#MSCOVID19 – natalizumab extended interval dosing

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More questions around managing MS during the COVID-19 pandemic; this time in relation to natalizumab (Tysabri) dosing.

The COVID-19 NHS crisis is a double-whammy for pwMS. First, it is redeploying staff away from MS services to work on the frontline. Secondly, the message has gone out to stop pwMS coming to NHS hospitals, or even connecting with other healthcare facilities such as GP practices, in an attempt to prevent them from being exposed to SARS-CoV-2. Most MS centres, including ours, have converted all of our clinics to telemedicine. Saying that I saw a very anxious patient with recently diagnosed highly-active MS in our urgent face-2-face neurology clinic yesterday. She needed to be seen as she was in the middle of an attack and in my opinion, should start on a high-efficacy DMT as soon as possible (possibly natalizumab). I am not prepared to make her wait 3, 6, 9, 12 or 18 months to access a high-efficacy therapy and bridging her on a low efficacy DMT would not be in her best interests. If time is brain why should we be compromising on her treatment because of COVID-19? Do you agree?

Seeing this patient face-2-face yesterday helped. She was very anxious and being face-2-face allowed me to counsel her properly. The consultation felt right and is a possible example of why you can’t necessarily do everything using a telemedicine portal. 

One of the consequences of COVID-19 is that some pwMS are finding it difficult getting hold of NHS staff and getting their questions answered, which is one the reasons I started the MS-Selfie COVID-19 & MS microsite. Some centres such as ours have converted all our patients on natalizumab onto 6-weekly infusions, others have pushed this out to 8 weeks and some patients from other centres are reporting that their natalizumab infusions have been suspended indefinitely. The mixed messages around dosing and/or suspending dosing is causing a lot of anxiety (see my daily Q&A sessions on MS-Selfie). 

Is it safe to suspend natalizumab infusions?

No, it is not safe. I am particularly concerned that some patients are having their natalizumab infusions stopped without a definite date for recommencing their infusions or at least transitioning them onto another DMT to prevent rebound disease activity, which can on rare occasions be life-threatening. 

How does extended interval dosing work?

Yes, EID looks safe. Real-life data suggest from a clinical perspective it is not associated with an obvious increase in disease activity (relapses). However, the data on this is preliminary and Biogen is currently doing a study to address whether or not EID is associated with any loss of disease activity. This is called the NOVA trial and will include MRI monitoring as part of the outcome. One thing that is clear is that EID reduces the risk of PML in JCV positive patients substantially. 

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 desaturation of the immune cells causing MS, possibly the memory B cells, is insufficient not to allow these cells to traffic and to reactivate MS. It is clear that not all cells are made equal when it comes to the effect of natalizumab. Importantly, there are several other adhesion molecules on cells that impact on their adhesion (stickiness) 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.

How safe is extended interval dosing and does it matter if it is every 6 or 8 weeks?

Everyone gets a standard natalizumab dose of 300mg every 4 weeks. This means a 50kg person gets double the relative dose compared to a 100kg person. The half-life of antibody therapies, such as natalizumab, is linked to how much drug or antibody is given. Therefore for the 50kg smaller person, 8 weeks may be fine, but for the larger 100kg person 8 weeks is too long a gap. Based on the real-life data 6 weeks seems to be a good compromise. Therefore I personally would not be comfortable recommending an 8-week interval for all patients. Slide 38 in the deck below demonstrates that as the dosing interval increases so does the impact of  body weight on natalizumab’s efficacy. 

In reality every person with MS on natalizumab should probably have personalised dosing based on actual saturation of the VLA-4 molecule or equivalent biomarker (e.g. sVCAM-1). This would get us away from guessing and optimising the effectiveness of natalizumab at the same time as decreasing the risk of PML or other CNS complication linked to reduced immunosurveillance. 

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.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

32 comments

  • Will English hospitals consider 30min Natalizumab infusion and syringe saline flush to reduce exposure risk in hospitals, save time & free up time for other MS patients who are being switched to Natalizumab from riskier DMTS? It’s happening in the Alfred Hospital in Melbourne, Australia & apparently Biogen are fine with it. Obviously easier if patients have been on Natalizumab for several years.

    • I want to go further and try a bolus IV injection of the 15mL of natalizumab solution over 2 mins and to drop the post-infusion monitoring in patients who have been on natalizumab more than a year and are anti-natalizumab antibody negative.

      • Thanks- I’ll ask my team if they’ll consider this. I’m JCV- and been on Natalizumab for over 10 years.

  • As always, thanks for the advice. I am starting Natalizumab on April 14th. We are headed towards winter in Australia and the flu vaccine is now available. Is it ok and recommended to get the flu vaccine on April 7th?

  • Thank you for the update. What about MRI monitoring and JCV testing during this ‘unprecedented’ time? The former is suspended at most hospitals at the moment but is usually part of the monitoring of people on Natalizamab. Is this safe? Also, fewer visits to hospital will likely mean less regular JCV testing for most of these people. Is that safe? Thanks.

    • In our centre, no urgent blood and MRIs are on hold. This would be considered non-urgent. Our scanners are considered hot, i.e. you could be exposed to SARS-CoV-2 infected patients, which is something you want to avoid.

  • I am at your centre and on Natalizumab and hearing that people have had infusions suspended in the country is worrying.

    If things gets worse, should I brace myself for the possibility that Natalizumab will be suspended indefinitely at Barts too?

    • No everything is going ahead as planned. We have moved our infusion unit to the Dental Hospital that is a cold unit and separate from the RLH, i.e. no COVID-19 patients to protect vulnerable patients. We are also sharing the unit with several other disease areas.

  • I have been on extended dosing for about 5 years now. I started at 6 weeks and slowly have moved out to 9 weeks. I am on the low end of the weight scale and was hoping that by further extending I could lower my titer level. I am monitored by MRI every 4 months and have fortunately been stable. Although as has been reported and commented here: lack of change on an MRI does not show the whole picture. Adding further complication or lack of knowledge I am peri-menopausal.

    I have been preaching that we need a test that measures receptor saturation or half life for this medicine. It is too effective to just deny use of the drug in all JCV+ patients.

    My infusion center long ago got rid of the saline drip for the 2nd hour if you had been on the medicine for more than a year with no issues. I love the idea of a quick injection.

    I am part of the TOUCH program in the US and it is time Biogen adjust what data they acquire at each infusion.

    As always, I could not live calmly with my MS with out you and all of the docs on the blog.

    Debbie

    • Thanks. Looks like your centre wants to innovate. The real innovation will come with a subcutaneous injection that you give yourself.

      • Is there not the risk of increasing the development of anti-drug antibodies if the subcutaneous route is used? Lots of Lagerhans professional antigen-presenting cells in the skin.

  • “personalised dosing based on actual saturation of the VLA-4 molecule or equivalent biomarker (e.g. sVCAM-1)”

    How can we get that done?

    • there are lab based kits for this maybe it can be done as a service but I dont know about this, this is NDG’s domain

      • Don’t worry about it – I wouldn’t get it done out of a clinical trial anyways…

        I was just trying to figure out whether Biogen is going down this line. My gut feeling is that natalizumab revenue will drop with EID, even if the drug is priced on a patient/year basis irrespective of number of infusions.
        There is no way they can get away with a 50% price inflation per infusion overnight to make up for lost revenue.

        Hence why BIIB will on balance avoid rocking the boat to protect the $400m quarterly sales they earn from Tysabri.

        • They are going done the route and the clinicians are rather pushing for this route.
          sVCAM Its a biomarker for activity I think, when cells enter I bet VCAM is shed,

  • I know this is a post about Tysabri but it’s for me thinking….I wonder if extended dosing intervals for ocreluzimab will be considered at some stage in the future? Perhaps deciding dosing intervals according to CD19 cell count? COVID-19 is leading to lots of changes in neurology and not all of them are necessarily bad despite the anxiety they cause for patients as well as providers.

    • Yes, that is part of our ADIOS trial proposal. We are in the process of writing a grant to do the ADIOS trial.

  • Hi Prof G,

    As one of your patients I’m finding it hard to get hold of anyone to adjust my appointment. I had hoped to move my appointment from 6 weeks to longer but I was simply told to come on the previously agreed date as it will be hard to adjust the date.

    I am nervous and worriedp about coming to get my infusion. Do you think it’s safe for us to come to get out medicine right now, or do you think some more focus should be made on making home visits or other locations than hospitals an option?

    • We have moved the infusion unit to the dental school, which is cold, i.e. no COVID-19 patients. I think it is safe. What you don’t realise is that this epidemic is going to last many more months that the government expects it to last.

      • Thank Professor

        I do get it to be honest. I am a realist; I know that if we were to simply relax the social distancing then things will just peak again.

        The key is testing to understand what % of people have already had the virus. If this figure is more significant than we know now. Say 50%, then that would be a game changer perhaps.

        But until that is known , or Antivirals that make a significant difference, all the eventuality of the vaccine, I can see has been this position for many many months.

        Best wishes to you and the other workers in the hospitals protecting us all. Pre covid, and today.

        One final question, how risky is it going for a run where there are other people. Even if you adhere to social distancing. Can the virus be easily spread through the air? Or am I right in my understanding, that while it’s possible, the more common form of transmission is via surfaces?

  • Been diagnosed with multiple sclerosis before in 2015, and I was a woman of 50. They put me on Rebif which I took until 2017 and was switched to Copaxone. I had two relapses on Rebif, none so far on Copaxone. I do notice my balance was getting worse, and my memory, as well as erectile dysfunction and spasms’ had no choice to sick for other solution and I was introduce to totalcureherbsfoundation.com which I purchase the MS herbal formula from the foundation, the herbal supplement has effectively get rid of my multiple sclerosis and reversed all symptoms,the biggest helped I had was totalcureherbsfoundation.com They walked me through the proper steps, im highly recommending this herbal formula to anyone who needs help.

  • Would this mean a patient is at their most vulnerable (to COVID 19 infection) immediately after infusion?…Thank you in advance.

    “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 desaturation of the immune cells causing MS, possibly the memory B cells, is insufficient not to allow these cells to traffic and to reactivate MS. It is clear that not all cells are made equal when it comes to the effect of natalizumab.”

  • Hi. I have been on mab since November 2013 after 2 disastrous months on interferon b causing epileptic seizures. I weigh 65-70 kgs (season pending!) and relapse free since Oct 13. Body is working good so its brain (dizziness and numbness as normal). We agreed with my doctor to push intervals to 8 weeks 6 months ago.
    The only difference is that once administered the medicine can be felt in my body. This is how I felt during the initial stages of the therapy back in 2013, during the first 2 days following the drip. Otherwise things looking good!

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