March 2014 natalizumab PML update. #MSBlog #MSResearch
“The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; I continue to be told by Biogen-Idec that if you are not a health professional you should not be reading this presentation. If you are a MSer you should be reading my previous post that has been designed for you.”
Headline information
“As of the 6th March 2014 there have been 448 cases of natalizumab-associated PML. This represents an increase of 9 cases from last month; the number of cases each month is going down. The mortality associated with PML in this setting is currently 24%, i.e. 108 MSers have died as result of PML. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of well over 123,000 MSers been treated with natalizumab worldwide with over 320,000 years of natalizumab exposure.”
“It is now clear that the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented Biogen-Idec with JC virus serological testing. This is a success story and it should be reassuring for MSers on natalizumab.”
“Good news for UK MSers at high-risk of PML who have been waiting for permission from NHS England to switch to fingolimod; we have just been given a provisional green-light to go ahead with switching. This is a big relief for me; once we have cleared our list of patients I will sleep more easily at night.”
“The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:
“We have developed a simple infographic to help you intergrate all this information. You can download and print this infographic for your own information.”
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 following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; I continue to be told by Biogen-Idec that if you are not a health professional you should not be reading this presentation. If you are a MSer you should be reading my previous post that has been designed for you.”
Headline information
“As of the 6th March 2014 there have been 448 cases of natalizumab-associated PML. This represents an increase of 9 cases from last month; the number of cases each month is going down. The mortality associated with PML in this setting is currently 24%, i.e. 108 MSers have died as result of PML. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of well over 123,000 MSers been treated with natalizumab worldwide with over 320,000 years of natalizumab exposure.”
“It is now clear that the numbers of MSers developing PML are falling due to the successful risk mitigation strategy that has been implemented Biogen-Idec with JC virus serological testing. This is a success story and it should be reassuring for MSers on natalizumab.”
“Good news for UK MSers at high-risk of PML who have been waiting for permission from NHS England to switch to fingolimod; we have just been given a provisional green-light to go ahead with switching. This is a big relief for me; once we have cleared our list of patients I will sleep more easily at night.”
“The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:
- JCV serostatus
- Duration of treatment
- Previous exposure to immunosuppression
In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models.”
“We have developed a simple infographic to help you intergrate all this information. You can download and print this infographic for your own information.”
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. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above.”
CoI: multiple
I'm not sure I can agree with your positive assessment. I suspect it's because as a researcher you see MS at the population level while we see it at the personal level. 108 people have died – they will all be relatively young. The company has made huge profits from this drug. Researchers / doctors have received consulting fees etc. I have seen no data as to whether this drug has a real impact on the disease e.g. does it stop the transition to SPMS, does EDSS remain constant over 10 years etc. in the autumn Alemtuzumab should become available. I've seen no references to PML as a side effect. The side effects if monitored look manageable. As a neuro advising a recently diagnosed patient with RRMS, could you really steer a patient to Tysabri over Alemtuzumab (the latter is more effective, better safety profile, more convenient for the patient, an probably cheaper over 3 years)? What would you advise me if I was diagnosed with fairly aggressive MS at the end of the year?
There is new evidence that suggests you can have JC virus DNA while testing negative for the virus with the standard tests. http://www.nejm.org/doi/full/10.1056/NEJMc1308784I would never want to stay on this drug for a long time, and it would be my last option.
As a JCV Ab-negative person I would very much like to know how I can maintain that status…There seems to be very little knowledge on how it infects you. The wait and see approach and get tested every 6th month is bleak. I've read somewhere that you get infected through salvia..is'nt there anything to be done.. should I get everyone close to me tested, it's hard not to share things when your'e family.. is it not better to make sure that that we can keep on staying negative (in a positive way)Have a nice Easter//Swedish Sara