Background/Purpose:   Bardoxolone methyl (BARD), an activator of the transcription factor Nrf2, and inhibitor of NF-kB, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. In an initial analysis of 24 patients enrolled in a Phase 2 study of BARD in WHO Group I pulmonary hypertension (PAH) patients receiving one or more background PAH therapies, a statistically significant 22 m increase in 6-minute walk distance (6MWD) compared to placebo was seen after 16 weeks of treatment¹. A subset of six participants enrolled with connective tissue disease-associated PAH (CTD-PAH) demonstrated numerically larger changes in 6MWD than those with other forms of PAH. The current analysis reports longer-term safety and efficacy data for patients in the initial report through 32 weeks total weeks of treatment (16 weeks of blinded treatment followed by 16 weeks of treatment during the open-label extension) of the ongoing LARIAT study.

Methods:   WHO Group 1 PAH patients (n = 24) were randomized in a 1:3 ratio to receive once-daily placebo or bardoxolone methyl at doses of 2.5, 5, or 10 mg for 16 weeks. Participants who completed the 16-week treatment period were eligible to continue in an open-label extension study and received BARD individually adjusted up to a maximum once-daily dose of 10 mg. The primary efficacy variable, 6MWD, was measured at baseline and at Weeks 4, 8, 12, 16, 20, and 32. Investigators and participants remain blinded to their initial treatment assignment.

Results:   Overall, 18 (75%) subjects (14 bardoxolone methyl, 4 placebo) entered the extension study and completed Week 32 of the study at doses of 2.5 mg (n = 5), 5 mg (n = 5), and 10 mg (n = 4). The previously reported gain in 6MWD was sustained through 32 weeks of extended treatment with BARD. BARD-treated participants with CTD-PAH (n = 6/14) had similar sustained increases in 6MWD through Week 32. Additionally, the metabolic effects at Week 16 observed with BARD (decreased weight and creatine kinase) were sustained through Week 32. Fewer adverse events were reported during the extension study than during the first 16 weeks of treatment. The most frequently reported adverse events that occurred in >10% of patients treated with BARD during the extension study were fatigue, arthralgia, muscle spasms, nausea, and sinus congestion.

Conclusion:   Bardoxolone methyl was well tolerated in patients with PAH and led to sustained improvements in 6MWD for up to 32 weeks without evidence of attenuation. References:

1. Oudiz. Initial Data Report from ‘LARIAT’: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy. Presented at CHEST 2015.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bardoxolone-methyl-produces-durable-benefits-in-participants-with-pulmonary-arterial-hypertension-data-from-an-open-label-extension-study/