al. AAN 2023;S16.009). The cumulative percent brain-volume change (PBVC) was < 1.5% over the five-year period. The proportion of patients free of 6-month CDP was 84.5% at month 36 and 82.3% at month 48. The overall adherence rate at four years was 95.1% in patients receiving continuous ofatumumab (Alvarez et al. AAN 2023;P8.002).