Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study

ABSTRACT

Background

Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users.

Methods

Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs).

Results

Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT.

Conclusions

The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.

KEYWORDS:

• Adverse events
• dimethyl fumarate
• fingolimod
• multiple sclerosis
• population-based study
• teriflunomide

Acknowledgments

Preliminary findings from this work were included in a poster presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis ACTRIMS Forum 2020 (West Palm Beach, Florida, US; February 27th-29th 2020).

The authors would like to acknowledge Ms. Shary Zhang (University of British Columbia) and the late Ms. Hui Chen (Manitoba Centre for Health Policy) for their helpful contributions to initial analyses for this project. They are grateful to Dr Galina Vorobeychik, MS Clinic, Burnaby Hospital (Fraser Health); Dr Kristen Attwell-Pope, Vancouver Island MS Clinic (Island Health); and Dr Alexander Rauscher, BC Children’s Hospital (PHSA), for their help and support as study co-investigators, with accessing laboratory data.

The authors acknowledge the Manitoba Centre for Health Policy for use of the Population Health Research Data Repository under project #2016-007 (HIPC #2015/2016-42). Access to, and use of, BC data was facilitated by Population Data BC (https://www.popdata.bc.ca). The bodies regulating administrative data access that approved the study included the following: the British Columbia Ministry of Health, the BC Vital Statistics Agency, BC PharmaNet, LifeLabs Medical Laboratory Services, Providence Health Care Society, Children’s and Women’s Health Centre of BC, the BC Provincial Health Services Authority, the five regional BC Health Authorities (Vancouver Coastal, Vancouver Island, Fraser, Interior and Northern), and the Manitoba Health Information Privacy Committee The results, inferences, opinions, and conclusions presented are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, Population Data BC, the BC Data Stewards, or other data providers is intended or should be inferred.

Author contributions

The corresponding author takes responsibility for the integrity of the data and the accuracy of the data analysis. The analysts and principal investigators at each site had full access to the data at each site (BC: Elaine Kingwell, Helen Tremlett, Feng Zhu; MB: Ruth Ann Marrie, Randy Walld). Helen Tremlett, Ruth Ann Marrie, Elaine Kingwell and Tingting Zhang designed the study and obtained funding. All authors contributed to the interpretation of the data. Elaine Kingwell and Helen Tremlett drafted the manuscript. All authors revised the manuscript critically for intellectual content, approved of the final version to be published and agree to be accountable for all aspects of the work.

Declaration of interest

E Kingwell was supported through research grants from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. In addition, during the last five years, she received travel expenses to give presentations, or attend CME conferences, from ACTRIMS, ECTRIMS, and the MS Society of Canada. R Carruthers is Site Investigator for studies funded by Roche, Novartis, MedImmune, and EMD Serono, and receives research support from Teva Innovation Canada, Roche Canada and Vancouver Coastal Health Research Institute. He has received honoraria from Roche, EMD Serono, Sanofi, Biogen, Novartis, and Teva. C Evans receives funding from the Canadian Institutes of Health Research and the Saskatchewan Health Research Foundation. RA Marie receives research funding from the Canadian Institutes of Health Research, the MS Society of Canada, the National MS Society, Consortium if Multiple Sclerosis Centres, Crohn’s and Colitis Canada, Research Manitoba, the MS Scientific Research Foundation, US Department of Defense and the Waugh Family Chair in Multiple Sclerosis. H Tremlett is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support is received from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation. In addition, in the last five years, she has received research support from the Multiple Sclerosis Society of Canada (Don Paty Career Development Award); the Michael Smith Foundation for Health Research (Scholar Award) and the UK MS Trust; speaker honoraria and/or travel expenses to attend CME conferences from the Consortium of MS Centres (2013, 2018), the National MS Society (2014, 2016, 2018), ECTRIMS (2013, 2014, 2015, 2016, 2017, 2018, 2019), Biogen Idec (2014), and American Academy of Neurology (2013, 2014, 2015, 2016, 2019). All speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by Dr Tremlett’s research group. The authors have no other other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was supported by the Multiple Sclerosis Society of Canada (EGID:2624; PI:HT).