We propose the very early use of natalizumab to maximise outcomes in people with very early relapsing MS.
In the European Union, natalizumab is licensed to treat adults with highly active relapsing-remitting multiple sclerosis for the following patient groups:
- Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (DMT)
or
- Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
The reason for this restrictive labelling is historical and relates to the undefined risk of developing PML prior to the implementation of JC virus serological testing to derisk PML. As a consequence of natalizumab’s restricted label, an increasingly small number of patients with MS are being treated with natalizumab.
Natalizumab’s attributes of being a very high efficacy agent, having a rapid onset of action, being relatively safe in the short-term (12 months) and having the ability to reverse its mode of action (washout or using plasma exchange) make it the ideal DMT to treat active MS acutely to prevent further damage.
There is emerging evidence that the earlier you treat MS the better the outcome. We have anecdotal evidence, from individual patients, that even short delays in starting DMTs may have consequences for individual patients with multiple sclerosis. In many parts of the world healthcare systems are not configured for the rapid diagnosis and treatment of multiple sclerosis, which results in many pwMS waiting months, and in some cases years, to be diagnosed and treated. We feel this laissez-faire approach to the management of MS is wrong and is counterintuitive to how we approach other neurological diseases in particular stroke where time matters.
We hypothesise that by treating people who are likely to have MS acutely with natalizumab we will improve outcomes, i.e. these patients will acquire less disability and may even have improved rates of disability improvement, compared to patients managed in a standard way.
We have therefore designed the #AttackMS Natalizumab trial to test these hypotheses and have approached Biogen to fund and/or sponsor this study.
The trial plans to recruit patients with clinically isolated syndromes, with an abnormal MRI (two or more lesions suggestive of demyelination), within 7 days of onset and to randomise them to being treated with natalizumab (300mg ivi 4 weekly) or placebo. Subjects will then be managed according to a protocol that will ensure they are diagnosed and considered for licensed treatments within an 8-week period. The latter has been chosen as it is within the timeframe set out by an international panel of MS experts as being an appropriate period of time for being diagnosed with MS and started on treatment (please note in most healthcare systems it takes longer than this). At 8 weeks, i.e. after their third infusion of natalizumab or placebo, subjects will be unblinded; those on natalizumab will then continue on natalizumab for another 10 infusions and those on placebo will be started on the DMT that their treating neurologist and themselves have chosen. Subjects will then be followed for a further 10 months.
The primary outcome will be an area-under-the-curve (AUC) analysis of serum neurofilament levels, a biomarker of neuroaxonal damage, performed on serial blood samples taken over the period of the study. Secondary outcome measures will include MRI, clinical and patient-related outcome measures (PROMS).
MRI metrics will include (1) new T2 lesions as a marker of focal inflammation, (2) single lesion MTR as a marker of remyelination, (3) T1 hypodensity as a marker of tissue damage. Clinical outcomes will focus on disease improvement using a composite of the EDSS, T25W, 9HPT, SDMT, and low-contrast visual acuity (LCVA). PROMS will include a fatigue scale and important symptom for pwMS that has been shown to be improved by natalizumab.
At the end of the 12 months of the study treating neurologists and participating subjects in the natalizumab arm will be informed about their JCV serostatus and a decision will be made to continue on natalizumab or switch to another DMT. Subjects will then be rolled over into an extension study to be followed for a further 12 to 24 months to collect long-term clinical and MRI outcomes. The latter is important to assess brain atrophy or brain volume loss.
What we are interested in hearing from you the MS community is this trial ethical and do you think the scientific principles underpinning it are sound?
If you work for Biogen and are reading this blog post and are wearing your commercial hat you will see this trial may be the vehicle you need to resuscitate natalizumab as a mainstream DMT and to convince the EMA to reconsider natalizumab role in the management of MS and grant it a first-line license it deserves; particularly for people who are JCV seronegative.
At Barts-MS we are so convinced that the #AttackMS treatment paradigm will improve MS outcomes for individuals with MS that we have started using it already in a few isolated patients with highly active MS. We want to take this paradigm to all our of our patients. Yes, all of our patients, because we want to maximise their outcomes.
From a political perspective, this trial may nudge the MS community to be more proactive about treating MS and cement the message that we have been promoting for several years that ‘Time is Brain’. Why should we value the MS brain any less than the stroke brain?
CoI: multiple
Is tgis push for Tysabri in amswer to the recent alemtuzumab restrictions?
The say on the blog until now has been that tysabri is a short term plug (regardless of JC status) to buy time and look for an adequate long term solution (alemtuzumab, hsct….) that reduces BVL more adequately.
Yes and no. Alemz is an IRT therefore is irreversible and suitable for the #AttackMS trial.
Yes. The #AttackMS trial addresses several points and will hopefully act as a catalyst to treat MS actively as early as possible and to allow us to use natalizumab 1st line.
Another point most neurologists accept natalizumab as being one of our most effective DMTs so will understand what we are proposing to achieve with this study.
This is wonderful news. I am fortunate to have been under the care of a neurologist in the US who believed this to be true over 13 years ago. He essentially stopped my MS in its tracks. While I started on Avonex, after 8 weeks, I could not get to a full dose and he immediately transitioned me to Trysabri. Over the years, I seroconverted. We have since put me on extended dosing with no change in lesion load and no change in my EDSS.
My fingers are crossed that this will get funding.
There is no reason why at the end of 12 months someone could continue natalizumab if JCV seropositive patients using an extended interval dosing schedule.
Hasn’t Nat been available in quite a few other countries for people early in post- diagnosis stage? No problems with the ethics of the trial but is there not evidence from countries prescribing Nat early after diagnosis to show it ‘works’ in the way you propose? Or does this not count as ‘evidence’ since just historical data rather than official trial? Not a scientist so don’t know these things! Even if it is just interesting data can it not at least be considered along with your trial? But maybe you can’t collect it in a systematic enough way, if at all? Anecdotally what you suggest seems to be the case.
A contemporary thinker would fight for making Cladribine the first DMT for CIS and early MS in order to try stoping the disease on its tracks or make its course milder. With the way you suggest, you don’t save brain, you just make sure that MS will be a chronic debilitating disease long term.
Unfortunately cladribine is irreversible and requires a lot of baseline screening that makes it unsuitable for #AttackMS. Similarly for the anti-CD20 therapies.
Unfortunately cladribine is an IRT and therefore irreversible and not suitable for #AttackMS trial. Nothing stopping you switching to cladribine at 12 months.
12 months later can be too late to stop it on its tracks…
Like its known in diabetes I, you should intervene fast otherwise any intervention to regulate immune responses is in vain.
To put 12 months into perspective the last pan-EU study showed the average time from symptom onset to MS diagnosis was 8.1 years. At least this study will improve on that and get people onto a highly effective treatment before formal diagnosis.
Why Cladribine rather than one of the other IRTs?
In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003.
https://www.ncbi.nlm.nih.gov/pubmed/29051829
And of course safety. The alternative IRT is only Lemtrada.
I for one think it is ethical. I was put on Natalizumab as soon as I was diagnosed and it’s worked perfectly for me with zero side effects. I’ve been on it for 2 years now.
“I was put on Natalizumab as soon as I was diagnosed ”
Only those patients would not be diagnosed as this trial wants to bypass even the controvertial new McDonald criteria.
Great that you started Tysabri early on your -diagnosed- disease though!
I am no expert, but to me it seems ethical and should be adopted ASAP.
I like the design. It’s succinct. In my mind, the ‘ethics’ of the study turns on the 8-week placebo period and whether the underlying hypothesis has clinical equipoise. I don’t see a problem with either.
I am a CIS patient with no new lesions (on 3T) and no new relapses after 2 years. No OCBs either. Are you telling me that I should have used a drug that protects from lesions and relapses before I would need it, a drug that the longer you are on it the longer you endanger high JCV and thus necessary withdrawal?
Are you comfortable receiving no treatment or a lower efficacy treatment knowing there is a chance your CIS may progress to MS? Also, if in another two years you do show signs of progression would you still think you shouldn’t have started a higher efficacy drug sooner? It’s all about the level of risk you are willing to assume, with disease and treatment.
Personally, I think the question being asked in this study is important.
I keep close monitoring of MRIs every 6 months and the moment I see more lesions I will opt for a treatment (I would still prefer a disease modifying drug that would harness the disease early though).
But with no OCBs you have to look really hard for any other causes for these episodes (somehow atypical in my case), as we did (for example I have antiphospholipid antibodies). Things I wouldn’t have known until after I was initiated with an MS drug, because it could be MS too among the others!
There are often grey areas, thats why there are criteria to meet to be diagnosed with the disease and not a “if its looks like a duck, its a duck” guess. In my case, with no OCBs I would always live with the doubt, do I really have MS, I never got any new lesions or relapses, never met the criteria (add to that the studies suggesting that a percentage of CIS patients do not convert to CDMS ever).
There is no “therapeutic” potential in Tysabri either, that you would take it for a while and you could exit with less posibillities of converting. Its rather the opposite, you could exit worse than you entered because of the rebound efffect. No gain there for CIS.
(oh, about the two lesions in the criteria of this study, for the radiologist I have two lesions, for my guru MS doctor only one looks like typical MS lesion, so go figure!)
To sum it up, it could be an interesting trial if it was better designed: More than two lesions on initial MRI, NfL, OCBs, other antibody tests. Few patients relapse again within a month (till tests are out), more would have to get an unecessary expensive drug monthly with unknown side effects for them.
Nearly 1 in 5 People Thought to Have MS Have Been Misdiagnosed
https://www.msard-journal.com/article/S2211-0348(19)30048-3/fulltext
I have been diagnosed cis for 4 yrs now. I have over 20 brain lesions, one spinal and positive lumbar puncture, after suffering with optic neuritis, leg weakness and mixing up words. I had one historical event about 10 yrs ago but no mri evidence from then to include it for diagnosis . I have contacted nurse on several occasions over the years with new symptoms but diagnosis remains the same As they’re obviously not disabling enough. No new lesions. I’ll be interested to see outcome of this study.