Multiple Sclerosis (MS)


Bafiertam (monomethyl fumarate) is an oral medication for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary progressive muscular sclerosis (SPMS).1

The treatment was approved by the US Food and Drug Administration (FDA) in April 2020 after showing bioequivalence to Tecfidera® (dimethyl fumarate, or DMF).2

Treatment is initiated in patients with a starting dose of 1 95 mg tablet taken twice a day for 7 days. After 7 days, the dose is doubled to 2 95 mg tablets (190 mg total) taken twice a day during the maintenance period.1

Bafiertam was developed and is distributed by Banner Life Sciences.

Mechanism of Action

MS is a chronic inflammatory disease affecting the central nervous system (CNS). The overactivity of T- and B-lymphocytes targets the myelin sheath surrounding axons, leading to demyelination and eventual neurodegeneration.

Bafiertam is composed of monomethyl fumarate (MMF), the active metabolite derived from the breakdown of both DMF and Vumerity® (diroximel fumarate, or DRF) inside the body. The exact mechanism of how MMF works in MS patients is not fully understood but it has been shown to have immunomodulatory and neuroprotective effects.3 Research into the effects of DMF has shown that it is rapidly metabolized into MMF and then works through the mediation of the nuclear factor erythroid-derived 2-related factor (Nrf-2) pathway as well as other pathways.3

MMF has been shown to affect the composition and phenotypes of immune cells present through a shift to an anti-inflammatory state.3 The shift also inhibits the ability of immune cells to infiltrate the CNS. Inside the CNS, MMF modulates the Nrf-2 pathway to increase the survival of oligodendrocytes, increase the amount of anti-inflammatory M2 microglia, reduce levels of activated astrocytes, and increase antioxidant activities for a neuroprotective effect.3

Independent of the Nrf-2 pathway, MMF can also inhibit the infiltration of neutrophils into the CNS and activation of microglia through hydroxycarboxylic acid receptor-2 (HCAR-2) pathways as well as suppress nitrous oxide (NO) production and astrocyte activation through the nuclear factor kappa B (NF-κB) pathway.3

Analysis of the pharmacokinetics and bioavailability of Bafiertam compared to DMF found that 2 95 mg capsules of Bafiertam are equivalent to 1 240 mg capsule of DMF.4

Warnings, Precautions, and Adverse Reactions

Warning and safety information for Bafiertam comes from the results of DMF clinical trials. DMF, and therefore Bafiertam, may cause serious adverse events such as anaphylaxis, angioedema, progressive multifocal leukoencephalopathy, lymphopenia, serious opportunistic infections such as herpes zoster, and liver damage.1 

There is insufficient data to support the use of Bafiertam in special populations including pediatric, geriatric, pregnant, and breastfeeding patients. Preclinical studies in animals indicated that Bafiertam may cause embryofetal and maternal toxicity.1

The most common adverse reactions observed at a 2% or higher incidence compared to placebo in studies of DMF include flushing, abdominal pain, diarrhea, nausea, vomiting, pruritus, rash, albumin present in the urine, erythema, dyspepsia, increased aspartate aminotransferase, and lymphopenia.1

Get detailed prescribing information on the Bafiertam monograph page at Rare Disease Advisor.

Efficacy in Trials and Trial Results

The approval of Bafiertam was based on its similarity to the already-approved prodrug, DMF, which had already been through extensive clinical testing in the DEFINE (NCT00420212) and CONFIRM (NCT00451451) trials to show its safety and efficacy in relapsing forms of MS.5,6

Bafiertam was tested in 2 clinical trials to prove its bioequivalence to DMF in healthy participants.

The first phase 1 trial (NCT04570670) recruited 50 healthy participants to receive a single dose of 190 mg of Bafiertam (taken as 2 95 mg capsules) or 240 mg of DMF.2 The trial was open-label and compared the bioequivalence of the 2 drugs through analysis of the area under the curve (AUC) for plasma concentrations and maximum observed concentrations (Cmax) of each. Results of the study showed that the AUC and Cmax between the 2 treatments were comparable.2 Both drugs also had similar safety profiles with mild flushing being the most common treatment-emergent adverse event (TEAE).2

Bafiertam was also studied in another phase 1 trial (NCT04022473) in healthy individuals to assess differences in gastrointestinal tolerability of the 2 treatments.7 In this study, healthy patients were randomized 1:1 to receive either 95 mg of Bafiertam or 120 mg of DMF twice a day for a week. Afterward, they would receive 190 mg of Bafiertam and 240 mg of DMF twice a day for another 4 weeks. Participants were also 3:1 female to male to account for MS being more prevalent in females. Drug capsules were over-encapsulated to double blind the study.

AUC values derived for the individual symptom scores on the Modified Overall Gastrointestinal Symptom Scale (MOGISS) were compared between the Bafiertam and DMF study groups. Results showed that the least squares mean AUC for each symptom favored Bafiertam but the differences were not significant.7 Adverse event and safety profiles were similar to those already reported for DMF.

References

1. Bafiertam. Package insert. Banner Life Sciences LLC; 2021. Accessed May 3, 2021.

2. UPDATE: FDA-approved oral BafiertamTM (monomethyl fumarate) now available for prescription. National Multiple Sclerosis Society. September 1, 2020. Accessed May 3, 2021.

3. Yadav SK, Soin D, Ito K, Dhib-Jalbut S. Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis. J Mol Med. 2019;97(4):463-472. doi:10.1007/s00109-019-01761-5

4. Lategan TW, Wang L, Sprague TN, Rousseau FS. Pharmacokinetics and bioavailability of monomethyl fumarate following a single oral dose of BafiertamTM (monomethyl fumarate) or Tecfidera® (dimethyl fumarate). CNS Drugs. 2021;35:567-574. doi:10.1007/s40263-021-00799-9 

5. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-1107. doi:10.1056/NEJMoa1114287

6. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-1097. doi:10.1056/NEJMoa1206328 7. Wynn D, Lategan TW, Sprague TN, Rousseau FS, Fox EJ. Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate. Mult Scler Relat Disord. 2020;45:102335. doi:10.1016/j.msard.2020.102335

Reviewed by Kyle Habet, MD, on 7/1/2021.

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