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HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.
In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.
A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.
Antibodies Precede PML
In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.
"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.
In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.
The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.
Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.
Serum Concentration Predicts Risk
The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.
For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.
In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.
Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.
Higher Survival With Early Diagnosis
Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.
In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.
Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.
The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.
Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.
The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.
Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.
PML Presentation Can Be Subtle
PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.
After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.
He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.
The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.
Immunosuppressant History Is Relevant
A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.
The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.
Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.
The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.
The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).
The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.
Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.
Each patient tested who continues to show JCV-antibody positivity well predating the development of PML (with virtually 100% sensitivity and specificity) makes us very confident in terms of putting individuals on therapy who are JCV-antibody negative. It also allows us to take individuals who are positive and focus our research on that smaller subgroup to further identify risk factors for development of PML.
In both camps, it gives us a tremendous step forward in terms of how to manage patients.
As you stratify the risk of these individuals, prior immunosuppression in combination with being antibody positive essentially confers a risk of PML of 8 in 1,000 after they’ve been on treatment for 2 years or more. That’s a relatively high risk.
What that means more than anything else is to really think carefully about how you approach treatment. Do you really want to use an immunosuppressant therapy early on? It’s important to realize that, when we look at the relationship between immunosuppression and PML, it makes no difference when the person received immunosuppression. It could have been 6 months before starting natalizumab or 10 years before. The risk is the same.
|
An annual MRI may not be frequent enough to catch PML early, but even 6 months may not be frequent enough. What we need are inexpensive quick-scanning methods that allow us to do more frequent scanning. Most of the scanning done in MS is a very costly endeavor. It involves gadolinium-enhancing studies, non-enhancing studies, lots of different pulse sequences. We really need a 5-minute scan that can be done every 3 months on people after they’ve been on therapy for 2 years and in high-risk patients – those who are JCV-antibody positive, for instance.
That kind of scan probably could be done for $200 or less and would not only be cost effective but incredibly useful. The technology doesn’t need to be created; it’s just a question of negotiating with our colleagues in radiology.
Revere P. Kinkel, M.D., is director of the multiple sclerosis center at Beth Israel Deaconess Medical Center, Boston. He has financial associations with Biogen Idec, Novartis, Acorda Therapeutics, and Teva Neuroscience.
If the assay becomes available, I’m sure I’ll start using it. I think it will be a lot clearer what to do with people who have a negative test and don’t have antibodies, and to be fairly confident that their risk is much lower than the general population of patients with multiple sclerosis. We’re not going to be doing this test on people who have mild MS; we’re going to be doing this in people who have a fairly high risk of bad outcomes if we don’t treat them aggressively.
What will be challenging is the 55% of people who will still have positive results, and what to tell them. Their risk of PML is four times higher than we thought it was, though still small: one in a few hundred instead of 1 in 1,000.
|
It would be immensely useful to have a rule-out MRI scan for PML versus our current scans to evaluate progression of multiple sclerosis, which is a very fine-cut scan with multiple directions. With the latter, you’re asking for a lot of information you don’t need to diagnose PML. But radiologists have to be comfortable doing that rule-out scan and willing to stand behind it.
Michelle Cameron, M.D., is a neurologist at Oregon Health and Science University, Portland. She has financial associations with Biogen Idec, Innovative Neurotronics, Teva Neuroscience, DJO Global, Mettler Electronics, and California Education Connection.
Each patient tested who continues to show JCV-antibody positivity well predating the development of PML (with virtually 100% sensitivity and specificity) makes us very confident in terms of putting individuals on therapy who are JCV-antibody negative. It also allows us to take individuals who are positive and focus our research on that smaller subgroup to further identify risk factors for development of PML.
In both camps, it gives us a tremendous step forward in terms of how to manage patients.
As you stratify the risk of these individuals, prior immunosuppression in combination with being antibody positive essentially confers a risk of PML of 8 in 1,000 after they’ve been on treatment for 2 years or more. That’s a relatively high risk.
What that means more than anything else is to really think carefully about how you approach treatment. Do you really want to use an immunosuppressant therapy early on? It’s important to realize that, when we look at the relationship between immunosuppression and PML, it makes no difference when the person received immunosuppression. It could have been 6 months before starting natalizumab or 10 years before. The risk is the same.
|
An annual MRI may not be frequent enough to catch PML early, but even 6 months may not be frequent enough. What we need are inexpensive quick-scanning methods that allow us to do more frequent scanning. Most of the scanning done in MS is a very costly endeavor. It involves gadolinium-enhancing studies, non-enhancing studies, lots of different pulse sequences. We really need a 5-minute scan that can be done every 3 months on people after they’ve been on therapy for 2 years and in high-risk patients – those who are JCV-antibody positive, for instance.
That kind of scan probably could be done for $200 or less and would not only be cost effective but incredibly useful. The technology doesn’t need to be created; it’s just a question of negotiating with our colleagues in radiology.
Revere P. Kinkel, M.D., is director of the multiple sclerosis center at Beth Israel Deaconess Medical Center, Boston. He has financial associations with Biogen Idec, Novartis, Acorda Therapeutics, and Teva Neuroscience.
If the assay becomes available, I’m sure I’ll start using it. I think it will be a lot clearer what to do with people who have a negative test and don’t have antibodies, and to be fairly confident that their risk is much lower than the general population of patients with multiple sclerosis. We’re not going to be doing this test on people who have mild MS; we’re going to be doing this in people who have a fairly high risk of bad outcomes if we don’t treat them aggressively.
What will be challenging is the 55% of people who will still have positive results, and what to tell them. Their risk of PML is four times higher than we thought it was, though still small: one in a few hundred instead of 1 in 1,000.
|
It would be immensely useful to have a rule-out MRI scan for PML versus our current scans to evaluate progression of multiple sclerosis, which is a very fine-cut scan with multiple directions. With the latter, you’re asking for a lot of information you don’t need to diagnose PML. But radiologists have to be comfortable doing that rule-out scan and willing to stand behind it.
Michelle Cameron, M.D., is a neurologist at Oregon Health and Science University, Portland. She has financial associations with Biogen Idec, Innovative Neurotronics, Teva Neuroscience, DJO Global, Mettler Electronics, and California Education Connection.
Each patient tested who continues to show JCV-antibody positivity well predating the development of PML (with virtually 100% sensitivity and specificity) makes us very confident in terms of putting individuals on therapy who are JCV-antibody negative. It also allows us to take individuals who are positive and focus our research on that smaller subgroup to further identify risk factors for development of PML.
In both camps, it gives us a tremendous step forward in terms of how to manage patients.
As you stratify the risk of these individuals, prior immunosuppression in combination with being antibody positive essentially confers a risk of PML of 8 in 1,000 after they’ve been on treatment for 2 years or more. That’s a relatively high risk.
What that means more than anything else is to really think carefully about how you approach treatment. Do you really want to use an immunosuppressant therapy early on? It’s important to realize that, when we look at the relationship between immunosuppression and PML, it makes no difference when the person received immunosuppression. It could have been 6 months before starting natalizumab or 10 years before. The risk is the same.
|
An annual MRI may not be frequent enough to catch PML early, but even 6 months may not be frequent enough. What we need are inexpensive quick-scanning methods that allow us to do more frequent scanning. Most of the scanning done in MS is a very costly endeavor. It involves gadolinium-enhancing studies, non-enhancing studies, lots of different pulse sequences. We really need a 5-minute scan that can be done every 3 months on people after they’ve been on therapy for 2 years and in high-risk patients – those who are JCV-antibody positive, for instance.
That kind of scan probably could be done for $200 or less and would not only be cost effective but incredibly useful. The technology doesn’t need to be created; it’s just a question of negotiating with our colleagues in radiology.
Revere P. Kinkel, M.D., is director of the multiple sclerosis center at Beth Israel Deaconess Medical Center, Boston. He has financial associations with Biogen Idec, Novartis, Acorda Therapeutics, and Teva Neuroscience.
If the assay becomes available, I’m sure I’ll start using it. I think it will be a lot clearer what to do with people who have a negative test and don’t have antibodies, and to be fairly confident that their risk is much lower than the general population of patients with multiple sclerosis. We’re not going to be doing this test on people who have mild MS; we’re going to be doing this in people who have a fairly high risk of bad outcomes if we don’t treat them aggressively.
What will be challenging is the 55% of people who will still have positive results, and what to tell them. Their risk of PML is four times higher than we thought it was, though still small: one in a few hundred instead of 1 in 1,000.
|
It would be immensely useful to have a rule-out MRI scan for PML versus our current scans to evaluate progression of multiple sclerosis, which is a very fine-cut scan with multiple directions. With the latter, you’re asking for a lot of information you don’t need to diagnose PML. But radiologists have to be comfortable doing that rule-out scan and willing to stand behind it.
Michelle Cameron, M.D., is a neurologist at Oregon Health and Science University, Portland. She has financial associations with Biogen Idec, Innovative Neurotronics, Teva Neuroscience, DJO Global, Mettler Electronics, and California Education Connection.
HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.
In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.
A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.
Antibodies Precede PML
In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.
"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.
In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.
The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.
Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.
Serum Concentration Predicts Risk
The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.
For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.
In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.
Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.
Higher Survival With Early Diagnosis
Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.
In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.
Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.
The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.
Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.
The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.
Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.
PML Presentation Can Be Subtle
PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.
After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.
He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.
The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.
Immunosuppressant History Is Relevant
A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.
The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.
Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.
The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.
The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).
The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.
Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.
HONOLULU – Results of five diverse studies on the risk of progressive multifocal leukoencephalopathy when using natalizumab to treat multiple sclerosis could change the way clinicians decide how to manage these patients.
In one of five presentations about natalizumab (Tysabri) that were given during one session at the annual meeting of the American Academy of Neurology, researchers confirmed that the presence of anti-JC virus (JCV) antibodies always precedes development of progressive multifocal leukoencephalopathy (PML). As a part of their study, the investigators developed a new assay to identify antibody-negative patients who could be at lower risk for PML when taking natalizumab. Another study looked at using serum natalizumab concentrations to predict the risk of PML.
A separate study found that earlier diagnosis of PML after symptom onset was associated with increased survival. A case presentation of PML presenting only with subacute amotivational syndrome raised questions about the need for more frequent brain MRIs. Another study confirmed that a history of taking an immunosuppressant medication at any point prior to taking natalizumab increased the risk for PML.
Antibodies Precede PML
In samples taken from four large clinical treatment trials, approximately 55% of patients with multiple sclerosis had anti-JCV antibodies, Dr. Meena Subramanyam said. (JCV infection is necessary for the development of PML.) In comparison, anti-JCV antibodies were detected in the blood of 100% of 25 patients who later were diagnosed with PML and from 100% of 39 patients with samples taken at or around the time of PML diagnosis.
"This shows that the PML patients were exposed to the virus prior to natalizumab treatment," Dr. Subramanyam said. She and her associates hold stock in and are employees of Biogen Idec, which comarkets Tysabri with Elan Pharmaceuticals.
In 17 of the 25 patients with blood samples prior to PML diagnosis, additional samples were taken after starting natalizumab. Another 39 patients had samples taken at the time of PML diagnosis or soon after. All were positive for anti-JCV antibodies. Treatment of PML for 17-98 months did not affect anti-JCV antibody positivity, though overall antibody levels fell.
The investigators used a unique two-step enzyme-linked immunosorbent assay to detect antibodies. Biogen Idec and Elan Pharmaceuticals plan to make the assay commercially available in Europe in May 2011 and in the United States soon after that, Dr. Subramanyam said.
Large clinical studies are ongoing to test the utility of anti-JCV antibody status for stratifying the risk of PML in patients given natalizumab for multiple sclerosis.
Serum Concentration Predicts Risk
The risk for PML increases after 2 years or more of natalizumab use, previous data show. A new study of biochemical samples from 207 patients on natalizumab for multiple sclerosis found that plasma concentrations of the drug increase over time, peaking after 20 months of therapy, reported Dr. John F. Foley of the Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, and his associates.
For comparison, they looked at data from two phase III trials of natalizumab, in which they also found longitudinal increases in mean natalizumab concentrations.
In the current study, samples taken in each 28- to 30-day infusion interval showed a mean 56% increase in drug concentrations over 45 months. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) trial, serum concentrations increased 70% over 30 months. In the Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL) trial, drug concentrations increased 99% over 30 months.
Theoretically, if elevated natalizumab concentrations are found to be associated with elevated risk for PML, it may be possible to make kinetic manipulations by changing dosing or adjusting infusion intervals to lower the risk for PML, Dr. Foley said. Studies are ongoing to explore this hypothesis.
Higher Survival With Early Diagnosis
Postmarketing data since November 2004 show that 78,800 patients worldwide have taken natalizumab and 102 of these patients developed PML. A study of the first 79 cases of PML found that 63 (80%) were alive in December 2010. Follow-up visits with these survivors ranged from 1 to 29 months since PML diagnosis. In the 16 patients who died, the time from diagnosis to death ranged from 1 to 11 months, reported Dr. Patrick Vermersch of the University of Lille (France) and his associates.
In all cases, natalizumab was stopped when signs or symptoms suggesting PML appeared, and most patients were treated by plasma exchange or immunoadsorption to rapidly remove the drug from circulation.
Compared with the patients who died, survivors were younger when diagnosed with PML, had a shorter time from symptom onset to diagnosis of PML, and had more localized disease on brain MRI. The likelihood of survival was not affected by the duration of natalizumab use or prior use of immunosuppressive therapy.
The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.
Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.
The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.
Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.
PML Presentation Can Be Subtle
PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.
After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.
He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.
The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.
Immunosuppressant History Is Relevant
A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.
The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.
Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.
The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.
The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).
The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.
Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.
FROM THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY