Clinical effects of natalizumab on multiple sclerosis appear early in treatment course

Abstract

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri(®) Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3 months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p < 0.0001) and in patients with highly active disease (0.30 vs. 0.94; p = 0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95 % CI 0.34-0.52); p < 0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0-3 months 0.26; p < 0.0001). Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3 months of treatment even in patients with more active disease.

Fig. 1

Annualized relapse rate over time (calculated for each 3-month interval) in AFFIRM patients overall (a) and with highly active disease (b) is shown for placebo-treated (solid gray line) and natalizumab-treated (solid black line) patients; 95 % CI are indicated by dashed lines. Rate ratios of natalizumab/placebo (95 % CI) for each time period are indicated in the graphs. *p < 0.01; **p < 0.001; ***p < 0.0001

Fig. 2

Annualized relapse rate over time in TOP patients is shown as a solid line; 95 % CIs are indicated by dashed lines. Five patients did not receive natalizumab and were excluded from post-baseline analyses

Fig. 3

Cumulative probability of relapse in AFFIRM patients overall (a) and with highly active disease (b) is shown for placebo-treated (gray line) and natalizumab-treated (black line) patients

Fig. 4

Cumulative probability of relapse in TOP patients is shown as a solid line; 95 % confidence band is indicated by dashed lines. Five patients did not receive natalizumab and were excluded from post-baseline analyses