As in other forms of PAH, connective tissue disease associated PAH (CTD-PAH), results in a progressive increase in pulmonary vascular resistance, which ultimately leads to right heart ventricular failure and death. CTD-PAH represents approximately 30% of the overall PAH population1,2.

CTD-PAH is a late and often fatal manifestation of many types of autoimmune diseases. The primary CTDs underlying CTD-PAH include scleroderma, lupus, and mixed connective tissue diseases; 10-15% of patients with scleroderma or lupus erythematosus have CTD-PAH3,4,5. 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%, while idiopathic PAH (I-PAH) patients have a five-year survival rate of approximately 68%8. As a result, CTD-PAH patients represent a subset of the PAH population with a significant unmet medical need.

Reata has received orphan drug designation for bardoxolone for the treatment of PAH by the FDA. In October 2016, Reata began enrolling patients in the Phase 3 CATALYST trial in CTD-PAH.

Click here for our recent highlights and key upcoming milestones.


In comparison to patients with I-PAH, patients with CTD-PAH have a higher occurrence of small vessel fibrosis and greater incidence of pulmonary veno-obstructive diseases9. A recently published meta-analysis of the response of CTD-PAH patients to vasodilator therapy in 11 registrational trials comprised of more than 2,700 PAH patients demonstrated that CTD-PAH patients respond less well than I-PAH patients to approved vasodilator therapies in both clinical worsening and improvements in six-minute-walk distance (6MWD) from baseline, with response in CTD-PAH patients (9.6 meters) approximately one-third of the response in I-PAH patients (30 meters)10.

The meta-analysis also demonstrated that I-PAH patients were more hemodynamically impaired than CTD-PAH patients, which likely explains why vasodilator therapy is more effective in I-PAH patients11.

Mechanism of Action

Bardoxolone methyl directly targets the bioenergetic and inflammatory components of PAH. PAH patients experience mitochondrial dysfunction, increased activation of NF-κB and related inflammatory pathways involved in reactive oxygen species (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 respiration12. Evidence potentially supporting the mitochondrial effects of the Nrf2 activators has been observed both pre-clinically and in clinical settings13,14. 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 PAH patients, due to its effects on energy production and cellular respiration, as have been characterized in preclinical studies with bardoxolone methyl and other Nrf2 activators15,16.
  • Potential effects beyond functional improvements: Bardoxolone methyl has potential anti-inflammatory, anti-proliferative, and anti-fibrotic effects and targets multiple cell types relevant to PAH, including endothelial cells, smooth muscle cells, and macrophages16-19. 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 outcomes16.
  • 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 PAH patients20. This lack of effects 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

    Results to date from the Phase 2 LARIAT trial have supported further development of bardoxolone methyl in CTD-PAH patients. Initial data from LARIAT were presented at the 2015 CHEST meeting. An important finding at the time was that bardoxolone methyl provided the greatest improvement in 6MWD to CTD-PAH patients. After this finding, we enrolled another cohort of only CTD-PAH patients and released data available on all CTD-PAH patients in LARIAT, at the time, in October 2016. In a subgroup analysis of this data, CATALYST-eligible patients treated with bardoxolone methyl (n = 14) showed a significant improvement in time-averaged 6MWD changes vs. placebo patients (n = 5). The placebo-corrected improvement in 6MWD for bardoxolone methyl-treated patients was 40.3 meters (p = 0.009).

    In October 2016, Reata began enrolling patients in the CATALYST trial. 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. 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 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 a total of approximately 200 patients. In 2015, the FDA granted our request for orphan drug designation for the treatment of PAH.

    Click here for our recent highlights and key upcoming milestones.


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