Comparative pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of Bafiertam® (monomethyl fumarate) versus Vumerity® (diroximel fumarate).

BACKGROUND: Bafiertam® (monomethyl fumarate [MMF]) and Vumerity® (diroximel fumarate [DRF]) are two FDA approved drug products for the treatment of relapsing forms of multiple sclerosis (MS) to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Vumerity® is a prodrug of MMF which requires enzymatic conversion of DRF to the active drug MMF, the moiety responsible for the therapeutic efficacy; whereas Bafiertam® contains MMF, providing the active drug directly without any need for enzymatic conversion. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and relative bioavailability of MMF from oral administration of two Bafiertam® capsules each containing 95 mg of MMF in comparison to two Vumerity® capsules each containing 231 mg of DRF, the therapeutic doses of each product. METHODS: This was a single-dose, open-label, randomized, 2-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Forty-four healthy male or female subjects were planned to receive each of the two treatments to assure 40 completed dosing: a single dose of 2  ×  95 mg Bafiertam® capsules and a single dose of 2  ×  231 mg Vumerity® capsules under fasting conditions in a randomized crossover fashion. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. MMF pharmacokinetic [PK] parameters were calculated and included maximum observed concentration (Cmax), time to reach Cmax (tmax), apparent half-life of MMF in plasma (t1/2), AUC0-t which is the area under the plasma concentration vs. time curve (AUC) from time zero (dosing time) to the last time point, t, with quantifiable MMF concentration, and AUC0-inf which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: Forty-one subjects completed the study as planned. MMF in Bafiertam® capsules was well and readily absorbed with a median tmax occurring at 4 h post dose, approximately 1 h later than that of Vumerity® capsules. However, the mean MMF Cmax from Bafiertam® (1969 ng/mL) was higher than that from Vumerity® (1121 ng/mL). The mean MMF AUC0-t and AUC0-inf from Bafiertam® (3503 and 3531 h*ng/mL) were also higher than those from Vumerity® (3123 and 3227 h*ng/mL), respectively. The geometric least-squares mean (GLSM) ratios (90% confidence interval), Bafiertam® vs. Vumerity®, for MMF Cmax, AUC0-t and AUC0-inf were 181.8 (158.2 - 208.8)%, 116.8 (107.9-126.5)% and 113.8 (105.3 - 123.0)%, respectively.  Both products were safe and well tolerated, as expected, with flushing being the most common adverse event for both products. CONCLUSIONS: The mean MMF AUC0-t and AUC0-inf were 14-17% higher after administration of Bafiertam® as compared to Vumerity® at their respective therapeutic doses under fasting conditions, however, this difference was not statistically or clinically significant. Although more clinical studies would be needed before making strong recommendations, results of this study may help with selecting appropriate fumarate products, especially when administering the product with food is clinically recommended.

Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate).

BACKGROUND: Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. OBJECTIVE: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera® capsule containing 240 mg of DMF, a prodrug of MMF. METHODS: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC0-inf, which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC0-t, AUC0-inf, and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera®, respectively. CONCLUSIONS: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera® DR 240 mg capsule. CLINICAL TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate.

BACKGROUND: Monomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability. METHODS: This was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability. RESULTS: Inferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted. CONCLUSIONS: Bafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.