Tecfidera (Dimethyl Fumarate - BG12)

Official Gazette number 94 of April 23, 2014 approved the new oral treatment Tecfidera (dimethyl fumarate) after approval by the European Medicines Agency and the Technical and Scientific Commission of AIFA based on data quality, safety and efficacy presented first issued a positive opinion the risk benefit ratio in multiple sclerosis.
From the exit of the news, have come several reports of concern. Trying the DMF (dimethyl fumarate) on the internet, one of the first sources emerges is Wikipedia where there is a reference to the toxicity of the product and the fact that its use is banned in the European Union.

Why not? Safety of DMF

Fumaric acid has been used for the management of Psoriasis for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS (multiple sclerosis). Its toxicity is dependent on dose and mode of administration. Randomized double-blind trials with placebo-controlled period of 2years [Study 1 (DEFINE) with 1,234 subjects and Study 2 (CONFIRM) with 1,417 subjects] in subjects with relapsing-remitting MS (RR-MS) show positive significant results. Compared with placebo-treated subjects Tecfidera had a clinically and statistically significant on:

• the proportion of subjects with a relapse at 2 years, primary endpoint of Study 1.
• the annualized relapse rate at 2 years, primary endpoint of Study 2.

Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.

Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. April 2015.

Side effects

The most common adverse reactions (incidence ≥10%) for patients treated with Tecfidera were the
redness(flushing) and gastrointestinal events(diarrhea, nausea, abdominal pain, pain
upper abdominal). Flushing and gastrointestinal events tend to occur at the beginning of therapy (especially during the first month) and in patients prone to redness and gastrointestinal events, these events may continue to occur intermittently during the entire treatment with
Tecfidera. The most commonly reported adverse reactions that lead to discontinuation of
therapy (incidence> 1%) in patients treated with Tecfidera were redness (3%) and events
Gastrointestinal (4%).

Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. April 2015.

Mechanisms of action of DMF

The mechanism of action of DMF in multiple sclerosis is probably triple and depends on its ability to regulate the activity of the immune system (immunomodulatory effects) and to counter the inflammation (anti-inflammatory) as well as by the protective on nerve cells (neuroprotective antioxidant).

Research in the experimental autoimmune encephalomyelitis model of MS showed:

• A reduced expression of mitogen stress activated kinase 1 under DMF therapy, as well as a diminished phosphorylation of p65. Consequently, expression of IL-6 and IL-12 was also reduced. DMF has also been shown to inhibit the activation of NF-kB by antigen-presenting cells, reducing peripheral activation of the adaptive immune system. FIGURE1.

• In addition, DMF reduce peripheral proinflammatory differentiation of CD4+ T cells by shifting the cytokine profile from Th1 toward a Th2 profil. FIGURE1.

• A potential neuroprotective role of DMF has been postulated and is currently thought to be mediated by its action on nuclear factor (Nrf-2) in astrocytes, oligodendrocytes and neurons. The antioxidant response seems to be induced by initial oxidative stress leads to transcription of ROS-protective genes. FIGURE 2.
  
  

Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. April 2015

Pharmacokinetics of DMF

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused prolonged QT interval prolongation of clinical significance.
After oral administration of Tecfidera, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. Therefore all pharmacokinetic analyses related to Tecfidera were performed with plasma MMF concentrations. Time to peak concentration of MMF after DMF administration is 2–2.5 h and its half-life is approximately 1h. Administration with food was found to reduce the maximum serum concentration after drug administration (Cmax) by 40% and delayed the time to reach maximum drug concentration (Tmax) by 2.5 h. The majority of ingested DMF (~60%) is excreted via exhalation, and smaller amounts via the renal system (~16%) and feces (~1%).

Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers. October 2013.

Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. April 2015.

Conclusions

The recent introduction on the market of this new drug has provided additional opportunity therapeutic practice for the patient because oral administration and less liver damage compared with other available treatments. The combined anti-inflammatory and antioxidant protection for the nerve tissue provides a twofold benefit opposing the progress of the disease and stimulating the nervous tropism. Multiple sclerosis is an inflammatory disorder that affects approximately 440,000 physician-diagnosed individuals in the USA and 1.5 million individuals worldwide.