CTD-PAH results in a progressive increase in pulmonary vascular resistance, which ultimately leads to right heart ventricular failure and death. CTD-PAH patients make up approximately 30% of the overall PAH population, or approximately 12,000 individuals worldwide1,2.

In comparison to patients with idiopathic PAH, or I-PAH, patients with CTD-PAH have a higher occurrence of small vessel fibrosis and greater incidence of pulmonary veno-obstructive diseases3. CTD-PAH patients treated with vasodilator therapies show 6MWD improvements only one-third as great as the improvements seen in I-PAH patients4. As a result, CTD-PAH patients represent a subset of the PAH population with a significant unmet medical need.


The primary CTDs underlying CTD-PAH include scleroderma, lupus, and mixed connective tissue diseases5. Patients with CTD-PAH are generally less responsive to existing therapies and have a worse prognosis than patients with other forms of PAH6,7. In the United States, the five-year survival rate for CTD-PAH patients is approximately 44%, with a median survival rate of approximately four years, whereas I-PAH patients have a median survival rate of approximately seven years8. As described in a recent large meta-analysis, pulmonary vascular resistance, mean pulmonary arterial pressure, and right atrial pressure are lower in CTD-PAH patients as compared to I-PAH patients9. This may explain why CTD-PAH patients treated with vasodilator therapies show 6MWD improvements only one third as great as the improvements seen in I-PAH patients4.

Mechanism of Action

Bardoxolone methyl directly targets the bioenergetic and inflammatory components of PH. PH patients experience mitochondrial dysfunction, increased activation of NF-κB and related inflammatory pathways involved in ROS signaling, cellular proliferation, and fibrosis. Bardoxolone methyl, through the combined effect of Nrf2 activation and NF-κB suppression, has the potential to inhibit inflammatory and proliferative signaling, suppress ROS production and signaling, reduce the production of enzymes related with fibrosis and tissue remodeling, and increase ATP production and cellular respiration10. Evidence potentially supporting the mitochondrial effects of the AIMS has been observed both pre-clinically and in clinical settings11,12. By addressing a novel pathway in PH, we believe that bardoxolone methyl may provide additional benefits beyond current PAH therapies, including:

  • Increased functional capacity: We believe the bioenergetic effects of bardoxolone methyl may result in increased functional capacity, the ability to perform everyday functions, for PH patients, due to its effects on energy production and cellular respiration, as have been characterized in preclinical studies with bardoxolone methyl and other AIMs13,14.
  • Potential effects beyond functional improvements: Bardoxolone methyl has potential anti-inflammatory, anti-proliferative, and anti-fibrotic effects and targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages14-17. We believe that bardoxolone methyl may, over an extended period of time, affect the synergistic effects of vasoconstriction, thrombosis, fibrosis, and vascular remodeling within the pulmonary arterial system, potentially improving patient outcomes14.
  • Potential as a combination therapy: To date, it has been observed that bardoxolone methyl does not induce systemic hemodynamic effects or drug-to-drug interactions in PH patients18. This may provide clinicians with greater flexibility in dosing, ultimately result in a more favorable safety profile, and allow for use in combination with other therapies with a greater incremental effect than an additional vasodilator.

Development Program

Reata has initiated the Phase 3 CATALYST study. CATALYST is an international, randomized, double-blind, placebo-controlled trial examining the safety, tolerability, and efficacy of bardoxolone methyl in patients with WHO Group I CTD-PAH when added to standard-of-care vasodilator therapy. Patients will be on up to two background therapies and will be randomized one-to-one to bardoxolone methyl or placebo. Patients will be enrolled at 100 sites in the US, Canada, Australia, Japan, Mexico, Europe, Israel, and South America. Study drug will be administered once daily for 24 weeks. Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. The primary endpoint is the change from baseline in six-minute-walk distance (6MWD) relative to placebo at Week 24. The secondary endpoint is time to first clinical improvement as measured by improvement in WHO functional class, increase from baseline in 6MWD by at least 10%, or decrease from baseline in creatinine kinase (as a surrogate biomarker for muscle injury and inflammation) by at least 10%. The trial will enroll between 130 and 200 patients. Data from CATALYST are expected to be available during the first half of 2018.


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