VUMERITY offers the well-understood safety of dimethyl fumarate (DMF) with additional data on GI tolerability from patient-reported outcomes^1,2

Pivotal trial study design¹

The efficacy and safety of dimethyl fumarate were demonstrated in 2 studies (Study 1 and Study 2), both of which enrolled patients with RRMS who had experienced at least 1 relapse over the year preceding the trial or had an MRI scan demonstrating at least 1 gadolinium-enhancing lesion within 6 weeks prior to randomization.

Study 1: a 2-year, randomized, double-blind, placebo-controlled study in which 1234 patients with RRMS were randomized to receive dimethyl fumarate 240 mg BID (n=410), dimethyl fumarate 240 mg TID (n=416), or placebo (n=408).

Study 2: a 2-year, randomized, double-blind, placebo-controlled study in which 1417 patients with RRMS were randomized to receive dimethyl fumarate 240 mg BID (n=359), dimethyl fumarate 240 mg TID (n=345), an open-label comparator (n=350), or placebo (n=363).

The only approved dose of dimethyl fumarate is the 240 mg BID dose.

The adverse reactions presented in the table below are based on safety information from 769 patients treated with dimethyl fumarate 240 mg twice a day and 771 placebo-treated patients.

The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) were flushing, abdominal pain, diarrhea, and nausea.

• Dimethyl fumarate caused GI events (eg, nausea, vomiting, diarrhea, abdominal pain, and dyspepsia)
• 4% of patients treated with dimethyl fumarate and less than 1% of placebo patients discontinued due to GI events
• The incidence of serious GI events was 1% in patients treated with dimethyl fumarate
• The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with dimethyl fumarate compared with placebo
• Serious gastrointestinal (GI) reactions, including perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes, have been reported in the postmarketing setting with the use of fumaric acid esters, including VUMERITY, with or without concomitant aspirin use

• An increased incidence of elevations of hepatic transaminases in patients treated with dimethyl fumarate was seen primarily during the first 6 months of treatment, and most patients with elevations had levels <3 times the ULN during controlled trials
• Elevations of alanine aminotransferase and aspartate aminotransferase to ≥3 times the ULN occurred in a small number of patients treated with both dimethyl fumarate and placebo and were balanced between groups
• No elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN
• Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with dimethyl fumarate or placebo

• A transient increase in mean eosinophil counts was seen during the first 2 months of therapy

Study was funded by Biogen.

• EVOLVE-MS-2 was a phase 3, randomized, head-to-head, active-controlled, 5-week study to evaluate patient-assessed GI tolerability of VUMERITY versus dimethyl fumarate in patients with RRMS
• The EVOLVE-MS-2 study used an adaptive trial design in which data from Part A were used to evaluate the utility of GI symptom scales and to inform the GI tolerability endpoints and sample size for Part B
• Parts A and B were identical in study assessments. Following the completion of Part A, a planned, unblinded analysis of GI tolerability was performed to refine the primary endpoint to reflect the most sensitive measure for detecting a difference between VUMERITY and dimethyl fumarate and re-estimate sample size

^aIn study week 1, the titrated dose for VUMERITY was one 231-mg delayed-release capsule taken orally, twice daily. The titrated dose for dimethyl fumarate was one 120-mg delayed-release capsule taken orally, twice daily. From study weeks 2–5, the full dose for VUMERITY was two 231-mg delayed-release capsules taken orally, twice daily, and the full dose for dimethyl fumarate was one 240-mg delayed-release capsule taken orally, twice daily.

• The GI symptom intensity scales are not validated
• Results should be interpreted with caution due to the 5-week duration
• Patients were excluded if they had a history of GI surgery, clinically significant recurring or active GI symptoms within 3 months of screening, or chronic use of medical therapy to treat GI symptoms within 1 month of screening
• The results from this study are not included in the full Prescribing Information for VUMERITY. The US Food and Drug Administration did not consider the results of this study when approving VUMERITY

• Patients aged 18–65 years with a confirmed RRMS diagnosis
• Patients had no history of GI surgery, clinically significant recurring or active GI symptoms within 3 months of screening, or chronic use of medical therapy to treat GI symptoms within 1 month of screening

• Patients used 2 GI tolerability scales to self-assess the duration and severity of their GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea) on an 11-point patient-reported numerical rating scale using eDiaries
  • Individual Gastrointestinal Symptom and Impact Scale (IGISIS): patients self-assessed the intensity of each of the 5 GI symptoms twice daily, within 9 hours of taking each dose
  • Global Gastrointestinal Symptom and Impact Scale (GGISIS): patients self-assessed the intensity of any GI symptoms over the last 24 hours

• Number of days (relative to exposure) with any individual GI symptom intensity score ≥2 in the overall population

• Number of days (relative to exposure) with individual GI symptom intensity scores of ≥1 or ≥3 in the overall population
• Number of days (relative to exposure) with an individual GI symptom intensity score of ≥2 in patients from Part B only
• Number of days (relative to exposure) with global GI symptom intensity scores of ≥1, ≥2, or ≥3 in the overall population
• Worst individual GI symptom score by study week

Overall, 19.3% of patients (17 out of 88) in the VUMERITY group and 30.6% of patients (37 out of 121) in the DMF group used concomitant medications to treat GI-related AEs during the treatment period

• Days were not consecutive
• Patients taking VUMERITY reported fewer days with an individual GI symptom intensity score of ≥2 in an analysis of data collected from Part B only (adjusted rate ratio, 0.52 [95% Cl, 0.36-0.76])

^bIntensity of nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea reported twice per day. ^cPatients completed ≥1 postbaseline tolerability eDiary assessment and were included in the analysis of patient-assessed GI tolerability.

• Days were not consecutive
• Patients taking VUMERITY reported fewer days with an individual GI symptom intensity score of ≥2 in an analysis of data collected from Part B only (adjusted rate ratio, 0.52 [95% Cl, 0.36-0.76])

^dIntensity of nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea occurring within the last 9 hours of taking the study drug. ^eCompleted ≥1 postbaseline tolerability eDiary assessment and were included in the analysis of patient-assessed GI tolerability.

• Days were not consecutive
• Patients taking VUMERITY reported fewer days with GI symptoms rated ≥1, ≥2, or ≥3 on the 0 to 10-point global GI symptom and intensity scale
• Upper GI events (upper abdominal pain, nausea, and vomiting) were less severe with VUMERITY. Lower GI symptoms (lower abdominal pain and diarrhea) were similar between VUMERITY and dimethyl fumarate

^fIntensity of nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea occurring within the last 9 hours of taking the study drug. ^gCompleted ≥1 postbaseline tolerability eDiary assessment and were included in the analysis of patient-assessed GI tolerability.

^hAnalysis of covariance model; factors include study parts, region (United States and non-United States), age, and body mass index.

ⁱPatients were randomized.

^jVUMERITY, n=253; DMF, n=251.

Study was funded by Biogen.