Friday, 3 March 2017

#ClinicSpeak & #Neurospeak: natalizumab PML update

Are you are natalizumaber who is gambling on not getting PML? #ClinicSpeak #NeuroSpeak #MSBlog

Recently, I haven't been updating you regularly about natalizumab-associated PML. After the recent blog traffic around alternative facts and the EudraVigilance PML figures I thought I should resume and start posting the official Biogen figures every quarter. 

The following is Biogen's quarterly update; if you are not a HCP you shouldn't be reading the document. The headline data is that there are now 161,300 pwMS who have been exposed to natalizumab with over 525,000 patient-years of exposure. As of the 1st December 2016 there have been 698 confirmed cases of PML (695 with MS and 3 with Chron's disease). The mortality of PML in these patients has been 23%, i.e. 161 people have died.

My opinion is that nobody who is JCV seropositive should be started on natalizumab and those who are seropositive on the drug should be derisked and switched to an alternative treatment. The use of the JCV antibody index may reassure some people that they are at low risk, but at the end of the day the risk is not zero. Despite me giving this advice several of our patients are reluctant to stop natalizumab simply because they know how bad their MS was before they started the drug and don't want to take a chance of rebound activity or not responding to the switch therapy. 



CoI: multiple

12 comments:

  1. I am not an HCP, but a patient. I read it and found it extremely useful to better understand my risk of PML. Please keep us posted with similar documents.

    I find it surprising that the risk of PML has not been decreasing the last years, as both pwMS and neuros are more aware of it and I'd expect they'd follow derisking strategies. But then, as you pointed out, it is a very effective drug and people dread to imagine their lives without that.

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  2. But how high is a high titre level?

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    1. I think values greater than 1.5 are considered to be high, as the risk of PML increases significantly.

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  3. Is there risk of PML with Ocrelizumab?

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  4. The risk of PML with ocrelizumab may be greatly reduced relative to natalizumab if we consider it similar to the risk of rituximab. I believe Berger's Handbook of Clinical Neurology 2014 estimates the risk of PML with rituximab at 1 in 30,000 on page 364. However, only time will tell what the PML risk is with ocrelizumab used in a large patient population.

    However, PML risk with natalizumab on extended dosing, going 5 to 8 weeks between infusions, may be remarkably low, also. I am not aware of any case of PML reported in any patient on natalizumab going 5 to 8 weeks between infusions rather than 4 weeks. If someone has information to the contrary, please inform us, won't you?

    More than 900 patients have been on extended dosing for over two years, I believe, with zero cases of PML reported that I am aware of.

    In any case, if no one gets PML on extended dosing, or very, very few get PML relative to standard 4-week dosing, then natalizumab is de-risked significantly and should be considered in that light, IMO.

    Extending time between doses reduces the concentration of natalizumab which may allow for improved immune surveillance against the JC virus that causes PML.

    It appears some neurologists pressure JCV+ patients off natalizumab without offering extended dosing as an alternative. Unfortunately, many pwMS on natalizumab suffer significant MS activity after they quit the effective drug they have been taking and replace it with something which may work, may work much less effectively, or may not work at all.

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  5. Rollo, may I ask how reliable I should consider your information regarding extended interval dosing might be? My son's (consistently >3.XX index) neuro hinted last month that a new study using TOUCH data is forthcoming. Since we are considering HSCT as the alternative to natalizumab going forward this data will be a factor.

    PML risk was played down at diagnosis over our concerns and rebound was basically dismissed as some distant chance in the future. Yet, here we are.

    Having said that, we do believe induction therapy was good. Had Ocre been available we might have gone that route despite its relative novelty.

    Thank you all - I think this blog and its readers are amazing.

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  6. Prof GG, hailing all frequencies. Why isn't there any update on PML number under tysabri since December 7th last year (756)?

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  7. I'm aware of a PML case on extended dosing, recently.

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  8. Spodaddyo, Apologizes for the exceedingly late reply!

    PML cases during dose extension on natalizumab.
    Analysis of Biogen’s Touch program which tracks about 90,000 patients using Tysabri reported 15 cases of PML in patients who were on extended dosing intervals.

    A neurologist at an MS Clinic informed me that 6 of the 15 cases were of patients who had been on extended dosing but had gone back to standard dosing of 4 weeks. The average interval on extended dosing was 6 weeks, according to that neurologist.

    Biogen’s TOUCH program data was interpreted as follows:
    Three separate definitions of standard-interval dosing (SID) and extended-interval dosing (EID) were analyzed from the TOUCH program tracking Tysabri patients.

    The first group analyzed was those who had fewer than 15 infusions in the last 18 months compared to those who had more than 15 infusions the last 18 months. There were 3 PML cases in 1,988 on extended dosing in this group and 89 cases of PML in 13,132 on standard dosing.

    The second group analysis defined extended dosing as anyone who had ever extended dosing for at least 6 months at any time in their treatment history with Tysabri. In this group there were 12 PML cases in 3,331 on EID and 71 cases of PML in 15,424 on SID who had not gone at least 6 months on extended dosing at some point in their treatment history. Apparently, some in this group were on EID but went back to SID. Perhaps, because MS was not sufficiently suppressed on EID.

    The third group analysis defined extended dosing as fewer than 10 doses per year and standard dosing as more than 10 doses per year. There were zero cases in 815 patients in this extended dosing group having less than 10 infusions per year compared to 96 cases of PML in 23,168 in the standard dosing group having more than 10 infusions per year.

    Sadly, the very bad news is that there remains a risk of PML even with EID.

    The good news is that PML risk is greatly reduced by extending time between doses.

    https://www.mdedge.com/neurologyreviews/article/162420/multiple-sclerosis/extended-interval-dosing-natalizumab-associated

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    1. Thanks for this info. Not all good but taking the positives from the bad news..Nice post

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