Gastrointestinal Symptoms in Early Dimethyl Fumarate Therapy John Foley, Tamara Hoyt, Angelene Christensen, Ryan Metzger Rocky Mountain MS Research Group, Salt Lake City, UT

FIGURE 5 TIME-COURSE OF SYMPTOM SCORES OVER BACKGROUND: 10 RESULTS: THE FIRST 14 DAYS OF DMF TREATMENT Dimethyl fumarate (DMF) is an oral therapy approved 9 for treatment of relapsing forms of multiple sclerosis FIGURE 1 8 Nausea TREATMENT TERMINATION DUE TO GI core 7 Diarrhea (MS). Though DMF is generally well tolerated, MAGISS: SYMPTOMS WAS UNCOMMON SS Upper Abd Pain 6 1-3 = mild gastrointestinal (GI) side effects are not uncommon, Lower Abd Pain

GIS 4-6 = moderate

1 A 5 7-10 = severe Indigestion particularly during initiation of treatment. A better Terminated Due to GI Symptoms Constipation eM Continued Treatment 4 Bloating understanding of the prevalence and intensity of ag 3 Flatulance Vomiting specific GI symptoms occurring with DMF could prove FIGURE 2 Aver useful in characterizing the GI response to DMF MOST PATIENTS EXPERIENCED GI 2 therapy, and help direct strategies to mitigate these 22 SYMPTOMS FOR AT LEAST ONE DAY 1 0 symptoms. Any GI Symptom of Any GI Symptom of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Total=23 Any Intensity Moderate-to-Severe Intensity Day

Symptoms OBJECTIVE: No Symptoms 2 FIGURE 6 The aim of this study was to further characterize the 5 ROCKY MOUNTAIN MS CLINIC PROTOCOL FOR MANAGEMENT prevalence, intensity and frequency of specific GI OF GI SYMPTOMS FOR PATIENTS ON DMF THERAPY symptoms during initiation of therapy. Decision to Start DMF Therapy 19 16 Advise to take DMF with fat bolus METHODS: (e.g. peanut butter, avocado) Twenty-four patients with relapsing-remitting MS were enrolled into Total=21 Total=21 **Symptomatic medications for GI symptoms *One patient did not rate several symptoms, and therefore was excluded here along with the patient an IRB-approved study and assessed for GI symptoms over the first who terminated treatment due to GI symptoms (Fig. 1) Pre-existing GI co-morbidities No Pre-existing GI co-morbidities Symptom Medication 2 weeks of DMF therapy, as part of a screening process to (e.g. gastric bypass recipient) Nausea odansetron determine eligibility for a subsequent evaluation of mitigation Begin extended* titration dosing Begin standard titration dosing Diarrhea loperamide strategies for GI symptoms. DMF was prescribed at 120 mg twice FIGURE 3 Abdominal Pain bismuth subsalicylate, simethicone daily for the first 7 days, then increased to 240 mg twice daily on day PREVALANCE AND ACUITY OF EACH SYMPTOM Indigestion omeprazole, antacids GI symptoms No GI symptoms GI symptoms Bloating simethicone 8. One patient terminated treatment due to flushing, and therefore Present for At Least One Day Average Peak Intensity Advise symptomatic medications** Continue with treatment plan Advise symptomatic medications** Flatulance simethicone 4 was excluded. Patients recorded their daily GI symptoms using the 100 Vomiting odansetron MAGISS:

Modified Acute GI Symptom Scale (MAGISS) - which evaluates 9 80 SEM 1-3 = mild

/- 3 4-6 = moderate symptoms on a 10-point intensity scale: upper and lower abdominal 7-10 = severe

e+ GI symptoms remain GI symptoms remain 60 or pain, nausea, vomiting, bloating, flatulence, diarrhea, constipation, atient s 2 Consider alternative DMT Re-start DMF therapy using Sc extended* titration dosing fP 40 and indigestion. Scores of 4-10 were considered ak Pe %o 1 *Extended titration dosing = 120 mg once daily for 1 week, then 120 mg twice daily for 1 week, then 120 mg in morning + 240 mg in evening for 1 week, then 240 mg twice daily.

moderate-to-severe intensity. One patient did not report symptom 20 an Me intensity for 4 of the symptoms, therefore was excluded from some 0 0 analyses. Data were analyzed using standard descriptive statistical a in n g g e a in n g g e se ai in tion in nc se ai in tion in nc u rrhea Pa at la u rrhea Pa at la a ia dP es lo u a dP es lo u CONCLUSIONS: N bd omit ig t N ia bd omit t methods using GraphPad Prism v6.05 (La Jolla, CA). D Ab V B la D Ab V ig B la rA Ind onstipation F rA Ind onstipation F C C • Over the first 2 weeks of DMF therapy, mild GI symptoms are common and wide-ranging. ppe ower ppe ower U L U L • Abdominal pain, nausea, and bloating are the GI symptoms most likely to be of higher TABLE 1 FIGURE 4 intensity during this time. PATIENT CHARACTERISTICS MODERATE-TO-SEVERE SYMPTOMS ARE GENERALLY NOT SUSTAINED • Few patients experience moderate-to-severe symptoms for a sustained period.

n = 23 Score > 3 for At Least One Day Mean Score Across All Days > 3.5 • GI symptoms very rarely lead to treatment termination at this early stage of therapy. Gender 83% female, 17% male 100 100 • Strategies that may prove helpful in mitigating GI symptoms could include: 1) accompanying

Body Weight (kg; median, range) 71, 55 - 118 80 80 MAGISS: DMF administration with fat-containing food, 2) utilization of over-the-counter medications for 1-3 = mild 1,2 4-6 = moderate GI symptoms, 3) extended titration dosing, or 4) dose reduction . Indeed, experience at this Age (years; mean ± st. dev., range) 46 ± 13, 27-72 60 60 7-10 = severe atient s center suggests improved tolerance of DMF utilizing these strategies. Disease Duration (years; median, range) 10, 0.2-38 fP 40 40 %o Mean Score >3.5

20 % of Patients with 20

0 0 REFERENCES: a a n n n g e a a n n g e DISCLOSURES: ng in ng se ai ai ti tion in nc se ai ti tion in nc 1. Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl u rrhe i at la u rrhe Pa i at la • Study supported by an Investigator-Initiated Trial grant from a dP dP es lo u a ia dP es lo u N ia om t N bd om ig t D Ab Ab V ig B la D A Ab V B la Biogen. Fumarate: A Delphi Study. Phillips TJ, Erwin AA, Agrella S et al. Neurol Ther. 2015 Dec;4(2):137-46. Ind onstipatio F Ind onstipatio F C C • JF has received personal honoraria from Biogen, Genzyme 2. Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label pper ower pper ower U L U L and Teva Pharmaceuticals for consulting services. Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE). Fox EJ, Vasquez A, • RM has a family member who is employed by Biogen. Grainger W et al. MS Care. 2016 Jan-Feb;18(1):9-18