Alemtuzumab, Cladribine, Fingolimod, Natalizumab, and Rituximab as First-Line Treatments in Adults With Highly Active Relapsing-Remitting Multiple Sclerosis

Key Messages

What Is the Problem?

• Relapsing-remitting multiple sclerosis (RRMS), the most common disease course of multiple sclerosis (MS), is a chronic immune-mediated disease with clearly defined episodes of new or increasing neurologic symptoms followed by periods of relative stability. In contrast, the highly active, aggressive disease course leads to rapid disability, and these patients face an unmet need.
• The principal goal of MS treatment is to delay and prevent the accumulation of disability by reducing the frequency of relapses.
• Currently reimbursed first-line drugs fail to prevent the consequences of irreversible damage to the nervous system.
• There has been a paradigm shift in clinical practice toward the use of a high-efficacy treatment strategy as early as possible during the inflammatory process to provide optimal clinical benefits in preserving neurologic function in patients with highly active RRMS.

What Did We Do?

• A systematic review of the clinical effectiveness and safety of alemtuzumab, natalizumab, cladribine, fingolimod, and rituximab relative to current first-line drugs in adults with highly active RRMS was conducted; it identified post hoc subgroup analyses from 5 randomized controlled trials (RCTs) and 1 prospective comparative cohort study.

What Did We Find?

• Evidence was uncertain and conclusions were limited by risk of bias and small sample sizes; conclusions for some outcome comparisons were also limited by imprecision and incomplete reporting.
• Compared to placebo, cladribine and natalizumab may result in a clinically important reduction in relapses, disability, and key MRI lesions. Alemtuzumab may result in a clinically important reduction in relapses compared to interferon, while fingolimod may result in a clinically important reduction in relapses compared to placebo. The clinical evidence was insufficient to determine the effect of fingolimod on relapses when compared with interferon. Harms outcomes, when reported, appeared consistent with the known harms profile of the drugs.
• Assessment of the effectiveness and safety of rituximab could not be performed due to the lack of evidence.
• Evidence was also lacking for many important outcomes such as health-related quality of life (HRQoL), instrumental activities of daily living, symptoms, and cognitive outcomes. No evidence could be identified to inform on treatment sequencing.
• Two pragmatic RCTs (the TREAT-MS and DELIVER-MS trials) are currently ongoing, aiming to compare an early, high-efficacy treatment strategy versus a traditional escalation treatment strategy, which may inform treatment sequencing.
• Further research is needed to compensate for clinical data gaps to inform an appropriate and relevant economic evaluation.

What Does This Mean?

• Jurisdictions may reconsider the current reimbursement criteria for drugs used in the first-line setting specifically for adults demonstrating highly active RRMS; however, caution should be taken given the gaps and uncertainty in evidence.
• Upon request from public drug plans, this review may inform a future implementation advice panel or expert committee recommendation.