Montelukast to Manage Tecfidera GI Side Effects

The immunomodulator dimethyl fumarate (Tecfidera, Biogen) has been available for the treatment of relapsing forms of multiple sclerosis since 2013.

Prescribers and patients recognize the gastrointestinal side effects of Tecfidera as a significant hurdle to therapy that can delay titration to the target dose, and although the gastrointestinal side effect profile reduces in severity over time, it can still be bothersome enough to lead to discontinuation of Tecfidera. Techniques to minimize the impact of the gastrointestinal side effects have included thorough patient counseling, administration of Tecfidera concomitantly with meals (Tecfidera is given twice daily, and fat-rich meals have been shown to reduce the severity of the gastrointestinal upset), and pharmacotherapeutic management of symptoms.¹

The solution to Tecfidera’s gastrointestinal reputation may lie in an unlikely place: the leukotriene receptor antagonist montelukast (Singulair, Merck). Tornatore and Amjad suggested the mechanism of Tecfidera-related gastrointestinal side effects involved eosinophils and attempted a small test of their theory.² They instructed 4 patients to take take montelukast 10 mg once daily in response to gastrointestinal adverse events while on Tecfidera 240 mg twice daily.

They evaluated the patient response to montelukast using a 15-question questionnaire called the Gastrointestinal Symptom Rating Scale (GSRS). The small patient population revealed a significant reduction in GSRS scales (81%, P <0.01), a symptomatic improvement within 72 hours, and the effect was maintained for up to 30 days. The results seem promising, but it would be a stretch to extrapolate a treatment to the entire Tecfidera multiple sclerosis patient population based off the results of a 4-patient cohort.

Further evidence may not be too far off. Biogen, the maker of Tecfidera, submitted a clinical trial protocol for MITIGATE (Study of Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis Receiving Tecfidera) in 2015 to further examine the use of montelukast in combination with Tecfidera.³

The phase 4 trial lists an enrollment target of 63 patients that should allow for a more robust examination of the effect of montelukast, and the 2 experimental arms are Tecfidera+montelukast and Tecfidera+placebo. The primary outcome will assess the same GSRS questionnaire as Tornatore’s small 4-patient cohort. According to Biogen medical information, the MITIGATE trial completed this July and is expected to read out in early 2018. I look forward to discussing the results of the MITIGATE trial in a future article.

References

• Phillips J, Erwin A, et al. Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study. Neurol Ther. 2015 Dec; 4(2): 137—146.
• Tornatore C, Amjad F. Attenuation of Dimethyl Fumarate-Related Gastrointestinal Symptoms with Montelukast. Poster Session VII at: Treatment of Specific Multiple Sclerosis Symptoms. Neurol. April 8, 2014 vol. 82 no. 10 Supplement P7.251
• ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US).2000 Feb 29 Identifier NCT02410278 Study of Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis Receiving Tecfidera(MITIGATE). April 2, 2015 [cited July 25, 2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT02410278?cond=dimethyl+fumarate+AND+montelukast&rank=1