SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.
The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.
Real-World Safety Data
While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.
To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.
The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.
Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).
Parsing the TOUCH Registry
With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.
“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”
The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.
The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.
The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.