PML | Siponimod US Safety Site

Progressive multifocal leukoencephalopathy

PML has been reported with an S1P receptor modulator and other MS therapies. Therefore, vigilance on the part of physicians and patients for signs and symptoms of infections is important while on therapy and for up to 1 month after cessation of treatment¹

Clinical trials

As of 25-September-2020, with cumulative clinical trial exposure of 7171 patient-years, no cases of PML have been reported²

Postmarketing

As of 25-September-2020, with cumulative postmarketing exposure of 2278 patient-years, no cases of PML have been reported³

** A 53 year-old female MS patient with suspected symptom and signs (MRI lesions) of PML was switched from natalizumab to siponimod after having been treated for around 5 years. Therapy with siponimod was stopped after diagnostic confirmation of PML (JCV PCR: 522 copies at CSF, and gadolinium enhancing lesions in the subcortical white matter of the left precentral gyrus), approximately 5 weeks after siponimod treatment initiation. As per the latest available information (mid-Feb 2022), the patient’s PML symptoms improved, and she was discharged from the hospital. The independent adjudication panel assessed the event of PML as attributable to natalizumab and unrelated to siponimod treatment.

About PML

PML background

PML is caused by reactivation of the JC virus, a ubiquitous human papovavirus that is typically acquired during childhood and remains latent in the kidneys and possibly other sites (eg, mononuclear cells, CNS)¹
PML is increasingly occurring as a complication of immunomodulatory therapy¹
Common symptoms/signs include clumsiness, hemiparesis, aphasia, dysarthria, hemianopia and cognitive impairment¹
PML is suspected in patients with unexplained progressive brain dysfunction, particularly in those with depressed cell-mediated immunity¹
CSF is analyzed for JC viral DNA using PCR; a positive result with compatible neuroimaging findings is nearly pathognomonic¹
Supportive management and management of underlying disorders are helpful in managing PML¹

Suspected or confirmed PML: Get Novartis support

Novartis support

Novartis can help physicians with the assessment of a suspected PML case, after the adverse event has been reported to the company via standard pharmacovigilance processes

Subsequently, there is access to an external expert MRI service and Novartis has constituted an external PML adjudication panel for case evaluation
If a second opinion on an MRI with atypical findings/suspicion of PML is requested, Novartis can support obtaining this through an MRI expert center (Medical Image Analysis Centre [MIAC]), University Hospital Basel, Switzerland. Novartis will not have access to the MRI and will only receive a report
In addition, Novartis can support logistics for shipment of CSF samples for testing for presence of JC DNA (PCR) at Unilabs A/S, Denmark. In this case, both the physician and Novartis receives the report

Last updated: February 2021. The page will be updated quarterly.

Abbreviations

CNS, central nervous system; CSF, cerebrospinal fluid; JC, John Cunningham; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy

References

1. Greenlee JE. Progressive Multifocal Leukoencephalopathy (PML). MSD Manual Professional Version. Accessed December 23, 2020. https://www.msdmanuals.com/professional/neurologic-disorders/brain-infections/progressive-multifocal-leukoencephalopathy-pml
2. Data on File, cutoff date 6-Apr-2020, Novartis Pharma AG.
3. Data on File, PSUR 2, cutoff date 25-Sep-2020, Novartis Pharma AG.