Extended interval dosing

Background

I have several patients who despite being JC virus (JCV) seropositive insist on staying on natalizumab despite alternative treatment options. I even have a few patients who, after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab (Nz). The reason given for the latter decision typically relates to the return of MS fatigue, or brain fog, after switching from Nz. Nz is remarkable in this regard and is the only DMT in which an n=1 trial is sufficient to know that the therapy works. Patients come back and literally say to you ‘I feel well, my fatigue has gone and my thinking is clear’. This is why anything that decreases the risk of PML for patients on Nz has to be a good thing.

At present we have JC virus testing (negative and positive), level of JCV antibodies (antibody index), a rising antibody index, previous exposure to immunosuppression, and treatment duration to help guide us with regard to the PML risk assessment. We also have frequent MRI monitoring (3-4 monthly) to detect PML early and plasma exchange to remove Nz as a backup option if one of our patients develops PML. This is why extended interval dosing (EID) may be another option at hand to reduce the risk of PML.

The theory behind EID is that some cells are less sensitive to the effects of Nz and that if you delay the next Nz infusion by 1 or 2 weeks the saturation of their surface receptors drops below a threshold and allows these cells to traffic into the central nervous system. If these less natalizumab-sensitive cells are the antiviral CD8+ T-cells and/or the natural-killer cells that fight viruses then this could allow immune surveillance of the CNS to occur. This will prevent PML from occurring. If you get the EID right the saturation of the immune cells causing MS, possibly the memory B cells, is sufficient not to allow MS to reactivate. It is clear that not all cells are made equal when it comes to the effect of Nz. Importantly, there several other adhesion molecules on cells that impact on adhesion (stickiness) of immune cells to the blood vessels in the CNS. It could also be a delicate balance between the availability of different accessory adhesion molecules that makes the difference.

These principles have been adopted by several neurologists in the USA and the data that is emerging from their centres suggests they are correct, i.e. despite being JCV+ve MSers on Nz on EID have a much lower risk of developing PML.

When Biogen, who market Nz, saw these EID results, they decided to interrogate their big database on the use of Nz in the USA. They are fortunate to have the so-called TOUCH programme, which is a mandatory database of all MSers on Nz in the USA. The TOUCH database allowed the statisticians to find people who are on EID and to compare them to standard interval dosing (SID) for PML risk. Because the TOUCH programme is real-life data and is not a clinical trial database the periods of EID are variable. To deal with this the statisticians defined three different types of EID with increasing stringency. The remarkable finding that EID was found to reduce the risk of PML compared to SID, and in the most stringently defined cohort of EID there were no cases, i.e. zero cases, of PML.

Abstract

Zhovtis Ryerson et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.

METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.

RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.

CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Actions

I have acted on this already and have offered EID to my patients who are at risk of PML on Nz. It is advisable to go to 6 weekly EID over several months so as not to precipitate preinfusion worsening of symptoms. I am now recommending 3 infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question that needs to be answered is whether or not EID will be associated with some loss of the effectiveness of Nz. However, it may be possible to walk a tightrope and get the dosing just right to prevent PML and to keep the MS at bay. We will now have to do trials to find the sweet spot for EID. This may not be simple in that we may have to dose each patient differently to get the right level of VLA-4 saturation to treat MS and to allow intermittent VLA-4 desaturation for selective anti-viral cell trafficking to prevent PML. I predict that personalised dosing will come to MSers on Nz; this will be based on body size and intermittent analysis of VLA-expression levels on cells to optimise the exact dose and duration between infusions.

I am personally thrilled by these results. Why? Anything that derisks PML for MSers on Nz is a good thing and it increases the chances of us getting our Nz #BrainAttack trial off the ground. It also potentially breathes new life into Nz for people with more advanced MS. The latter is important because Nz is one of the DMTs that is effective in more advanced MS, particularly on slowing down or preventing worsening of hand and arm function.