Several factors are involved in the pathogenesis and progression of CTD-PAH. Chronic activation of the transcription factor NF-κB, which controls several genes involved in immune response inflammation results in a perpetual state of mitochondrial dysfunction and inflammation.4 This promotes vascular proliferation, and ultimately, the chronic cardiac remodeling in CTD-PAH.5
Bardoxolone Methyl Mechanism of Action
Bardoxolone methyl targets several factors involved in CTD-PAH by activating Nrf2, a key regulator of cellular responses to oxidative damage due to inflammation and injury. Bardoxolone methyl acts by releasing Nrf2 from Keap1, allowing it to suppress NF-κB and activate transcription of many anti-inflammatory and antioxidant genes. Evidence potentially supporting the mitochondrial effects of the Nrf2 activators has been observed both preclinically and in clinical settings.
CATALYST is an international, randomized, double-blind, placebo-controlled trial examining the safety, tolerability, and efficacy of bardoxolone methyl in patients with WHO Group 1 CTD-PAH.
- Change from baseline in 6MWD relative to placebo at week 24
- Time to first clinical improvement, as measured by:
- Improvement in WHO functional class
- ≥10% increase from baseline in 6MWD or
- ≥10% decrease from baseline in creatinine kinase (as a surrogate biomarker for muscle injury and inflammation)
By addressing a novel pathway in PAH, bardoxolone methyl may provide additional benefits beyond current PAH therapies.
LARIAT was a phase 2 trial to assess the safety and efﬁcacy of bardoxolone methyl. Specifically, LARIAT was designed to determine the recommended dose range, the change from baseline in 6MWD, and the effect of bardoxolone methyl on pulmonary hypertension in patients with conditions including CTD, interstitial lung disease, and unknown causes.