PML risk stratification tool could affect natalizumab usage

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

[email protected]

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

[email protected]

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

[email protected]