Watch for PML after switching from natalizumab to fingolimod

BOSTON– Cases of progressive multifocal leukoencephalopathy in multiple sclerosis patients who switch from natalizumab to fingolimod treatment are more likely a result of the natalizumab exposure than the fingolimod exposure, according to an analysis of cases in the Novartis safety reporting database for fingolimod.

About 15%-20% of fingolimod-treated patients have prior exposure to natalizumab, and of 11 patients from the safety reporting database who have developed progressive multifocal leukoencephalopathy (PML) to date, all had prior natalizumab exposure, according to Dr. Norman Putzki.

The 11 patients with PML had been treated with natalizumab for a median of 4 years, Dr. Putzki, an employee of Novartis Pharma AG, Basel, Switzerland, said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The onset of PML, based on a retrospective review of MRI scans, was prior to the first fingolimod dose in 5 of the 11 patients, and between 3 weeks and 6 months after the first dose in 4 of the patients. Onset was unknown in the remaining 2 patients.

One additional case of possible PML was reported in a patient without prior natalizumab exposure. The patient had MRI features and the presence of AQP4 antibodies consistent with a diagnosis of neuromyelitis optica spectrum disorder, and clinical features that were consistent with a PML diagnosis, but the timing of onset in this patient could not be determined, Dr. Putzki said.

With more than 135,800 total patient-years of exposure, including during clinical trials and in the postmarketing period, no evidence of an association between fingolimod and PML has been found, he said.

Treatment with natalizumab, however, is an identified predisposing factor for PML development, and the risk is known to persist after treatment discontinuation. In fact, it is recommended that patients be monitored for any new signs or symptoms suggestive of PML for at least 6 months following discontinuation of natalizumab, he said, noting that this is particularly true for patients with John Cunningham virus (JCV) seropositivity, prior exposure to immunosuppressants, or long-term natalizumab exposure, as these patients may be at increased risk of developing PML.

With exposure to natalizumab for 25-48 months, the rate of PML in JCV-positive patients is 3/1,000 patients in those with no prior exposure to immunosuppressant therapy, and 13/1,000 in those with prior exposure to immunosuppressant therapy, whereas with exposure for 49-72 months, the respective rates are 7/1,000 and 9/1,000, he said.

Although definitive conclusions about PML risk and exposure to natalizumab and fingolimod cannot be made based on the current analysis, an excess risk due to an overlapping pharmacodynamic effect when switching from natalizumab to fingolimod was not established, and a risk of PML cannot be confidently attributed to fingolimod, Dr. Putzki said.

A baseline neurological examination and MRI scan prior to initiating fingolimod treatment may help – at least retrospectively – in attributing PML causality to natalizumab vs. fingolimod, he added.

“Vigilance for PML is warranted following natalizumab discontinuation irrespective of consecutive treatment approaches,” he concluded.

BOSTON– Cases of progressive multifocal leukoencephalopathy in multiple sclerosis patients who switch from natalizumab to fingolimod treatment are more likely a result of the natalizumab exposure than the fingolimod exposure, according to an analysis of cases in the Novartis safety reporting database for fingolimod.

About 15%-20% of fingolimod-treated patients have prior exposure to natalizumab, and of 11 patients from the safety reporting database who have developed progressive multifocal leukoencephalopathy (PML) to date, all had prior natalizumab exposure, according to Dr. Norman Putzki.

The 11 patients with PML had been treated with natalizumab for a median of 4 years, Dr. Putzki, an employee of Novartis Pharma AG, Basel, Switzerland, said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The onset of PML, based on a retrospective review of MRI scans, was prior to the first fingolimod dose in 5 of the 11 patients, and between 3 weeks and 6 months after the first dose in 4 of the patients. Onset was unknown in the remaining 2 patients.

One additional case of possible PML was reported in a patient without prior natalizumab exposure. The patient had MRI features and the presence of AQP4 antibodies consistent with a diagnosis of neuromyelitis optica spectrum disorder, and clinical features that were consistent with a PML diagnosis, but the timing of onset in this patient could not be determined, Dr. Putzki said.

With more than 135,800 total patient-years of exposure, including during clinical trials and in the postmarketing period, no evidence of an association between fingolimod and PML has been found, he said.

Treatment with natalizumab, however, is an identified predisposing factor for PML development, and the risk is known to persist after treatment discontinuation. In fact, it is recommended that patients be monitored for any new signs or symptoms suggestive of PML for at least 6 months following discontinuation of natalizumab, he said, noting that this is particularly true for patients with John Cunningham virus (JCV) seropositivity, prior exposure to immunosuppressants, or long-term natalizumab exposure, as these patients may be at increased risk of developing PML.

With exposure to natalizumab for 25-48 months, the rate of PML in JCV-positive patients is 3/1,000 patients in those with no prior exposure to immunosuppressant therapy, and 13/1,000 in those with prior exposure to immunosuppressant therapy, whereas with exposure for 49-72 months, the respective rates are 7/1,000 and 9/1,000, he said.

Although definitive conclusions about PML risk and exposure to natalizumab and fingolimod cannot be made based on the current analysis, an excess risk due to an overlapping pharmacodynamic effect when switching from natalizumab to fingolimod was not established, and a risk of PML cannot be confidently attributed to fingolimod, Dr. Putzki said.

A baseline neurological examination and MRI scan prior to initiating fingolimod treatment may help – at least retrospectively – in attributing PML causality to natalizumab vs. fingolimod, he added.

“Vigilance for PML is warranted following natalizumab discontinuation irrespective of consecutive treatment approaches,” he concluded.

BOSTON– Cases of progressive multifocal leukoencephalopathy in multiple sclerosis patients who switch from natalizumab to fingolimod treatment are more likely a result of the natalizumab exposure than the fingolimod exposure, according to an analysis of cases in the Novartis safety reporting database for fingolimod.

About 15%-20% of fingolimod-treated patients have prior exposure to natalizumab, and of 11 patients from the safety reporting database who have developed progressive multifocal leukoencephalopathy (PML) to date, all had prior natalizumab exposure, according to Dr. Norman Putzki.

The 11 patients with PML had been treated with natalizumab for a median of 4 years, Dr. Putzki, an employee of Novartis Pharma AG, Basel, Switzerland, said at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

The onset of PML, based on a retrospective review of MRI scans, was prior to the first fingolimod dose in 5 of the 11 patients, and between 3 weeks and 6 months after the first dose in 4 of the patients. Onset was unknown in the remaining 2 patients.

One additional case of possible PML was reported in a patient without prior natalizumab exposure. The patient had MRI features and the presence of AQP4 antibodies consistent with a diagnosis of neuromyelitis optica spectrum disorder, and clinical features that were consistent with a PML diagnosis, but the timing of onset in this patient could not be determined, Dr. Putzki said.

With more than 135,800 total patient-years of exposure, including during clinical trials and in the postmarketing period, no evidence of an association between fingolimod and PML has been found, he said.

Treatment with natalizumab, however, is an identified predisposing factor for PML development, and the risk is known to persist after treatment discontinuation. In fact, it is recommended that patients be monitored for any new signs or symptoms suggestive of PML for at least 6 months following discontinuation of natalizumab, he said, noting that this is particularly true for patients with John Cunningham virus (JCV) seropositivity, prior exposure to immunosuppressants, or long-term natalizumab exposure, as these patients may be at increased risk of developing PML.

With exposure to natalizumab for 25-48 months, the rate of PML in JCV-positive patients is 3/1,000 patients in those with no prior exposure to immunosuppressant therapy, and 13/1,000 in those with prior exposure to immunosuppressant therapy, whereas with exposure for 49-72 months, the respective rates are 7/1,000 and 9/1,000, he said.

Although definitive conclusions about PML risk and exposure to natalizumab and fingolimod cannot be made based on the current analysis, an excess risk due to an overlapping pharmacodynamic effect when switching from natalizumab to fingolimod was not established, and a risk of PML cannot be confidently attributed to fingolimod, Dr. Putzki said.

A baseline neurological examination and MRI scan prior to initiating fingolimod treatment may help – at least retrospectively – in attributing PML causality to natalizumab vs. fingolimod, he added.

“Vigilance for PML is warranted following natalizumab discontinuation irrespective of consecutive treatment approaches,” he concluded.