Drug‐induced progressive multifocal leukoencephalopathy in multiple sclerosis: European regulators' perspective

Anton, Ruxandra; Haas, Manuel; Arlett, Peter; Weise, Martina; Balabanov, Pavel; Mazzaglia, Giampiero; Prieto, Luís; Keller‐Stanislawski, Brigitte; Raine, June

doi:10.1002/cpt.604

Cited by 19 publications

(10 citation statements)

References 54 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These cases occurred in patients who had been receiving fingolimod therapy for between 18 and 65 months, and who were aged 34–63 years [ 61 , 72 ]. These cases of PML were not associated with sustained grade 4 lymphopenia [ 61 ]; more research is needed to determine the relationship between lymphopenia and the risk of developing PML [ 73 ]. The low frequency of PML with fingolimod therapy means that there is currently limited information available to identify factors associated with an increased risk of this infection.…”

Section: Safety Precautions For Fingolimod Therapymentioning

confidence: 99%

Benefit–Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis

Comı

Hartung

Bakshi

et al. 2017

Drugs

View full text Add to dashboard Cite

Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit–risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s40265-017-0814-1) contains supplementary material, which is available to authorized users.

show abstract

Section: Safety Precautions For Fingolimod Therapymentioning

confidence: 99%

Benefit–Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis

Comı

Hartung

Bakshi

et al. 2017

Drugs

View full text Add to dashboard Cite

show abstract

“…A modern model involves signal detection, signal validation (i.e., signal should represent a novel causal relationship between a drug and an event), signal prioritization (evaluation of clinical impact of the safety issue), and some other steps to drive the decision-making, also on the basis of data on how drugs are used in a population and how their utilization can be influenced. Drug consumption is also now frequently analyzed by regulators to evaluate the actual impact of risk minimization strategies in a specific settings, such as the risk of progressive multifocal leukoencephalopathy with multiple sclerosis therapies [10].…”

Section: The Regulator's Viewmentioning

confidence: 99%

Evolving Roles of Spontaneous Reporting Systems to Assess and Monitor Drug Safety

Raschi¹,

Moretti²,

Salvo³

et al. 2019

Pharmacovigilance

View full text Add to dashboard Cite

This chapter aims to describe current and emerging roles of spontaneous reporting systems (SRSs) for assessing and monitoring drug safety. Moreover, it offers a perspective on the near future, which entails the so-called era of Big Data, keeping in mind both regulator and researcher viewpoints. After a panorama on key data sources and analyses of post-marketing data of adverse drug reactions, a critical appraisal of methodological issues and debated future applications of SRSs will be presented, including the exploitation and challenges in evidence integration (i.e., merging and combining heterogeneous sources of data into a unique indicator of risk) and patient's reporting via social media. Finally, a call for a responsible use of these studies is offered, with a proposal on a set of minimum requirements to assess the quality of disproportionality analysis in terms of study conception, performing and reporting.

show abstract

“…According to the European Medicines Agency, early PML identification14 15 is a critical step in reducing mortality and residual disability 16–18. Early identification would be particularly useful for patients who cannot withdraw from NTZ treatment.…”

Section: Introductionmentioning

confidence: 99%

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution

Scarpazza

Signori

Prosperini

et al. 2018

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

ObjectiveEarly diagnosis of natalizumab-related progressive multifocal leucoencephalopathy (NTZ-PML) in multiple sclerosis has been deemed a major priority by the regulatory agencies but has yet to become a reality. The current paper aims to: (1) investigate whether patients with NTZ-PML pass through a prolonged presymptomatic phase with MRI abnormalities, (2) estimate the longitudinal PML lesion volume increase during the presymptomatic phase and (3) estimate the presymptomatic phase length and its impact on therapy duration as a risk stratification parameter.MethodsAll Italian patients who developed NTZ-PML between 2009 and 2018 were included. The data of patients with available prediagnostic MRI were analysed (n=41). Detailed clinical and neuroradiological information was available for each participant.Results(1) PML lesions were detectable in the presymptomatic phase in 32/41 (78%) patients; (ii) the lesion volume increased by 62.8 % for each month spent in the prediagnostic phase; (3) the prediagnostic phase length was 150.8±74.9 days; (4) PML MRI features were detectable before the 24th month of therapy in 31.7 % of patients in our cohort.ConclusionsConsidering the latency of PML clinical manifestation, the presymptomatic phase length supports the usefulness of MRI surveillance every 3–4 months. Early diagnosis could prompt a better outcome for patients due to the relationship between lesion volume and JC virus infection. The insight from this study might also have an impact on risk stratification algorithms, as therapy duration as a parameter of stratification appears to need reassessment.

show abstract

Drug‐induced progressive multifocal leukoencephalopathy in multiple sclerosis: European regulators' perspective

Cited by 19 publications

References 54 publications

Benefit–Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis

Benefit–Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis

Evolving Roles of Spontaneous Reporting Systems to Assess and Monitor Drug Safety

Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution

Contact Info

Product

Resources

About