Can more be done to derisk natalizumab; the case for EID?

Extended-interval dosing (EID) breathes new life into natalizumab. Does this mean our #BrainAttack trial in CIS and an ASCEND II+ trial in SPMS (including wheelchair users) has a chance of getting done (wink-wink)?

I have several patients who despite being JCV+ve insist on staying on natalizumab despite alternative treatment options? In fact, I have some patients who after switching to another DMT have opted to go back onto natalizumab. The reason given for the latter decision relates to the return of MS fatigue, or brain fog, after switching from natalizumab. Natalizumab is quite 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 natalizumab is 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 natalizumab as a backup option if one of our patients develops PML. This is why it is so exciting to hear that 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 natalizumab and that if you delay the next natalizumab 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 that 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 natalizumab. 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 some neurologists in the USA and the data that is emerging from their centres suggests they are correct, i.e. despite being JCV+ve pwMS on natalizumab on EID have a much lower risk of developing PML.

When Biogen, who market natalizumab, saw these results that decided to interrogate their big databases on the use of natalizumab in the USA. They are fortunate to have the so-called TOUCH programme that is a mandatory database of all pwMS on natalizumab 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. These data are so important to pwMS on natalizumab and the MS community that I have asked Lana Zhovtis Ryerson, the senior author of the poster and presentation at ACTRIMS to do a guest post on this very important topic. Good news she has accepted.

We at Barts-MS have acted on this already and have offered EID to a few of our patients at risk of PML on natalizumab. The question that needs to be answered is whether or not EID will be associated with some loss of efficacy of natalizumab. However, it may be possible to walk a tightrope and get the dosing just right to prevent MS and to keep the MS shredder at bay. We as an MS community 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 intermittent VLA-4 desaturation to allow selective anti-viral cell trafficking to prevent PML. I predict that personalised dosing will come to pwMS on natalizumab; 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 pwMS on natalizumab is a good thing and it increases the chances of us getting our natalizumab #BrainAttack trial off the ground (Biogen employees, I hope you are reading this post) and it also breathes new life into natalizumab possibly for people with more advanced MS. The latter is important because natalizumab is one of the DMTs that is effective in more advanced MS, particularly on slowing down or preventing worsening of hand and arm function. If Biogen were brave they would consider doing some of their EID saturation and mechanistic studies in SPMS as part of an ASCEND II+ trial; the + refers to extending the cohort into wheelchair users. If Roche is prepared to test ocrelizumab in PPMSers who are in wheelchairs, why wouldn’t you test natalizumab in SPMSers in wheelchairs? The unmet need in SPMS in terms of numbers is much larger than the PPMS population; the business case is a no-brainer (it writes itself).

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.


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