Reata Pharmaceuticals announced the enrollment of the first patient in its Phase 3 CATALYST study (NCT02657356) that will evaluate the effectiveness and safety of bardoxolone methyl in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH).
The study’s design will benefit from preliminary findings from the Phase 2 LARIAT trial (NCT02036970) currently ongoing in a group of CTD-PAH patients.
“With the initiation of CATALYST, we have brought bardoxolone methyl one step closer to CTD-PAH patients who respond poorly to currently available therapies, have a high mortality rate, and are in need of new therapeutic options,” Reata CEO Warren Huff said in a news release.
“Bardoxolone methyl has a novel mechanism of action that has the potential to complement current vasodilator therapy by addressing the bioenergetic impairment and chronic inflammation that are key features of CTD-PAH,” Huff said.
The CATALYST study is expected to initially enroll from 130 to 200 patients at 100 sites, including in the U.S. Patients will be randomly assigned to the bardoxolone methyl or placebo groups. Participants randomized to bardoxolone methyl will receive a once-daily dose over 24 weeks, starting at 5 mg and increasing to 10 mg at week 4, unless clinically contraindicated.
The treatment’s outcome will be measured by changes in the six-minute-walk distance (6MWD; a test assessing exercise capacity) compared to a placebo at week 24, improvement in functional class, increase from baseline in 6MWD by at least 10 percent, or decrease from baseline in creatine kinase (a biomarker for muscle injury and inflammation) by at least 10 percent. Data from the CATALYST study is expected to be available in the first half of 2018.
In preparation for the start of the CATALYST study, Reata analyzed the preliminary results of the Phase 2 LARIAT trial in which 22 CTD-PAH patients were treated with up to 10 mg of bardoxolone methyl or a placebo, having completed the 16-week treatment period (or terminated early). The results indicated that patients treated with bardoxolone methyl showed a statistically significant improvement in the 6MWD mean time-averaged compared to baseline, whereas patients on the placebo did not.
In the LARIAT trial, treatment with bardoxolone methyl was combined with approved vasodilator therapies without increasing the risk of hypotensive events or exacerbating their adverse event profile, demonstrating the therapy is safe and well-tolerated.
The trial also showed that anemic patients randomized to the placebo group and ongoing anemia treatment presented improvements in the 6MWD. This showed that treatment with iron supplements or erythropoietin can affect 6MWD values independently of bardoxolone methyl. For this reason, the CATALYST trial will not include patients with moderate to severe anemia, which represents a small percentage of the patient population.
“The additional LARIAT data have given us increased resolution on the treatment effect and safety profile of bardoxolone methyl in CTD-PAH patients. The initial LARIAT results in CTD-PAH patients have been replicated over a larger number of patients, and the drug has continued to be well-tolerated,” said Dr. Colin Meyer, MD, Reata’s chief medical officer.
“The additional Phase 2 experience allowed us to identify baseline anemia as a key factor that can influence placebo variability, and we have amended the CATALYST protocol to exclude patients with moderate to severe anemia,” he said. “With this change and the available efficacy data, we believe that the design, size, and statistical power of CATALYST are adequate to detect the treatment effect observed in our Phase 2 LARIAT trial.”
Both the CATALYST and LARIAT studies are recruiting participants.