Reata Pharmaceuticals has enrolled the first patient in its Phase 3 CATALYST trial (NCT02657356), exploring the potential benefits of bardoxolone methyl in people with pulmonary arterial hypertension (PAH) linked to connective tissue disease. The trial is continuing to recruit participants.
The company also reported that data from the ongoing Phase 2 LARIAT trial shows this group of patients responded better to bardoxolone methyl than had been seen in earlier studies also using blood vessel dilating drugs. Reata is now expanding LARIAT to test the treatment in more PAH patients with connective tissue disease, and is actively recruiting.
Bardoxolone methyl is an antioxidant inflammation modulator taken orally once a day. The drug acts on a protein called Keap1, which is usually active during the resolution stage of an inflammation. This interaction sets in motion a sequence of molecular events that increase antioxidants and decrease inflammatory signaling.
LARIAT (NCT02036970) includes patients with both idiopathic and connective tissue-linked PAH. The study found that bardoxolone methyl produced the greatest change in the 6-minute walk distance test (a test assessing exercise capacity) among patients with connective tissue disease.
This stands in contrast to earlier studies using blood vessel dilating PAH therapy, as a recent analysis of published data showed that patients with connective tissue disease had an average improvement of only about one-third of that seen in idiopathic patients.
A new analysis showed that among the 15 patients with connective tissue disease who received bardoxolone methyl and completed the 16 weeks of treatment in the LARIAT trial, the improvement on the 6-minute walk distance test was 38.2 meters. Correcting for the placebo effect, the distance was 28.4 meters.
Moreover, an analysis revealed that patients with moderate to severe anemia did not do equally well, and an analysis excluding these patients (two in the placebo group and one in the treatment group) revealed that the placebo-corrected improvement was 48.5 meters.
“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,” Colin Meyer, MD, Reata’s chief medical officer, said in a news release.
The CATALYST trial is also recruiting participants at 100 sites in the U.S., Canada, Australia, Japan, Mexico, Europe, Israel, and South America. Contact details and locations are available at that study’s clinicaltrials.gov webpage.
The trial plans to enroll between 130 and 200 patients, who will be randomized to receive bardoxolone methyl or placebo. Those receiving bardoxolone methyl will start at a 5 mg dose, which will be increased to 10 mg during four weeks. The treatment will continue for 24 weeks. As in the LARIAT trial, researchers will analyze the change in the 6-minute walk distance test at the end of the study.
Patients with moderate to severe anemia will be excluded from CATALYST since treatment with iron supplementation or erythropoietin could affect the results of the 6-minute walk distance test independent of bardoxolone methyl.
“With the initiation of CATALYST, we have brought bardoxolone methyl one step closer to connective tissue disease-PAH patients who respond poorly to currently available therapies, have a high mortality rate, and are in need of new therapeutic options,” said Warren Huff, Reata’s chief executive officer and president.
“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,” Meyer added.