Personalized extended interval dosing of natalizumab in relapsing remitting multiple sclerosis

Natalizumab, is effective in the treatment of relapsing remitting multiple
sclerosis (RRMS). Based on the different therapeutic dosages of 3-6 mg/kg in
phase II trials, a fixed dose of 300mg of natalizumab once every four weeks was
chosen for phase III trials in order that the majority of patients (with
weights ranging between 50 and 100kg) would fall between a dose of 3-6 mg/kg.
In 2006, a dose of 300mg every four weeks was approved by the EMA/FDA for the
treatment of RRMS. However, in this treatment regimen, natalizumab
concentrations may stay detectable in serum up to 200 days after cessation of
therapy.

Natalizumab binds to the α4 subunit of the α4ß1-integrin (VLA-4) receptor on
lymphocytes. Adhesion of the VLA-4 receptor with its ligand, the vascular cell
adhesion molecule-1 (VCAM-1) receptor on endothelial cells, mediates migration
of lymphocytes across the blood brain barrier. Natalizumab blocks this pathway
and hereby halts lymphocyte driven inflammatory demyelination within the
central nervous system.
Saturation of the α4-integrin receptor is associated with the natalizumab
concentration, which can be measured by ELISA in serum. The natalizumab
concentration peaks directly after infusion, after which an exponential decay
sets in. Significant disease activity returns when the receptor saturation
falls under 20% and receptor desaturation (defined as <50%) occurs when the
natalizumab concentration falls under 1-2.5µg/ml. After a standard 4-week
treatment interval, the natalizumab nadir concentration varies widely between
patients, ranging from 0.1-80µg/ml. However, the mean natalizumab nadir
concentration (25µg/ml), lies far above the therapeutic threshold, which
implies the large majority of patients has an excess of natalizumab at time of
re-dosing.

The major disadvantage of natalizumab is the risk of developing progressive
multifocal leukoencephalopathy (PML). PML is an opportunistic demyelinating and
possibly lethal brain infection caused by the John Cunningham (JC) virus.
Approximately, 55% of de Dutch population is positive for the JC virus, with
1-2% JC seroconversion annually. Unfortunately, the seroconversion rate in MS
patients treated with natalizumab appears to be substantially higher, which
remains poorly understood. Because of PML risk many JC virus positive patients
using natalizumab over 2 years have been forced to stop this effective therapy.
However, very recent evidence is showing a drastic decrease of the risk of PML
in patients with extended natalizumab infusion intervals.

After one year of treatment, intra-individual natalizumab nadir concentrations
stay stable in a set treatment interval, which makes this a suitable marker for
extending the treatment interval. A natalizumab nadir concentration of >10µg/ml
is considered high, and is a safe cut-off for extending infusion intervals in
those patients with high natalizumab nadir concentrations. Approximately 85-95%
of patients have natalizumab nadir concentrations above 10µg/ml.
As receptor desaturation (<50%) occurs when the natalizumab concentration falls
under 1-2.5µg/ml and significant disease activity seems to return when receptor
saturation falls under 20%, it seems plausible that the interval could be
safely extended to a natalizumab nadir concentration of 5µg/ml.

As of April 2021, the European Commission has granted marketing authorization
for subcutaneous (SC) injection of natalizumab. SC administration was studied
in 2 clinical trials (DELIVER (NCT00559702) and REFINE (NCT01405820)) where SC
administration showed comparable efficacy and safety to IV administration of
natalizumab (Plavina et al. 2016; Trojano M. et al. presented at AAN Annual
Meeting). Pharmacokinetic- and pharmacodynamics model-based simulations
resulted in comparable trough natalizumab serum concentration and α4-integrin
receptor saturation between SC and IV administration at a dose of 300 mg every
4 weeks (Zhao Y, et al. ACTRIMS 2021 virtual forum, P024).

In 2015, we started a Dutch multi-center trial (the PDNMS trial) with
personalized extended interval dosing (PEID) of natalizumab based on trough
concentrations in patients who did not show disease activity under natalizumab
the year prior to inclusion (no relapses, no new/enlarging T2 lesions or
gadolinium enhancing lesions on MRI). Sixty-one patients were included. The aim
was a natalizumab trough concentration of 10µg/ml. Natalizumab trough
concentration was measured before every infusion and the infusion interval was
prolonged when the concentrations >=15µg/ml in two consecutive infusions with
the same interval. Study follow-up was one year with an extension phase of one
year. Patients received a 3 monthly follow-up with a clinical evaluation and an
MRI brain scan (including gadolinium enhanced sequences). All patients remained
without disease activity (clinically and radiologically) during the first year
of PEID, proving our hypothesis that efficacy of natalizumab does not decrease
with PEID. Furthermore, all patients who completed the extension phase (n=22)
did not show any disease activity.

In 2020, the first patient was included in the NEXT-MS study, in which patients
received PEID with an aim trough concentration of 10 µg/mL in the main group
and 5 µg/mL in a subgroup. Results of our interim analyses showed comparable
disease activity between patients in the main group, the subgroup and the
control group (4-weekly infusions). The subgroup enabled participants to extend
time between infusions safely to 6.3 weeks (range 4-9). Furthermore, The NOVA
study was an international study that randomized patients between 4 and 6 week
natalizumab dosing intervals with a primary outcome measure of new or enlarging
T2 lesions during 72 weeks of follow-up. The results showed that natalizumab
administered every 6 weeks provides a high level of efficacy after 72 weeks in
stable RRMS patients who switched from the 4 week interval (Foley et al. 2022).
Although the primary outcome (estimated mean number of new/enlarged T2 lesions)
was higher in the 6 weeks group (0.20 [0.07 to 0.63] vs. 0.05 [0.01 to 0.22]),
this difference was evaluated as not clinically meaningful, since the lesions
were detected in 1 patient who discontinued natalizumab for 3 months and 1
patient who developed PML. There were no differences in annualized relapse rate
or new T1 hypointense lesions, and safety profile of natalizumab was similar
between the groups. In addition, recent studies showed a drastic decrease of
the risk of PML in natalizumab patients who received extended interval dosing
(EID).*

Personalized extended interval dosing with natalizumab serves multiple
purposes. Firstly, it puts the patients* individual biological needs centrally
and decreases overuse of natalizumab, increasing efficient use of healthcare
and expensive medication. Secondly, with extending infusion intervals the
disease burden of the patient decreases with fewer hospital visits. And
thirdly, the risk of PML is decreased with extending natalizumab infusion
intervals.

This study has been transitioned to CTIS with ID 2024-513105-31-00 check the CTIS register for the current data.

Primary Objective:
Our objective is to validate the safety, measured by radiological disease
activity, of personalized extended interval dosing of natalizumab to >=6 weeks
(with an aim natalizumab trough concentration of 5 µg/ml) in a large real-life
cohort across the Netherlands. Our objective is to follow at least 184 patients
on PEID for 2 years. Finally, we hope to provide sufficient data to implement
our strategy as standard natalizumab care in Dutch MS treatment guidelines.

Secondary Objectives:
- Determining clinical disease activity and disability progression in extended
patients
- Providing a cost analysis of PEID.
- To assess the influence of PEID on JC virus conversion, JC virus index,
incidence of progressive multifocal leukoencephalopathy.
-To determine treatment satisfaction and quality of life in this large
real-life setting cohort.
-To study the long-term stability of natalizumab trough concentration and the
prevalence of natalizumab antibodies in the standard 4 week interval.

The proposed trial is a national open label phase IV natalizumab cohort study
trial. Our aim is that the large majority of natalizumab treated RRMS patients
who are currently treated with PEID in the Netherlands will continue in this
study.We will continue the study with 24 participating centers. The study
duration is 96 weeks. This study will contain the PEID group, a control group,
and a historic control group. If patients desire a personalized natalizumab
treatment and have been treated with >=6 consecutive natalizumab infusions, they
have the opportunity of entering the study as a participant of the PEID study
group. Participants with a current treatment schedule of every 4 or 5 weeks
will have one measurement of natalizumab concentration in the current interval.
Participants will then directly switch to a treatment schedule of every 6
weeks. Participants with a current treatment schedule of >=6 weeks will have one
measurement of natalizumab concentration in the current interval. Participants
will then possibly further extend the treatment interval based on the
natalizumab concentration. The PEID study group will receive a personalized
treatment with an interval of >=6 weeks. If patients do not desire a
personalized treatment, they will be asked informed consent for the use of
their patient data and for the questionnaires as the control group. As this
introduces a bias, the PEID study group will be compared to a historical cohort
of Amsterdam MS Center. Furthermore, the patients of the control group will
also be asked to donate blood once for measuring of natalizumab trough
concentration.

Measuring natalizumab concentration and personalizing the interval
Prior to the natalizumab infusion, blood (5cc) will be taken from the drip feed
to measure the serum natalizumab trough concentration. Only when sampling
through the drip feed is not possible, patients will visit the laboratory for
measurement of natalizumab concentration. All blood will be send to Sanquin
Laboratory in Amsterdam. Sanquin Laboratory has an excellent logistic system
with nearly all hospitals in the Netherlands having a daily or 3-weekly
courier. Results of the natalizumab concentration is sent back to the hospital
within 2 weeks. Before the start of the new PEID protocol, the natalizumab
trough concentration will be tested. All patients that are currently on a 4
week or 5 week interval will then switch to a 6 week interval. The natalizumab
trough concentration will be measured every 3 consecutive treatments on the 6
week interval. For patients in the PEID study group with a current treatment
interval of >= 6 weeks, the personalized schedule will be based on the
natalizumab trough concentration.


Baseline assessment
A digital online national database will be used for entering the patient data.
Baseline information includes: age, date of diagnosis, start of natalizumab
treatment, JC virus state and index and baseline natalizumab trough
concentration measurements. Furthermore, patients will receive a digital
questionnaire regarding disease burden and MS related symptoms (Multiple
Sclerosis Impact Scale; MSIS-29)24, a questionnaire regarding impact,
convenience, satisfaction and side-effects of treatment (Treatment Satisfaction
Questionnaire for Medication; TSQM), a questionnaire regarding the wearing-off
effect and questionnaires for cost-utility analysis: treatment inventory of
costs in patients (TIC-P), EuroQol 5D (EQ-5D) and the Work Productivity and
Activity Impairment Questionnaire; Specific Health Problem (WPAI-SHP). A
re-baseline MRI-brain scan without gadolinium will be performed before start of
the new protocol when the previous MRI scan was >3 months ago and no MRI scan
is planned in the upcoming months. The advised MRI protocol consists of a 3D
fluid-attenuated inversion recovery and axial PD/T2-weighted sequences.

Yearly routine assessment
After the start of the personalized treatment, natalizumab trough
concentrations will be measured after every 3 infusions. Following routine
follow-up in natalizumab treated patients with RRMS, patients receive a yearly
clinical and radiological (MRI-brain) assessment. The advised MRI protocol
consists of a 3D fluid-attenuated inversion recovery and axial PD/T2-weighted
sequences. Furthermore, current protocol states a 6 monthly assessment of the
JC virus. In the study database, we will collect data regarding the treatment
schedule, follow-up natalizumab concentration, yearly MRI, (estimated) Expanded
Disability Status Scale (EDSS), relapses during the last year and the JC virus
state and index. Patients will receive the digital questionnaires after
approximately the first and second year. regarding the quality of life after
the first year of PEID. Follow-up will last 2 years. After the trial, patients
can, in agreement with their treating neurologist, decide to stay on their
personalized natalizumab treatment interval.

For patients switching from IV to SC administration of natalizumab, the trough
natalizumab concentration will be measured before every infusion for two years
starting from the first SC dose.

There is a minimal chance of increase of disease activity.