VUMERITY Delayed-release capsule Ref.[10024] Active ingredients: Diroximel fumarate

Cardiac Electrophysiology

At a dose 2 times the maximum recommended dose, VUMERITY does not prolong the QTc interval to any clinically relevant extent.

After oral administration of VUMERITY, diroximel fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Diroximel fumarate is not quantifiable in plasma following oral administration of VUMERITY. Therefore, all pharmacokinetic analyses related to VUMERITY were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with relapsing forms of multiple sclerosis (MS) and healthy volunteers.

Absorption

Following oral administration of VUMERITY, the median t_max of MMF is 2.5 to 3 hours. The peak plasma concentration (C_max) and overall exposure (AUC) increased dose proportionally in the recommended daily dose range (462 mg to 924 mg). Following administration of VUMERITY 462 mg in patients with MS, the mean C_max of MMF was 2.11 mg/L. The mean steady state AUC of MMF was estimated to be 8.32 mg.hr/L following twice daily dosing in patients with MS.

Effect of Food

In an open-label, randomized, balanced, crossover study, co-administration of VUMERITY with a high-fat, high-calorie meal (900-1000 calories, 50% of calories from fat) did not affect the AUC of MMF, but resulted in an approximately 44% reduction in C_max compared to fasted state [see Dosage and Administration (2.3)]. The MMF C_max with low-fat, low-calorie (350 to 400 calories, 10 to 15 g fat) and medium-fat, medium-calorie (650 to 700 calories, 25 to 30 g fat) meals was reduced by approximately 12% and 25%, respectively.

Relative to fasted state, the t_max of MMF was delayed from 2.5 hours (fasted state) to 4.5 hours (low-fat, low-calorie meal or a medium-fat, medium-calorie meal) and 7.0 hours (high-fat, high-calorie meal) in the fed state. There was no impact of low, medium, or high-fat meals on the AUC of MMF after administration of VUMERITY.

Distribution

The apparent volume of distribution for MMF is between 72 L and 83 L in healthy subjects after administration of VUMERITY. Human plasma protein binding of MMF is 27-45% and independent of concentration.

Elimination

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.

Excretion

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).

Specific Populations

Age (18-79 years), sex, and race (White, African American, and Asian) did not have clinically meaningful effects on the pharmacokinetics of MMF after administration of VUMERITY. The effect of hepatic impairment or severe renal impairment (CrCl <30 mL/min, Cockcroft-Gault) requiring hemodialysis on MMF pharmacokinetics is unknown.

Patients with Renal Impairment

A single-dose clinical study investigating the effect of renal impairment on the pharmacokinetics of diroximel fumarate and its metabolites MMF and HES was conducted. The study included cohorts with mild, moderate, and severe renal impairment and a healthy cohort (8 subjects per cohort) and found no clinically relevant changes in MMF exposure. However, HES exposure increased by 1.3, 1.8, and 2.7-fold with mild, moderate, and severe renal impairment, respectively, compared to the healthy cohort [see Use in Specific Populations (8.6)]. There are no data available on long-term use of VUMERITY in patients with moderate or severe renal impairment.

Patients with Hepatic Impairment

No studies have been conducted in subjects with hepatic impairment. However, hepatic impairment would not be expected to affect exposure to MMF and therefore no dosage adjustment is necessary.

Drug Interaction Studies

Diroximel fumarate metabolism does not involve CYP enzymes, therefore, no clinically meaningful interactions are expected when administered with CYP inhibitors or inducers.

In vitro studies found diroximel fumarate and its metabolites did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 enzymes in human liver microsomes or induce CYP1A2, 2B6, or 3A4/5 in cultured human hepatocytes.

Diroximel fumarate did not inhibit P-gp in vivo. The major circulating inactive metabolite of diroximel fumarate, HES, did not inhibit P-gp and was neither a substrate nor an inhibitor of BCRP, MATE1, MATE2-K, OAT1, OAT3, or OCT2.

Aspirin, when administered approximately 30 minutes before dimethyl fumarate, did not alter the pharmacokinetics of MMF.

Oral Contraceptives

In a study conducted with dimethyl fumarate, no relevant effects of MMF on oral contraceptive exposure were observed when administered with a combined oral contraceptive (norelgestromin and ethinyl estradiol). No interaction studies have been performed with oral contraceptives containing other progestogens.

Alcohol

Administration of VUMERITY at the same time with 5% v/v and 40% v/v ethanol did not alter total MMF exposure relative to administration with water, demonstrating that the coingestion of ethanol does not induce dose dumping. The mean peak plasma MMF concentration for diroximel fumarate was decreased by 9% and 21%, when co-administered with 240 mL of 5% v/v and 40% v/v of ethanol, respectively [see Dosage and Administration (2.3)].

Carcinogenesis

Oral administration of diroximel fumarate (0, 0, 30, 100, 300 or 1000 [females only] mg/kg/day) for 26 weeks to Tg.rasH2 mice resulted in no drug-related tumors.

Oral administration of diroximel fumarate (0, 0, 15, 50, or 150 mg/kg/day) to male and female rats resulted in an increase in tumors (Leydig cell adenomas of the testes) in males at the highest dose tested. At the higher dose (50 mg/kg/day) not associated with drug-related tumors, plasma exposures for MMF and HES (the major circulating drug-related compound in humans) were similar to (MMF) and less than (HES) those in humans at the recommended human dose (RHD) of 924 mg/day.

Mutagenesis

Diroximel fumarate was negative in the in vitro bacterial reverse mutation and in vivo rat micronucleus and comet assays. Diroximel fumarate was clastogenic (in the absence and presence of metabolic activation) in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes.

Impairment of Fertility

No adverse effects on fertility were observed following oral administration of diroximel fumarate to male rats (0, 40, 120, or 400 mg/kg/day) prior to and during mating with untreated females and, in a separate study, to female rats (0, 40, 120, or 450 mg/kg/day) prior to and during mating with untreated males and continuing to Gestation Day (GD) 7. At the highest doses tested, plasma exposures (AUC) for MMF were approximately 7-9 times that in humans at the RHD. Plasma levels of HES were not quantitated.

Kidney toxicity, including tubular changes (degeneration, necrosis, regeneration, hypertrophy) and/or interstitial fibrosis, were observed following oral administration of diroximel fumarate in rats and monkeys. In the chronic toxicology study in rats (0, 50, 100, or 300 mg/kg/day), adverse renal findings occurred at all doses tested. Plasma exposures (AUC) at the low dose (50 mg/kg/day) were similar to (MMF) or less than (HES) those in humans at the RHD. In the chronic toxicology study in monkeys (0, 15, 50, or 150 mg/kg/day), adverse renal findings occurred at all but the lowest dose tested (15 mg/kg/day), which was associated with plasma MMF and HES exposures (AUC) less than those in humans at the RHD.

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 Clinical Pharmacology (12.3)].

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). The starting dose for dimethyl fumarate was 120 mg twice or three times a day for the first 7 days, followed by an increase to 240 mg twice or three times a day. Both studies included patients who had experienced at least 1 relapse over the year preceding the trial or had a brain Magnetic Resonance Imaging (MRI) scan demonstrating at least one gadolinium-enhancing (Gd+) lesion within 6 weeks of randomization. The Expanded Disability Status Scale (EDSS) was also assessed and patients could have scores ranging from 0 to 5. Neurological evaluations were performed at baseline, every 3 months, and at the time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2 in a subset of patients (44% in Study 1 and 48% in Study 2).

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. The percentages of patients who completed 96 weeks on study drug per treatment group were 69% for patients assigned to dimethyl fumarate 240 mg twice a day, 69% for patients assigned to dimethyl fumarate 240 mg three times a day, and 65% for patients assigned to placebo groups.

Dimethyl fumarate had 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 results for this study (240 mg twice a day vs. placebo) are shown in Table 2 and Figure 1.

Table 2. Clinical and MRI Results of Study 1:

Figure 1. Time to 12-Week Confirmed Progression of Disability (Study 1):

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. The percentages of patients who completed 96 weeks on study drug per treatment group were 70% for patients assigned to dimethyl fumarate 240 mg twice a day, 72% for patients assigned to dimethyl fumarate 240 mg three times a day, and 64% for patients assigned to placebo groups.

Dimethyl fumarate had a statistically significant effect on the relapse and MRI endpoints described above. There was no statistically significant effect on disability progression. The dimethyl fumarate 240 mg three times daily dose resulted in no additional benefit over the dimethyl fumarate 240 mg twice daily dose. The results for this study (240 mg twice a day vs. placebo) are shown in Table 3.

Table 3. Clinical and MRI Results of Study 2: