SESSION TITLE: Late Breaking Abstracts
SESSION TYPE: Late Breaking Abstract Slide
PRESENTED ON: Tuesday, October 27, 2015 at 08:45 AM - 10:00 AM
PURPOSE: Bardoxolone methyl (BARD), an Nrf2 activator and NF-κB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. To determine if BARD could complement approved therapies in PAH patients, we designed a phase 2, dose-ranging, randomized, placebo-controlled, double-blind trial (LARIAT) to assess exercise capacity and safety in patients taking stable PAH background therapy. This analysis reports initial safety and efficacy data in the ongoing study.
METHODS: WHO Group 1 PAH patients (n = 24) were randomized in cohorts of 8 patients in a 1:3 ratio to receive once-daily placebo or BARD at doses of 2.5, 5, or 10 mg for 16 weeks. Each cohort completed week 4 assessments before the next dosing cohort opened. Patients were WHO functional class II or III and using stable doses of at least one approved PAH therapy; those with BNP > 200 pg/mL or eGFR < 45 mL/min/1.73 m2 were excluded. The primary efficacy variable, 6MWD, was collected at baseline and every 4 weeks post-randomization. A Safety Review Committee monitored the study, and we offered all eligible participants open-label extension therapy after the initial 16 weeks.
RESULTS: All patients were taking at least one oral PAH therapy (an endothelin receptor antagonist or a PDE-5 inhibitor) and 63% were on two therapies. Average age was 56 years, 75% were female, and 54% and 33% had idiopathic or connective tissue disease-associated PAH, respectively. Final data will be presented, but analysis thus far supports the following statements. Using a mixed-model repeated measures analysis, the 6MWD for patients receiving BARD across all doses (placebo n=6; BARD n=18) was significantly greater than placebo (p<0.05). Each dose showed an increase relative to placebo. As evidence of its metabolic effects, BARD significantly reduced weight. BNP levels were unchanged. Two patients discontinued study drug prematurely due to an adverse event (AE) (1/6 placebo and 1/18 BARD). No clinically meaningful differences were noted in safety variables including vital signs and laboratory data. No drug-related serious AEs were reported. The most frequent AEs reported were headache, back pain, upper respiratory infection, decreased appetite, dyspnea, and diarrhea.
CONCLUSIONS: BARD significantly increased placebo-corrected 6MWD in PAH patients on background oral PAH therapies and was well-tolerated at doses up to 10 mg. Further clinical development of BARD in PAH is warranted.
CLINICAL IMPLICATIONS: BARD is a promising, new experimental treatment for PAH.
DISCLOSURE: Ronald Oudiz: Other: Study Investigator, Consultant fee, speaker bureau, advisory committee, etc.: PI of exercise sub-study Colin Meyer: Employee: Employee of Reata Pharmaceuticals, Shareholder: Shareholder of Reata Pharmaceuticals Melanie Chin: Employee: Employee of Reata Pharmaceuticals, Shareholder: Shareholder of Reata Pharmaceuticals Jeremy Feldman: Other: Study Investigator Angie Goldsberry: Employee: Employee of Reata Pharmaceuticals, Shareholder: Shareholder of Reata Pharmaceuticals John Mc Connell: Other: Study Investigator Peter McCullough: Consultant fee, speaker bureau, advisory committee, etc.: Safety committee member for Reata-sponsored LARIAT study Megan O'Grady: Employee: Employee of Reata Pharmaceuticals, Shareholder: Shareholder of Reata Pharmaceuticals Fernando Torres: Other: Study Investigator Aaron Waxman: Other: Study Investigator R White: Other: Study Investigator The following authors have nothing to disclose: Victor Tapson
The abstract reports initial results from a phase 2 clinical study of a new drug being developed by Reata Pharmaceuticals that is not yet approved.