VUMERITY Offers the Well-Understood Safety of dimethyl fumarate With Additional Data on GI Tolerability From Patient-Reported Outcomes1,2

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.

Adverse reactions in Study 1 and Study 2 reported for dimethyl fumarate
240 mg BID at ≥2% higher incidence than placebo

     
  DMFn=769 Placebon=771
Flushing 40% 6%
Abdominal pain 18% 10%
Diarrhea 14% 11%
Nausea 12% 9%
Vomiting 9% 5%
Pruritus 8% 4%
Rash 8% 3%
Albumin urine present 6% 4%
Erythema 5% 1%
Dyspepsia 5% 3%
Aspartate aminotransferase increased 4% 2%
Lymphopenia 2% <1%

GI Events

  • 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

EVOLVE-MS-2 study design2

  • 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

Patients who completed EVOLVE-MS-2 could roll over into EVOLVE-MS-1, a 96-week open- label study

*In 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.

Limitations and disclosures

  • 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

Key eligibility criteria

  • 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

GI tolerability assessments

  • 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

Primary endpoint

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

Secondary endpoints

Secondary endpoints were assessed in this study, but results are not presented here.

 

  • 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

Patients self-reported 46% fewer days (relative to exposure) with GI symptoms on VUMERITY vs dimethyl fumarate

Primary endpoint

Based on Part A and Part B

Over a 5-week treatment period, VUMERITY showed a 46% reduction (P=0.0003) in the number of days (adjusted rate ratio, 0.54 [95% CI, 0.39–0.75]) patients experienced a GI symptom intensity score rated ≥2 on an Individual GI Symptom and Impact Scale (a 0- to 10-point scale)

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

  • These days are not consecutive

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

0.8% of patients taking VUMERITY discontinued due to GI AEs, compared with 4.8% of those taking dimethyl fumarate

Disposition of Patients With RRMS in EVOLVE-MS-2

     
Patients, n (%) VUMERITY§n=254 DMF§n=252
Received ≥1 dose of study drug 253 (99.6) 251 (99.6)
Completed the treatment period 245 (96.8) 233 (92.8)
Mean (SD) days of treatment exposure, IGISIS 35.2 (4.2) 34.2 (5.9)
Mean (SD) days of treatment exposure, GGISIS 33.3 (4.8) 32.6 (5.6)
Rolled over to EVOLVE-MS-1 239 (94.5) 225 (89.6)
Discontinued the study 8 (3.2) 18 (7.2)
AE leading to discontinuation during the treatment period 4 (1.6) 14 (5.6)
GI AE leading to discontinuation 2 (0.8) 12 (4.8)
Upper abdominal pain 0 5 (2.0)
Diarrhea 1 (0.4) 3 (1.2)
Abdominal pain 0 3 (1.2)
Vomiting 1 (0.4) 2 (0.8)
Abdominal distension 0 1 (0.4)
GI pain 0 1 (0.4)
Nausea 0 1 (0.4)

§Patients were randomized.

VUMERITY, n=253; DMF, n=249.

GI AEs Experienced in ≥5% of Patients in Either Group

     
System organ class preferred term, n (%) VUMERITYn=253 DMFn=251
Any AE 198 (78.3) 210 (83.7)
GI disorders 88 (34.8) 123 (49.0)
Diarrhea 39 (15.4) 56 (22.3)
Nausea 37 (14.6) 52 (20.7)
Upper abdominal pain 17 (6.7) 39 (15.5)
Abdominal pain 16 (6.3) 24 (9.6)
Lower abdominal pain 15 (5.9) 17 (6.8)
Vomiting 9 (3.6) 22 (8.8)