The number of cases of Tysabri (natalizumab) that are associated with progressive multifocal leukoencephalopathy (PML) — a serious brain infection — in multiple sclerosis (MS) patients living in Sweden fell between 2006 and 2018, a study shows.
Notably, the data highlighted that this drop was likely due to the introduction of a risk management plan (RMP) in 2012 that advises switching Tysabri-treated patients at risk of PML to other highly effective disease-modifying therapies (DMTs).
These findings are consistent with those previously reported in France, and support the implementation or continuation of such risk-minimization strategies in MS patients on Tysabri, the researchers noted.
The study, “Reduction of the risk of PML in natalizumab treated MS patients in Sweden: an effect of improved PML risk surveillance,” was published in the journal Multiple Sclerosis and Related Disorders.
Marketed by Biogen, Tysabri is an approved therapy for relapsing MS. It works by preventing immune cells from entering the brain, ultimately lowering brain inflammation and reducing disease relapses.
While its effectiveness was established in clinical trials and real-life studies, Tysabri’s usefulness “has been limited due to an increased risk of progressive multifocal leukoencephalopathy (PML), a severe opportunistic infection of the brain caused by the John Cunningham virus (JVC),” the researchers wrote.
This rare and often fatal disease can occur in Tysabri-treated patients due to low numbers of immune cells in the brain.
To date, three main risk factors of Tysabri-associated PML have been identified and used in algorithms for patient selection and safety monitoring: the presence of antibodies against JCV (suggestive of exposure to the virus), previous immunosuppressive treatment, and more than two years of Tysabri use.
Despite these improvements in PML risk assessment, the global frequency of Tysabri-associated PML increased until mid-2016, after which it appeared to stabilized at a rate of about four cases per 1,000 Tysabri-treated patients.
However, a 23% annual drop in Tysabri-associated PML rate was reported in France between 2013 and 2016, suggesting that more recent risk surveillance strategies may be working.
Researchers now evaluated changes in the rates of Tysabri-associated PML and in the proportion of high-risk MS patients in Sweden by retrospectively analyzing data — between June 1, 2006 and Dec. 31, 2018 — from the population-based Swedish MS registry (NeuroReg).
The impact of a risk management plan, started in 2012 in the country, in PML rates and risk was also analyzed. The plan considered all three main risk factors, as well as the levels of anti-JCV antibodies, in assessing a patient’s risk of PML. If risk was seen to rise, the patient would be advised to change to another highly effective DMT.
Data covering 3,128 MS patients who started with Tysabri between 2006 and 2018 were analyzed; 53.8% of these patients began treatment before plan’s introduction (2006–11).
After its implementation (2012–18), a lower proportion of Tysabri-treated patients were positive for anti-JCV antibodies (37.8% vs. 63.9%).
By Dec. 31, 2018, 804 patients worldwide had experienced PML, including nine in Sweden. Two of these nine patients died from PML-associated complications.
All Swedish cases had initiated Tysabri treatment between 2007 and 2010, with treatment duration ranging from about 1.5 to eight years. Seven of these patients showed antibodies against JCV, and six had been previously treated with interferon-beta.
About 77.8% of PML cases were diagnosed before the introduction of the risk management plan, with the highest number (three cases) occurring in 2011, representing a rate of 2.38 cases per 1,000 person-years (the gathered follow-up years of all patients).
Two of the three remaining PML cases were diagnosed in 2012 (1.51 cases per 1,000 person-years), with the last one occurring in 2018 (1.02 cases per 1,000 person-years).
The team noted that while the risk management plan was introduced in 2012, it was not yet established that year, and that the last PML case in 2018 did not comply with Swedish MS care guidelines.
In addition, treatment duration was shorter in patients initiating Tysabri after the plan’s introduction, than in those initiating it earlier — mean of 32.6 months in the period 2012–18, and 60.1 months in the period 2006–11. The cumulative PML risk was also significantly lower after the plan’s adoption.
The number of MS patients treated with Tysabri dropped over time, with 1,100 patients receiving Tysabri by Dec., 2018, and 21 (1.9%) of them being considered at increased risk of PML.
The possibility to switch from Tysabri to rituximab treatment in patients at higher PML risk after 2012 “has probably strengthened the utility of PML risk surveillance,” the researchers wrote. “This may have contributed to the reduction of PML incidence and partly explaining the increase of off-label rituximab treatment of MS in Sweden.”
Overall, the estimated PML rate by December 2018 was six times lower in Sweden than globally — 0.7 vs. 4.15 cases per 1,000 person-years.
These findings highlight the reduction in Tysabri-associated PML cases in Sweden since the therapy’s launch.
“The Swedish nationwide PML risk surveillance program seemed to have reduced the PML incidence,” the researchers wrote. “A less pronounced decline in PML incidence has recently been observed in France, but not globally.”
Overall, these data suggest that the drop in PML in Sweden was linked to the effective implementation of the risk management plan, supporting the importance of continuous risk monitoring in Tysabri-treated patients and of switching high-risk MS patients to other highly effective DMTs.
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