Tysabri Observational Program (TOP): long-term safety and effectiveness of natalizumab treatment in relapsing-remitting multiple sclerosis over 15 years

Objective: This Tysabri Observational Program (TOP) final analysis evaluated the 15-year safety and effectiveness of natalizumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: This multinational, real-world observational study assessed natalizumab-associated serious adverse events, annualised relapse rates (ARRs) and disability progression/improvement in patients with RRMS. These outcomes were evaluated in subpopulations receiving short- (1–2 years) versus long-term (≥10 years) natalizumab and in patients who switched from intravenous to subcutaneous (SC) natalizumab formulation. The probability of conversion to non-active secondary progressive multiple sclerosis (SPMS) was assessed in patients who remained on versus discontinued natalizumab after ≥1 year. Results: As of November 2023, TOP enrolled 6319 patients. Median time on natalizumab was 4.13 years. There were no new safety signals after up to 15 years of treatment. Marked, sustained reductions in pretreatment ARR occurred with natalizumab independent of baseline disease indicators (eg, Expanded Disability Status Scale score). On natalizumab, the ARR decreased by 91.5% after 15 years, relative to the year before baseline. At 15.5 years, cumulative probabilities of 24-week confirmed disability progression and improvement were 48.5% and 38.8%, respectively. Long-term natalizumab treatment significantly decreased ARR compared with short-term treatment. Switching from intravenous to SC formulation did not affect ARR after 1 year post-switch. The cumulative probability of converting to non-active SPMS was significantly lower in patients remaining on natalizumab compared with those who discontinued (0.22 vs 0.29, respectively). Conclusions: Follow-up of over 15 years did not reveal new safety concerns and confirmed sustained real-world effectiveness of natalizumab in patients with RRMS (NCT00493298).