Lack of natalizumab concentration increase before PML argues against extending dosing interval

 

Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.

Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.

HUNG KUO CHUN/Thinkstock

The hypothesis that reducing natalizumab serum concentration may reduce PML risk stems from reasoning that after 12 months of natalizumab treatment, the serum concentration of the drug in most patients is thought to be at a level that is high enough to cause 100% saturation of its target, the alpha₄ integrin receptor. The thinking on risk reduction is such that if the dosing interval is extended from 300 mg every 4 weeks to a maximum of 300 mg every 8 weeks, then PML susceptibility may decline.

Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.

The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.

“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.

“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.

The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.

[email protected]

 

Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.

Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.

HUNG KUO CHUN/Thinkstock

The hypothesis that reducing natalizumab serum concentration may reduce PML risk stems from reasoning that after 12 months of natalizumab treatment, the serum concentration of the drug in most patients is thought to be at a level that is high enough to cause 100% saturation of its target, the alpha₄ integrin receptor. The thinking on risk reduction is such that if the dosing interval is extended from 300 mg every 4 weeks to a maximum of 300 mg every 8 weeks, then PML susceptibility may decline.

Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.

The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.

“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.

“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.

The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.

[email protected]

 

Serum concentrations of natalizumab do not appear to rise before patients with relapsing-remitting multiple sclerosis are diagnosed with progressive multifocal leukoencephalopathy, contradicting the hypothesis that exposure to elevated concentrations of the drug is a risk factor for the disease, according to findings from a prospective, observational cohort study.

Zoé L.E. van Kempen, MD, and her colleagues at VU Medical Center Amsterdam noted that a small but increasing number of “neurologists are extending dose intervals of natalizumab [Tysabri] with the primary aim of reducing the risk of PML [progressive multifocal leukoencephalopathy] by lowering the natalizumab exposure per patient,” which also potentially has the benefit of decreasing drug costs, as well as clinic or hospital visits. However, there have been no prospective studies that confirm that extending natalizumab dose intervals does not affect efficacy.

HUNG KUO CHUN/Thinkstock

The hypothesis that reducing natalizumab serum concentration may reduce PML risk stems from reasoning that after 12 months of natalizumab treatment, the serum concentration of the drug in most patients is thought to be at a level that is high enough to cause 100% saturation of its target, the alpha₄ integrin receptor. The thinking on risk reduction is such that if the dosing interval is extended from 300 mg every 4 weeks to a maximum of 300 mg every 8 weeks, then PML susceptibility may decline.

Dr. van Kempen and her coinvestigators investigated this hypothesis by comparing serum concentrations of natalizumab in 5 patients with PML and 10 age- and sex-matched controls from a cohort of 219 relapsing-remitting multiple sclerosis patients taking natalizumab who had blood samples routinely drawn every 12 weeks before the infusion of natalizumab (Mult Scler. 2016 Dec 13. doi: 10.1177/1352458516684023). These 10 controls had a mean concentration of 23.8 mcg/mL, which was in the same range as the 18.9 mcg/mL level observed before the diagnosis of PML in the 5 cases from the cohort. The five cases also did not show a rise in concentration before the diagnosis of PML and did not have concentrations fluctuate more than 11 mcg/mL during treatment. The patients with PML received a mean of 43 infusions, whereas controls received an average of 106 infusions. A median number of 5 pre-PML samples underwent testing, compared with yearly concentration measurements in the 10 controls who had at least 7 years’ treatment duration.

The increased risk of PML that has been documented in other studies with more than 24 months of natalizumab treatment also was not explained in this study by a rise in serum concentration over long-term follow-up.

“Although this cohort is too small to draw definite conclusions, our results do not support the hypothesis of high serum concentrations as a risk factor for developing PML,” the investigators wrote.

“With our small cohort in mind and insufficient data on this subject so far, neurologists should be careful in extending dose intervals and not overstate a possible decrease in the risk of developing PML. Obviously, if neurologists choose to extend dosing intervals of natalizumab in [John Cunningham virus]–positive patients, these patients should still receive stringent PML monitoring according to current recommendations,” they advised.

The study received support from the Brain Foundation Netherlands. Five of the authors reported financial ties to various pharmaceutical companies that market MS drugs, including Biogen, which markets natalizumab.

[email protected]