FDA-Approved Medications: New Data on Previously Approved Medications
- 300 mg given via IV infusion
- Approved in 2004 for RMS
This monoclonal antibody acts against a molecule involved in the activation and function of lymphocytes, which are immunesystem cells produced to fight infection and disease. It also acts against the passage of lymphocytes into the central nervous system (CNS). The CNS consists of the brain, spinal cord, and optic nerves.
The FDA approved Tysabri in 2004 on the basis of the Phase III AFFIRM trial, in which Tysabri reduced the risk of progression of disability by 42 percent to 54 percent, and reduced the annual rate of relapse by twothirds. Tysabri was voluntarily withdrawn from the market in 2005, after three cases of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection caused by the JC virus, were identified in patients taking the medication. Tysabri became available again in 2006, based on the implementation of a comprehensive risk-management program that includes testing potential Tysabri users to see if they have anti-JC virus antibodies.32
Since then, researchers have been exploring ways to minimize the risk of PML associated with Tysabri use. In one retrospective study, investigators reviewed four years’ of clinical and MRI data from individuals with RMS at six MS treatment centers in Italy to see if extended-interval dosing of Tysabri reduces PML risk without diminishing the medication’s efficacy. In the United States, the standard dosing of Tysabri is 300 mg infused intravenously over the course of one hour, every four weeks.33 In this Italian study, patients either received Tysabri every 35 days (standard-interval dosing group), received it at longer intervals stretching up to 56 days (extended-interval dosing group), or started with 35-day dosing and then were switched to extended-interval dosing. A total of 532 participants were included in the first-year analysis, and approximately half of those individuals (270) were still being followed at four years. None of the participants developed PML.
During the first year of treatment, 84.9 percent of patients (421) in the standarddosing group (had no evidence of MS disease activity, compared with 73.6 percent of patients (111) receiving extended-interval dosing. That difference in disease-free prevalence between groups narrowed at Years 2 and 3, however, and the prevalence was virtually the same at Year 4. These findings suggest that the differences in Tysabri treatment effectiveness between standard and extended-interval dosing dissipate with treatment duration.34
Meanwhile, data from a retrospective, multicenter cohort study in France describe a drop in Tysabri-related PML associated with the physicians’ ability to identify at-risk patients.
The researchers focused on 6,318 people in a French MS patient database who had been treated with Tysabri during a 10-year period. There were 45 cases of PML among those 6,318 patients. After adjusting for patient age and sex, and using statistical analysis to estimate yearly incidence rates, the researchers found a much higher incidence in PML from 2007 to 2013 compared with subsequent years. They note that since 2012, physicians have had information on factors that increase a patient’s risk for developing PML. Those risk factors include testing positive for anti-JC virus antibodies, having previously used an immunosuppressive medication, and having received Tysabri for two years or longer. The investigators surmise that, armed with this knowledge, physicians in recent years have had a greater ability to determine whether a patient is a good candidate for Tysabri or would be better suited to receive another DMT. In support of this conclusion, they note that starting in 2013, estimated PML incidence has decreased by 23 percent each year. 35, 36
Meanwhile, new data on long-term use of Tysabri suggest that the sooner the agent is started, the longer function can be preserved. In a nationwide, prospective cohort study, researchers identified 2,306 individuals with RMS from neurology clinics across Sweden who had been diagnosed with MS after January 1, 1995 and had been receiving Tysabri for at least one year. Researchers divided the patients into two groups — those who began Tysabri within three years of MS onset, and those who started treatment more than three years after onset — and then measured rates of cognitive and physical decline. The patients were also compared with three sets of similar patients: those who had been diagnosed before 1995, who were treated with interferon beta-1a or glatiramer acetate injections, or who received no treatment.
During a median six-year follow-up period, patients who started Tysabri later showed more rapid increases in Expanded Disability Status Scale scores (indicating worsening of disease) and declines in Symbol Digit Modality Test scores (indicating worsening of cognitive function), compared with patients who started the medication sooner. However, disease progression in both Tysabri groups was slower than that seen in the groups of patients with pre-1995 onset, interferon or glatiramer acetate treatment, or no treatment.10