Natalizumab Has Long Term Efficacy and Safety That is Well Controlled With Use of the JCV Index
In results presented at the European Committee on Treatment and Research for Multiple Sclerosis (ECTRIMS) conference in Berlin, Germany, data on the use of natalizumab (NTZ) (Tysabri; Biogen, Cambridge, MA), which is a monoclonal antibody therapy for patients with relapsing multiple sclerosis (MS), were presented.
In the Tysabri Observational Program (TOP), an open-label, prospective study, interim analysis showed the ARR for patients taking NTZ was reduced by 89.4% (from 1.99 pre-NTZ to 0.21 on NTZ; P < .001).
Regardless of patients’ Expanded Disability Status Scale (EDSS) scores and exposure to other treatments for MS, ARR decreased by 86.7% or more (P < .001). At 10 years, cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were 32.9% and 35.5%, respectively. This analysis reinforces that NTZ is effective as long-term treatment for patients with relapsing MS.
Treatment with natalizumab is known to increase the risk of progressive multifocal leukoencephalopathy (PML), a rare opportunistic viral brain infection associated with death or severe disability. Risk factors that increase the risk of PML are the presence of anti-John Cunningham virus (JCV) antibodies, prior immunosuppressant use, and longer duration of treatment with natalizumab.
In patients who are positive for antibodies to JVC and have not used immunosuppressants previously, the antiJCV antibody response (“index”) correlates with PML risk and allows improved risk stratification. The longitudinal stability of the index in patients treated with NTZ or PBO over 2 years was assessed in the ASCEND (NCT01416181) study conducted in patients with secondary progressive MS. A total of 889 patients were randomly assigned to receive placebo (n = 449) or NTZ (n = 440) and their JCV index was assessed at baseline, week 48 and week 96 of treatment. Changes in the mean index value from baseline to weeks 48 and 96 were −0.12 at both points for those treated with placebo and -0.19 and -0.20 respectively for those treated with NTZ. Variability of index scores for individual patients was low; the majority had ≤ 0.5 increase in index between visits (90.3% placebo; 88.0% NTZ), and few patients an increase > 1 (PBO, 5.0%; NTZ, 3.5%).
This analysis provides evidence that treatment with NTZ is not correlated with changes in the index and the stability of the index supports its use for individual patient management.
Additionally, a retrospective study of the incidence of confirmed PML cases in a global safety database maintained by the manufacturer of NTZ from November 2009 to November 2017 was evaluated. This analysis showed that of 180,656 patients who had received ≥ 1 natalizumab dose (total exposure: 625,451 patient-years), overall natalizumab-associated PML incidence was 4.19/1000 patients. An increase in overall monthly incidence reported from 2012 leveled off in mid-2016; overall incidence remained between 4.18-4.24/1000 over the last 21 months. This stabilization coincides with introduction and publication of the JCV index, suggesting that risk stratification factors successfully stabilizing PML incidence.