Until 18th October, bardoxolone methyl (Abbott/Reata) and BG-12 (Biogen) had two things in common: the nrf2 transcription factor complex as their molecular target; and their candidacy for blockbuster status.
Then Reata halted clinical development of bardoxolone, following an excess of unspecified serious adverse events and mortality among the treated patients in the Phase 3 BEACON trial in chronic kidney disease.
Almost simultaneously, the FDA paused for breath in their assessment of BG-12, delaying a decision on approval – although Biogen argue that the delay is unrelated to the sudden collapse of the bardoxolone programme.
Should Biogen shareholders be concerned? Is this the end of the road for nrf2 activators?
Ironically, the presumed similarity of mechanism is also less certain than has often been assumed. Both compounds can react covalent with nrf2 and modulate its activity, but the extent to which nrf2 is central to the beneficial effects or the adverse events seen with bardoxolone is an open question.
If the data with BG-12 supported approval before the Reata announcement then nothing should change. And nrf2 remains an attractive target for non-covalent modulators – both bardoxolone and BG-12 suggest, but don’t yet prove, that this pathway is an important one in a range of disease processes.
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