Natalizumab PML Update: August 2013

August 2013 PML update:  How many MSers have died from PML? #MSBlog #MSResearch

“The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the slideshow at the bottom is for professional eyes only.”

“As of 2nd July 2013 there have been 395 cases of natalizumab-associated PML; 92 (23%) MSers have died from PML and 303 (77%) are alive. Please note that the majority of those surviving have a poor functional outcome. Alarming as these figures sound you need to keep them in context; firstly, over 118,000 MSers have been treated with natalizumab, and secondly, these risks and the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented with JC virus testing. Slide 13 is the most important slide regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosupression
In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and will need to be incorporated into future risk models.”

Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.

“The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch.”

CoI: multiple

19 thoughts on “Natalizumab PML Update: August 2013”

    1. That´s kind of obvious, but as a JC- I would very much like to know what kind of infection and I also would like to know why being JC+ doesn´t pose a major problem until you had it for 2 years..Best regards..//Sewdish Sara

    2. Hi Sara,It seems most people catch JC virus early in life, not sure if it's symptomatic or not. Seems primarily to be water borne. The JC virus can lie dormant in some cells of the brain such as oligodendrocytes where it is held under control by cells of the immune system. In some situations where the immune system is suppressed such as immunodeficiency or where immune cells cells are prevented from getting into the brain such as with natiluzumab the virus can reactivate and cause PML. This only seems to be a problem after 2 years of treatment with natiluzumab where the JC virus seems to take at least this long to reactivate under these conditions.Hope this helps!

    3. Well the early in life sounds good… I will stay away from murky waters then. It does seem odd that we don't know more about it.Because it has been known since the 70´s.Thank´s and take care//Swedish Sara

  1. Do you expect that Biogen will split out the Use Of Natalzumab in a post-marketing setting (slide 9) by JC+ and JC- ? Also, now there are alternatives for JC+ new-to-DMT MSers do you think there is / will be a declining focus on improving PML diagnosis & treatment ?

    1. Lisa you sound like a business analyst. I have a policy of not responding to analysts; too many conflicts of interest and I am really not interested in the market. Your questions are rhetorical; the way you have worded them is self-explanatory. Hopefully the MS community, rather than Biogen-Idec, will set the rules.

    2. I am a MSer that has been on Tysabri for over four years and have known that I am JC+ for almost two years. I have never worked in the pharmaceutical industry.Obviously you don't like my style of writing – so I should look elsewhere for answers to my genuine questions – Thanks for your sensitive response

    3. Apologies for the harsh interpretation. Does the following help?The rumour on the block is that Biogen-Idec have are considering applying 1st-line license for JCV-ve MSers. I suspect they don't want any JCV+ve MSers to stay on Natalizumab long-term to reduce the number of MSers who develop PML. The figures are climbing too high and this will expose natalizumab to a competitor, for example alemtuzumab or ocrelizumab. Both these agents are induction therapies and hence are more appealing than natalizumab. Biogen-Idec also have Daclizumab in development; I am very excited about this drug as it appears to have an impact on progression over and above its impact on relapses. Daclizumab may be ideal for JCV+ MSers. The other option is to treat or eliminate JCV from the body. This is a strategy I proposed several years ago but it fell on deaf ears. This would take too long; by the time it came to market natalizumab would be off patent and other more effective drugs will be on the top of the pile. Hence no interest from Biogen. At the moment natalizumab seems to be the most effective drug we have, but until we see a head-2-head with fingolimod we won't know. Once alemtuzumab is licensed and available this will be the most effective drug, but until we see head-2-head studies against natalizumab and fingolimod we won't know. Don't forget it is horses for courses; because you are doing well on one drug it doesn't mean you are going to do as well on another drug. It is all about biology.

    4. I previously read an article that quoted someone as saying Daclizumab may be unapprovable due to hepatic and autoimmune side effects. From your comment above, it seems like you have hope for it to be approved someday?Thanks for your time as always!

    5. Please name the source of the article…was it competitor company?See the post on hepatitis

    6. OK thanks as these words of people with doubts were attributed to the mouth of Prof G, then I think his answer above provides some type of answer

  2. Nataluzimab is currently a profitable drug and therefore there is an incentive to monitor and treat. Furthermore we have yet to see what happens with other drugs. PML has shown itself to be a risk of immunosuppression and it is not just nataluzimab where this problem has shown itself

    1. Dr Freedman; not Prof G.Mark Freedman, MD, of the University of Ottawa, who was not involved in SELECT or SELECTION, told MedPage Today that the autoimmune issue could make the drug unapprovable, despite what he said was "a very potent [efficacy] signal without too much worrisome problems" in the initial phase.He noted that the SELECT-SELECTION program had alleviated one safety concern for the drug, arising from its mechanism of action.Because the drug targets the IL-2 pathway, he explained, some researchers worried that it might actually exacerbate rather than relieve MS. "A lot of cells use IL-2 to move, including regulatory T cells," Freedman said. The strong efficacy benefit clearly indicates that those concerns were groundless.But, he added, "I'm a little discouraged by the emerging autoimmune abnormalities — and they're not single organ."He acknowledged that the developers of another investigational MS drug, alemtuzumab (Lemtrada), have not been discouraged by its propensity to induce autoimmune thyroid disease.But that's a less serious condition than the hepatic and renal autoimmune conditions seen in the daclizumab study, said Freedman, who is an investigator in an ongoing phase III trial of the drug."This might not be a sustainable therapy," he said.

    2. it said "Giovannoni said, Nevertheless, other researchers suggested that the problem was serious enough to jeopardize the drug's future in MS" not "Giovannoni said. Nevertheless, other researchers suggested that the problem was serious enough to jeopardize the drug's future in MS"my mistake.This is one opinion. The worry based on stopping the IL_2 is because it should block T reg cells and make disease according to immunological dogma…however this appears not to be happening and maybe so much for T reg cells I had a good look for studies were this happened in relapsing EAE to my surprise I found one. As Dr Freedman says this fear was "groundless"Gee is this Break my balls day we have Get It Right! earlier someone called MouseDoc can kiss it! "You are the despot of the blog" and that David Cameron and I could pass for brothers and then someone called David Cameron suggesting otherwiseNothing to do with same disgruntled punter getting spammed, by multiple administrators, I hope.

  3. Biogen's figures look on the light side compared to FDA reports, applying the death rate to these figures is a lot of deaths in absolute terms

    1. I couldn't see the number of deaths in this link. Yes, I suspect Biogen's figures will be light as they are only reporting deaths due to PML and not those due to other reasons, e.g. suicide, sudden death, malignancies, co-morbidities, etc. The FDA figures will come from Biogen.

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