BG-12
Other names	Tecfidera, dimethyl fumarate
What is it for?	Relapsing remitting multiple sclerosis (MS)

• BG-12 is an experimental drug treatment for relapsing remitting multiple sclerosis. It is given as a tablet, two or three times daily.


• BG-12 may reduce the activity and impact of inflammatory cells in the central nervous system and have neuroprotective effects.


• In phase III studies, BG-12 reduced annual relapse rates by about 50% compared to placebo.


• Few serious side effects have occurred in clinical trials. The most common side effects have been:
  
  
  • flushing and feeling hot
  
  
  • gastrointestinal upset - diarrhoea, nausea, abdominal pain
  
  
  • headache
  
  
  
  


• On 21 March 2013, CHMP (Committee for Medicinal Products for Human Use), part of the European Medicines Agency,recommended that BG-12 should be granted a license for treatment of adults with relapsing remitting multiple sclerosis. NICE has begun preliminary work on the appraisal with a decision expected in January 2014.

How does it work?

The mechanism of action is not fully understood, but preclinical studies have suggested that BG-12 may have complex neuroprotective and anti-inflammatory effects, acting via the Nrf-2 pathway. Activation of the Nrf-2 pathway defends against oxidative-stress induced neuronal death, protects the blood-brain barrier and supports maintenance of myelin integrity in the central nervous system.

How is it taken?

BG-12 is taken orally as tablets, two or three times per day.

What are the results so far?

In a phase II study, different doses of BG-12 were compared to placebo in people with relapsing remitting MS over 24 weeks of treatment. BG-12 significantly reduced MRI-detectable brain lesion activity. A 32% reduction in relapse rate was also observed but could not be considered significant since this measure was not included in the study design.

Two phase III trials found BG-12 effective at reducing the number of relapses to approximately half of that seen inthose taking placebo. In one study (DEFINE) the progression of disability was reduced for people taking BG-12; this effect was not seen in the second study (CONFIRM).

This 2 year study compared BG-12 taken either two or three times daily and placebo in more than 1200 participants with relapsing remitting MS. Compared to placebo, the drug reduced the annual relapse rate by 53% for the twice daily dosing and 48% for the three times a day dosing.

BG-12 twice daily reduced the risk of disability progression by 38% while BG-12 three times per day reduced this risk by 34%.

MRI scans showed that, after two years, people receiving BG-12 had significantly fewer brain lesions compared to placebo.

This two year study with 1232 participants was similar to DEFINE, but with an additional group who took glatiramer acetate (Copaxone) for comparison.

BG-12 reduced annual relapse rate by 44% for the twice-daily dose and by 51% for the three times daily dose, compared to placebo. In contrast, glatiramer acetate reduced relapse rate by 29%.

BG-12 twice daily reduced the risk of disease progression by 21% and for three times daily by 24%. These results were not statistically significant.

Side effects

The most common side effects were:

• flushing and feeling hot


• gastrointestinal upset - diarrhoea, nausea, abdominal pain


• headache

What further studies are planned?

No further clinical trials are currently underway.

References

Fox RJ, et al.
Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis
New England Journal of Medicine 2012 367:1087-1097
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Gold R, et al.
Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
New England Journal of Medicine 2012 367:1098-1107
Read abstract

Kappos L, et al.
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Lancet 2008;372:1463-1472.
Read abstract

Kappos L, et al.
Effect of BG-12 on contrast-enhancing lesions in patients with relapsing-remitting multiple sclerosis: subgroup analyses from the phase 2b study.
Multiple Sclerosis 2011 Aug 30. [Epub ahead of print]
Read abstract

MacManus DG, et al.
BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis.
J Neurol. 2011 Mar;258(3):449-56.
Read abstract