Monday, 26 February 2018

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.

ProfG    

25 comments:

  1. Great post.

    But you could have added for the sake of completion that EID Natalizumab is not expected, on average, to out perform first line treatments after the age of 40.5.

    An untested but fare assumption in my view.

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    1. Re: "... to out perform first line treatments after the age of 40.5."

      The meta-analysis your are referring to was based on EDSS progression over 2-3 years. This the wrong time-frame for EDSS and the wrong focus. In the ASCEND trial the 3-year analysis was positive on T25W and almost positive on the EDSS; if the trial was longer it would have been positive. For EDSS you need at least 3 years to get an answer, this is called therapeutic lag. In the ASCEND trial it was positive on hand function at 2-years. This is because the arm and hand have reserve capacity.

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    2. I think we need to rewrite the length-dependent axonopathy paper. the messages seem to be too complicated to be getting through. May be should call it the EDSS-Blinkers Hypothesis. Let's get rid of the EDSS and the MS World would be in a much better place.

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    3. Thank you - as you say above, BIIB could query their now massive post-marketing database for figures.

      Do you not wonder why nothing has ever been puiblished by them on treatment adhesion, SPMS conversion rates, etc...?

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  2. Thank you for posting this. I suddenly tested JC+ve after 5 years on natalizumab with a titre of 4.25. My neuro and I agreed that it's the best treatment for me, beta interferon having failed spectacularly, and he wants me to stick with it. I now have an infusion every eight weeks and an MRI every sixteen, and after nearly two years of this there's no sign of any problems at all. No new lesions, no worsening symptoms and no PML. I've searched for information to find out whether there had been enough data gathered yet to analyse, and it looks like there has.

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    1. How confident are you with this data? Does it make you feel like you will not get PML? Why natalizumab over potentially PML-safer options?

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    2. MRI every 16 weeks! that's a lot of radiation...

      Cancer risk maybe?

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    3. MRI does not involve irradiation, it's a high strength magnetic field.

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    4. You are right - but what about gadolinium? I remember reading a post on this matter on this blog several months ago....

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    5. You are right too. There have been some safety concerns regarding gadolinium, indicating it propbably should not be used repeatedly. The post you mention is here;
      http://multiple-sclerosis-research.blogspot.com/2017/07/more-on-safety-of-mri-contrast-agents.html

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    6. So the obvious question to Jen is : is you 16-weekly MRI regimen gadolinium enhanced?

      I am having 1 gadolinium scan a year only (JCV-) and am not even comfortable with that...

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    7. I'm very pragmatic. I'm aware that it's a risky strategy, but when I discussed it with my neuro there was a lot of data already and we felt that the evidence then was good enough to make the decision to stick with a drug that had helped me so much. He's a cautious man and I trust his advice. I don't think I can feel entirely sure that I won't get PML - apart from anything else, my risk is stupidly high at something like 1/85 - and I know that if I do get PML then a plasma exchange isn't going to rescue me and leave me with no ill effects. I think I've made a rational decision in choosing to stick with the drug that's kept me well, having been so ill before I started, and I'm being carefully monitored. This doesn't mean I never wake with a start in the middle of the night worried about it, but I could be run over by a cliché tomorrow and I won't let fear rule my life.

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    8. Sorry, missed the part about gadolinium enhancement. I don't have gadolinium every time, it's maybe 1 in 3 times. My kidneys are perfectly healthy though, so there's no reason that I wouldn't be excreting it. I can't find any reliable info about gadolinium toxicity other than stories about a couple of brands having had their licences removed. Mostly, Google gives me clickbait and Facebook pages.

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    9. Turns out that if you reply again before one comment is approved, only your second comment appears. So my original response, fortunately still hanging about on the clipboard:
      I'm very pragmatic. I'm aware that it's a risky strategy, but when I discussed it with my neuro there was a lot of data already and we felt that the evidence then was good enough to make the decision to stick with a drug that had helped me so much. He's a cautious man and I trust his advice. I don't think I can feel entirely sure that I won't get PML - apart from anything else, my risk is stupidly high at something like 1/85 - and I know that if I do get PML then a plasma exchange isn't going to rescue me and leave me with no ill effects. I think I've made a rational decision in choosing to stick with the drug that's kept me well, having been so ill before I started, and I'm being carefully monitored. This doesn't mean I never wake with a start in the middle of the night worried about it, but I could be run over by a cliché tomorrow and I won't let fear rule my life.

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    10. The question that comes to mind is of course how valuable gadolinium is in detecting PML?

      I would skip it otherwise....

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    11. p.s. Jen (same anon here as everywhere else on this post). I full respect the decisions you are taking, how you've approached them and why you are sticking to them.

      I can't congratulate you enough for educating yourself and deciding out of conviction (which is what I was trying to get out of DrBenJ a couple of days ago when I kept pointing out the irrelevance of the logic in his the CART risk/benefit paradigm).

      Well done and a very good luck.

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    12. The MRIs are also used to check for MS activity, which is important when I'm only getting Tysabri every eight weeks instead of every four. In the event that my MS was active, or had recently been active, there would be gadolinium-enhancing lesions that might indicate that an eight-week dosing interval was too long for me and that perhaps I should go to seven weeks (and mess up the infusion nurses' schedules), or choose a different treatment. I'm still not worried about gadolinium.

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  3. I think Biogen needs to do more work around IED. We need to know about effects of natalizumab on different cell types. Does natalizumab have semi-selective effects on different cell types in terms of trafficking? I want to know if EID is associated with any fall-off in efficacy. And more.

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  4. Many Tysabri patients complain that the drug wears out at 24-28 days and they start feeling fatigue and brain fog days before their next infusion. Maybe MRI results can be kept stable but what about the rest of the symptoms that Tysabri is good at keeping at bay?

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    1. I thought I was feeling that way after a year or so, but it was psychosomatic. I'd heard various people complaining that they needed their fix during week 4, that it was wearing off but they'd feel fantastic as soon as they'd had their infusion, and so on and so on. So I thought it was normal and I would feel the same, and then I felt rough in Week 4 because I expected to feel rough. I came to the realisation that I was imagining it, as a drug with the kind of half-life that natalizumab has could not possibly have cleared my system in that short a time. I wondered whether I'd start feeling it on the eight-week cycle, but I feel fine. This is Week 8, infusion in three days.

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    2. In the final few days before a Tysabri infusion I experience cog and physical fatigue and both bladder & bowel stop working properly. I would be interested in EID but do have a worry about new lesions

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    3. I agree with Jen. Had the feeling a few days before, but after 12 years no longer. fI have been on extended dosing for 2 years and no new lesions and feel great. And I am older than 43! I too have GAD only every other. Our radiologist has changed which GAD we get. This news is very positive for me. I am often asked why I don't switch to Ocrevus. The short answer is lack of data. We have so many patient years of data on Tysabri and not so much on Ocrevus. Let alone a good data set on JCV+ previous tysabri patients switching.

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  5. Oh - and I have to give credit where credit is due: Kudos to the Original Poster (G. Gio) for moderating (i.e. replying to) the comments section.

    It motivates the rest of us for asking (hmm, mostly silly) questions.

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  6. This is the best news ever. I have been in contact and following Lana Zhovtis Ryerson from the beginning. I am a pwMS who after 10 years became JC+. I started at 8 weeks EID. After 3 or 4 infusions at this spacing my MRI showed possible activity. I was moved to 7 weeks and have been there since. I have had no new activity.

    My Neuro treats the EID as a moving scale to ensure no new activity. If the EID does not keep the MS at bay, it is not a very good DMT.

    I also believe that personalized dosing will be important. Not only for Tysabri but for Ocrevus as well. These are serious medications that change the dynamics of your immune system and while we all work the same generally, individual tweaks could play an important role.

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  7. Is there any realistic way of using an 18 month natalizumab break to de-risk? STATA results would suggest that this is enough to re-set individual risk.

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