Last year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), an oral, reversible covalent inhibitor of the E3 ligase KEAP1, became the first drug approved for Friedrich’s Ataxia. Omaveloxolone was previously highlighted as a Molecule of the Month in July 2023. Now, this 2023 Molecule of the Year nominee reflects a historic milestone for neurological drug discovery. This comprehensive explainer dives into Nrf2 and its history and target rationale, how omaveloxolone works, how the drug was discovered and made its way from an academic cancer drug to approval for Friedreich’s ataxia, whether liver enzyme elevations should be concerning, its synthesis, and why it’s a big deal.