Multiple sclerosis:

Indications for: VUMERITY

Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Clinical Trials:

The efficacy of Vumerity is based upon bioavailability studies in patients with relapsing forms of multiple sclerosis and healthy subjects comparing oral dimethyl fumarate delayed-release capsules to Vumerity delayed-release capsules (see full labeling).

The clinical studies described below were conducted using dimethyl fumarate. 

The efficacy and safety of dimethyl fumarate were demonstrated in two studies (Studies 1 and 2) that evaluated dimethyl fumarate taken either twice or three times a day in patients with relapsing-remitting multiple sclerosis (RRMS).

Study 1: Placebo-Controlled Trial in RRMS 
Study 1 was a 2-year randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. The primary endpoint was the proportion of patients relapsed at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of Gd+ lesions, annualized relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks. Patients were randomized to receive dimethyl fumarate 240 mg twice a day (n=410), dimethyl fumarate 240 mg three times a day (n=416), or placebo (n=408) for up to 2 years. The median age was 39 years, median time since diagnosis was 4 years, and median EDSS score at baseline was 2. The median time on study drug for all treatment arms was 96 weeks.

Results showed that treatment with dimethyl fumarate achieved a statistically significant effect on all of the endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The following results are for dimethyl fumarate 240 mg twice daily vs placebo, respectively:

  • Proportion relapsing (primary endpoint): 27% vs 46% (relative risk reduction, 49%; P <.0001)

  • ARR: 0.172 vs 0.364 (relative reduction, 53%; P <.0001)

  • Proportion with disability progression: 16% vs 27% (relative risk reduction, 38%; P =.005)

  • Mean number of new or newly enlarging T2 lesions over 2 years: 2.6 vs 17 (P <.0001)

  • Percentage of patients with no new or newly enlarging lesions: 45% vs 27%

  • Number of Gd+ lesions at 2 years: 0.1 vs 1.8 (relative odds reduction, 90%; P <.0001)

  • Mean number of new T1 hypointense lesions over 2 years: 1.5 vs 5.6 (P <.0001)

Study 2: Placebo-Controlled Trial in RRMS 
Study 2 was a 2-year multicenter, randomized, double-blind, placebo-controlled study that also included an open-label comparator arm in patients with RRMS. The primary endpoint was the annualized relapse rate at 2 years. Additional endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, number of Gd+ lesions, proportion of patients relapsed, and time to confirmed disability progression as defined in Study 1. Patients were randomized to receive dimethyl fumarate 240 mg twice a day (n=359), dimethyl fumarate 240 mg three times a day (n=345), an open-label comparator (n=350), or placebo (n=363) for up to 2 years. The median age was 37 years, median time since diagnosis was 3 years, and median EDSS score at baseline was 2.5. The median time on study drug for all treatment arms was 96 weeks.

Results showed that treatment with dimethyl fumarate achieved a statistically significant effect on the relapse and MRI endpoints described above and the 240 mg three times daily dose showed no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The following results are for dimethyl fumarate 240 mg twice daily vs placebo, respectively:

  • ARR: 0.224 vs 0.401 (relative reduction, 44%; P <.0001)

  • Proportion relapsing: 29% vs 41% (relative risk reduction, 34%; P =.002)

  • Proportion with disability progression: 13% vs 17% (relative risk reduction, 21%; P =.25)

  • Mean number of new or newly enlarging T2 lesions over 2 years: 5.1 vs 17.4 (P <.0001)

  • Percentage of patients with no new or newly enlarging lesions: 27% vs 12%

  • Number of Gd+ lesions at 2 years: 0.5 vs 2.0 (relative odds reduction, 74%; P <.0001)

  • Mean number of new T1 hypointense lesions over 2 years: 3.0 vs 7.0 (P <.0001)

Adult Dosage:

Swallow whole. Initially 231mg twice daily for 7 days, then increase to maintenance dose of 462mg twice daily. If maintenance dose not tolerated, temporarily reduce back to initial dose. Within 4 weeks, resume maintenance dose; if not tolerated, consider discontinuing.

Children Dosage:

Not established.

VUMERITY Contraindications:

Concomitant dimethyl fumarate.

VUMERITY Warnings/Precautions:

Obtain a CBC including lymphocyte count prior to initiation, after 6 months, and every 6–12 months thereafter; consider interruption if lymphocyte counts <0.5×109/L persist for >6 months. Pre-existing low lymphocyte counts: not studied. Monitor for herpes zoster, other serious opportunistic infections; evaluate and treat if occurs; consider withholding until infection resolved. Monitor serum aminotransferase, alkaline phosphatase, and total bilirubin prior to initiation and during treatment; discontinue if significant liver injury is suspected. Discontinue if anaphylaxis or angioedema occurs. Withhold and evaluate at first sign/symptom suggestive of PML. Administration with non-enteric coated aspirin (up to 325mg) or food may reduce incidence/severity of flushing. Moderate or severe renal impairment: not recommended. Pregnancy. Nursing mothers.

VUMERITY Interactions:

Avoid concomitant alcohol, high-fat and/or high-calorie meal/snack.

Adverse Reactions:

Flushing, abdominal pain, diarrhea, nausea, vomiting, pruritus, rash, albumin urine present; lymphopenia, liver injury.

Metabolism:

In humans, diroximel fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, to the major active metabolite, MMF, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. Fumaric and citric acid, and glucose are the major metabolites of MMF in plasma.  

Esterase metabolism of diroximel fumarate also produces 2-hydroxyethyl succinimide (HES), an inactive major metabolite.

Drug Elimination:

MMF is mainly eliminated as carbon dioxide in the expired air with only trace amounts (less than 0.3% of the total dose) recovered in urine. The terminal half-life of MMF is approximately 1 hour, and accumulation of MMF does not occur with multiple doses of Vumerity. HES is mainly eliminated in urine (58-63% of the dose was excreted as HES in urine).

Generic Drug Availability:

NO

How Supplied:

Del-rel caps—106 (Starter Pack), 120 (Maintenance Pack)