There is news about Natalizumab (Tysabri®), which was expected, but it is still good that clarity now exists: In August 2021, the first results of the NOVA study were communicated, which compared the effectiveness of two different dosage intervals of Natalizumab – namely the standard dosage every 4 weeks versus the dosage with extended dose interval every 6 weeks. The NOVA study has now shown that the extended
dosage interval (extended interval dosing, EID – every 6 weeks) is statistically similarly effective
as administration in the standard dosage interval (every 4 weeks).
Why is this important? Well, for some time now, it has been assumed that extending the
dose interval (which could also be described as a reduction in the annual total dose of natalizumab) significantly reduces the risk of progressive multifocal leukoencephalopathy (PML), the main side effect of natalizumab (we had addressed this topic in MS-Docblog 2016 once before). At that time, a retrospective data evaluation of the American TOUCH registry (a registry prescribed by the US Food and Drug Administration (FDA) with
several 10,000 patients for monitoring safety-relevant aspects under therapy with
Natalizumab) showed that an extended dosing interval is associated with a significantly lower
PML risk than therapy with the approved dosing interval. The most recent
analysis of this registry now shows an 88% risk reduction when extending the
dosing interval.
Consequences of extending the dose interval unclear
The evaluation of the TOUCH registry could not provide any information about the effectiveness of
Natalizumab with an extended dosing interval. It remained unclear whether and in how many
patients the MS became active again after an extension of the dosing interval. Nevertheless
a hint for reducing the PML risk with extended dosing interval already found its way
into the professional information: “It is assumed that a Tysabri® dosing interval extended compared to the approved
dosing interval (averaging about 6 weeks) is associated with a lower risk of PML in
anti-JCV antibody-positive patients. When using an extended dosing interval, caution is advised because the efficacy of an
extended dosing interval has not been proven and the associated benefit-risk ratio
is currently unknown.” Thus, the risk of reduced therapeutic efficacy was
placed in the responsibility of the doctor and patient.
This important information gap could now be closed by the NOVA study. In the
study, the approved standard dosing interval (standard interval dosing, SID, n = 248)
300 mg intravenously (IV) every 4 weeks was compared with an extended dosing interval (extended interval
dosing, EID, n = 251), 300 mg IV every 6 weeks. For inclusion in the study, the
patients had to have been treated with Natalizumab in the standard dosing interval for ≥12 months.
Both groups were followed for a period of 72 weeks. The primary study endpoint was
the number of new or enlarged T2 lesions, which in the SID group was 0.05 and in the EID-
group was 0.20. The difference was not statistically significant (p=0.0755), as were the
differences of all relevant secondary endpoints. The result of the NOVA study thus proves,
that minimizing PML risk through an extended dosing interval does not lead to a diminished
effectiveness of Natalizumab therapy. However, it must be said that
with the NOVA study, no statements can be made as to whether the changed
dosing interval actually leads to a PML risk minimization. Here, only the
retrospective data from the TOUCH registry can still be used as a basis.
Risk minimization strategy for JCV-Positives
In light of the now more complete data situation, the extended dosing interval can be used as a
risk minimization strategy for JCV-positive patients. However, careful monitoring must continue to take place even with an extended dosing interval. The results of the
NOVA study refer to the i.v. administration of Natalizumab. In view of the similar
pharmacodynamics of subcutaneous Natalizumab injection, the approach can also be applied to
patients who are treated with Natalizumab s.c.
