BG12, or dimethyl fumarate is a small molecule currently approved for use in plaque psoriasis in Germany that is undergoing studies for use in relapsing remitting MS. Biogen-Idec (BIIB) initially licensed the worldwide rights for BG-12 (ex Germany) from Fumapharm and then purchased Fumapharm in 2006. Fumaderm was approved for use in moderate to severe psoriasis in Germany in 1994 and became the leading oral agent for that indication in Germany. BG-12 is an enteric coated medication that was derived from Fumaderm (mixed fumarate acid esters) and is felt to have better gastrointestinal side effect profile. BG-12 has two putative mechanisms of action that can lead to downregulation of inflammation and possibly neuroprotection. It has been shown to inhibit Nf-kB activation that plays an important role in the upregulation of the immune response. Additionally, it activates the Nrf1 transcription pathway that has been shown to defend against oxidative stress induced neuronal death. Data to be presented at he AAN implies a suppressive action on macrophage function.
Results from a Phase II study for 24 weeks that was extended to 48 weeks were reported in October, 2008. 247 patients were randomized to receive 120 mg BG-12 daily, 120 mg three times daily or 240 mg 3 times daily and compared to a placebo group. At 24 weeks, placebo patients were placed on 240 mg three times a day. Primary endpoints were MRI based on new lesions on MRI at weeks 12, 16, 20 and 24. Annualized relapses were calculated from 24 and 48 week data. The higher dose reduced Gadolinium enhanced lesions by 69% between weeks 12 and 24, compared to placebo and performed well on other MRI criteria. Further study showed a possible neuroprotective effect with fewer gadolinium positive lesions evolving into new T1 hypointense lesions. The annualized relapse rate was reduced 32% during the first 24 weeks and reportedly decreased further during the second 24 weeks (not placebo controlled). Side effects included abdominal pain, flushing and hot flash sensation. There were no serious adverse effects. Two large Phase III studies are underway. DEFINE will compare 240 mg BG-12 twice a day or three times a day to placebo with the primary endpoint being proportion of patients relapsing over two years. CONFIRM will compare these two doses of BG-12 to Copaxone with the primary endpoint being annualized relapse rate at two years.
Analysis of Efficacy
BG-12 met its primary MRI endpoints and showed a 32% reduction in relapse rate in a study with 4 cohorts not powered to prove clinically efficacy. Though numbers were not presented, further reduction in relapse rate was noted between weeks 24 and 48, implying a possible lag in efficacy. Efficacy is likely similar to the interferons, though unlikely to be as strong as cladribine or FTY-720. Compared to Laquinimod, the relapse rate reduction was similar and the MRI data was mildly more robust. Only the higher dose significant MRI efficacy, while lower doses of BG-12 were less effective. As with Laquinimod, it is uncertain whether there could be higher efficacy on higher doses. The finding that relapse rate reduction improved further during the second 24 week period predicts that the Phase III studies might show an even more robust clinical response. The Phase I study was not powered or long enough for disability measures to be measured. These will be determined in the Phase III studies.
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