Extending Tysabri dose intervals controls RRMS activity
NEXT-MS: Maintaining blood level threshold as effective as standard regimen
Extending Tysabri (natalizumab) dosing intervals based on the drug’s blood levels was as effective at controlling disease activity in people with relapsing-remitting multiple sclerosis (RRMS) as the approved four-week dosing regimen.
That’s according to results from NEXT-MS (NCT04225312), a Phase 4 clinical trial studying whether tailoring Tysabri’s dosing schedule to maintain blood levels above a certain threshold is as effective at reducing MS disease activity and disability progression as the standard dosing regimen.
“Therapeutic drug monitoring can be used by clinicians to (further) extend [Tysabri] treatment intervals, thereby lowering treatment burden for patients and healthcare costs, and potentially further reducing treatment risks,” the researchers wrote.
The trial’s details were published in “Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS)” in the Journal of Neurology, Neurosurgery and Psychiatry.
Tysabri is an approved antibody-based MS therapy that’s been shown to decrease relapse rates, slow disability progression, and prevent new brain lesions from forming. It’s administered at 300 mg every four weeks via intravenous (into-the-vein) infusions. However, it can trigger progressive multifocal leukoencephalopathy (PML), a life-threatening brain infection, so less frequent dosing has been proposed to reduce that risk without affecting the treatment’s effectiveness.
A recent clinical trial called NOVA suggested the dosing interval can be safely extended to six weeks.
Testing Tysabri dosing intervals
Sponsored by Amsterdam UMC, the NEXT-MS study tested different dosing intervals based on predefined concentrations of Tysabri in the blood of treated patients. The trial enrolled 376 adults with RRMS who had received at least six infusions of Tysabri.
The standard four-week dosing regimen was chosen by 60 participants, while 251 received infusions when Tysabri levels dropped to 10 micrograms (mcg)/mL, and 65 were treated when levels reached 5 mcg/mL.
The study’s primary goal was to compare the number of new or enlarging lesions, based on MRI scans, between the 10 mcg/mL group and a historical group of patients previously given the standard four-week regimen.
Recent interim data demonstrated only a few patients showed disease activity on MRI scans across all the study groups. In that analysis, most participants had been followed for more than a year and the median time between infusions was five weeks in the 10 mcg/mL group and six weeks in the 5 mcg/mL group.
Levels of neurofilament light chain (NfL), a nerve damage marker, also remained stable throughout the study. No cases of PML were reported, indicating the tailored treatments could be a promising alternative to standard Tysabri treatment.
Results of NEXT-MS trial
In this published report, the median follow-up across all study groups was longer, at 86.9 weeks, about 20 months. Consistent with the interim data, the 10 mcg/mL group received infusions at a median five-week interval, ranging from four to eight weeks. The 5 mcg/mL group was treated a median of every six weeks, with intervals ranging from four and nine weeks.
Top-line data showed the number of new or enlarging lesions was similar in the 10 mcg/mL group and the historical four-week dosing group. In general, the incidence of new or enlarging lesions was 10 per 1,000 person-years in the 10 mcg/mL group, and 24.7 per 1,000 person-years in the historical group. Person-years is a measure that accounts for the total number of patients and the amount of time each person spent in the study.
Similar findings were observed in the 5 mcg/mL group and those who continued with four-week dosing.
“There was no evidence for differences in radiological disease activity between all study groups,” the researchers wrote.
The rate of relapses in the 10 mcg/mL group was lower than in those who previously received a four-week dosing regimen. One person in the 10 mcg/mL group had a relapse compared with nine in the historical dataset. No relapses occurred in the 5 mcg/mL group and the four-week NEXT-MS dosing group.
Changes in Expanded Disability Status Scale (EDSS) scores, a measure of disability, were comparable across all study groups. Fifteen participants (9%) in the 10 mcg/mL group had disability progression, while 11 (6.6%) had disability improvement. In the 5 mcg/mL group, five patients (7.9%) had disability progression and five showed improvement.
NfL levels in the 5 mcg/mL group significantly decreased over time, but these changes were small and comparable to the 10 mcg/mL group, whose NfL levels remained stable. There were no reports of PML or differences between the groups in testing positive for the John Cunningham virus that causes PML.
“Personalised EID [extended interval dosing] of [Tysabri] by therapeutic drug monitoring is a promising approach to optimise treatment intervals,” the researchers said.
Marcus Koch, MD, PhD, an associate professor of neurology at the University of Calgary, in Canada, in an editorial published alongside the study, wrote: “The NEXT-MS results show that personalised EID using [Tysabri levels] is feasible. Its introduction into clinical practice will reduce treatment burden and cost, and likely also improve treatment safety.”
The trial investigators will continue a modified version of the NEXT-MS study called SUPERNEXT, based on these findings. Participants will change their Tysabri regimen to infusion intervals of six weeks or more based on 5 mcg/mL levels.
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