Irving, Texas-based Reata Pharmaceuticals, Inc. announced initial data from the LARIAT (A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Pulmonary Hypertension) trial (ClinicalTrials.gov Identifier: NCT02036970) evaluating bardoxolone methyl in pulmonary arterial hypertension (PAH) patients at the annual meeting of the 2015 American College of Chest Physicians (CHEST), running from October 25 to 28 at the Palais des Congrès de Montrèal Convention Center.
The presentation, entitled “Initial Data Report from LARIAT: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy,” was delivered as part of the CHEST conference’s October 27, 2015, Late-Breaking Abstracts session from 8:45 to 10:00 am by Ronald Oudiz, MD, Professor of Medicine, David Geffen School of Medicine at the University of California Los Angeles (UCLA). Dr. Oudiz is Director of the Pulmonary Hypertension Center and a Faculty Cardiologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Southern California. The presentation slides can be seen here: http://reatapharma.wpengine.com/wp-content/uploads/2015/10/LARIAT_CHEST_Final.pdf.
The objective of the LARIAT study, which assesses the safety, efficacy, and tolerability of bardoxolone methyl relative to a placebo in patients with pulmonary hypertension, is to determine the recommended dose range, evaluating the change from baseline in 6-minute walking distance (6MWD), and to determine the effect of bardoxolone methyl in pulmonary hypertension associated with connective tissue disease, interstitial lung disease, and idiopathic etiologies. The latter include subsets of patients with WHO Group III or WHO Group V PH following 16 weeks of study participation. All patients participating in the clinical trial were on stable doses of background PAH therapies at baseline and throughout the study.
PAH is a life-threatening disease involving multi-organ endothelial dysfunction, characterized by abnormally high pressure in the network of small pulmonary arteries and veins leading to and from the lungs due in part to narrowing of the pulmonary vasculature as a result of inflammation, remodeling, proliferation, and endothelial dysfunction. Mitochondrial dysfunction has also been implicated in PAH. PAH patients experience increased pressure on the right side of the heart, ultimately leading to ventricular failure and death.
Although PAH does not involve metastasis or disruption of tissue boundaries, it shares some features with cancer, including hyperproliferation and resistance to apoptosis, or programmed cell death, of vascular smooth muscle and other cells. Further, impaired energetics of skeletal muscle is a common feature of PAH.
PAH has been estimated to affect 15 to 20 thousand people in the United States, predominantly middle-age women. The disease can strike anyone, but individuals with connective tissue diseases such as scleroderma, liver disease, or HIV infection are more likely than the general population to have PAH. Available treatments can provide symptomatic improvement, primarily by relieving vasoconstriction (e.g., by inhibiting signaling in the endothelin-1 pathway), but they do not directly suppress inflammation or proliferation pathways and the disease continues to progress. Consequently, there is a very high unmet clinical need for new therapy; PAH has a high mortality rate with 60 percent to 80 percent of patients dying within five years of diagnosis.
In the LARIAT trial, efficacy analyses showed bardoxolone methyl increased 6MWD at doses of 2.5 to 10 mg through 16 weeks of treatment. Patients treated with bardoxolone methyl demonstrated a statistically significant mean increase in 6MWD compared to baseline of 22 meters and a placebo-corrected difference of 21.4 meters (p = 0.037).
Reata says an extensive body of research by leading academics and in-house Reata scientists has demonstrated that bardoxolone methyl and related compounds have highly potent antioxidant and anti-inflammatory properties, including beneficial effects on endothelial dysfunction, as well as anti-proliferative and anti-fibrotic effects. The company notes that while many current therapies have shown limited efficacy in improving 6MWD performance in patients who have baseline 6MWD values greater than 450 meters, 6MWD changes in patients with baseline values greater than 450 meters were similar to those with baseline values less than 450 meters. Changes in 6MWD were associated with improvements in metabolic parameters, including mean weight loss of 3 kilograms relative to placebo and reductions in creatine kinase, a marker of muscle inflammation.
Notably, patients with connective tissue disease associated PAH (CTD-PAH), who typically experience less therapeutic benefit from approved PAH therapies, demonstrated a mean increase from baseline in 6MWD of 30 meters and a placebo-corrected change of 44 meters. This change may reflect the novel anti-inflammatory, metabolic, and mitochondrial effects of bardoxolone methyl.
Safety analyses from LARIAT also demonstrated that bardoxolone methyl was well-tolerated with relatively fewer discontinuations in bardoxolone methyl-treated patients compared to those who received placebo. No drug-related serious adverse events were reported, and the adverse event profile was manageable. Importantly, unlike previous observations in a subset of patients with advanced kidney disease, no fluid retention events or less severe manifestations of fluid retention were observed in the LARIAT PAH subjects. No meaningful or dose-related changes in blood pressure, heart rate, other measures of fluid status, and echocardiographic parameters were noted.
Reata completed an end of phase 2 interaction with the U.S. Food and Drug Administration in October, and reports that the FDA concurred with the company’s proposal for an initial phase 3 study in CTD-PAH patients using 6MWD as the primary endpoint. The primary endpoint will be assessed after 24 weeks of treatment. Reata plans to initiate this first phase 3 study in 2016 and is considering additional studies in other subtypes of PAH.
“The initial data from LARIAT are very encouraging and indicate that bardoxolone methyls novel mechanism of action may provide a new approach to PAH therapy. Clinically, these effects may acutely translate to increased muscular function, and as we have observed in preclinical models, may reduce pathological cardiovascular remodeling in the long-term,” says Colin Meyer, MD, Reata’s Chief Medical Officer. “This pharmacology is particularly meaningful to PAH patients with connective tissue disease. These patients have autoimmune disease that causes their PAH, and their inflammatory disease processes often involve more remodeling than other subtypes. This explains why these patients often do not respond well to approved vasodilator therapy relative to idiopathic PAH patients and represent a subset of the PAH population with significant unmet need.
“On the basis of these data and recent interactions with the FDA, we are excited to announce that we are planning to initiate a phase 3 study of bardoxolone methyl in patients with CTD-PAH in 2016,” Dr. Meyer said.
Bardoxolone methyl is an experimental, oral once daily antioxidant inflammation modulator (AIM) that has received orphan drug designation for the treatment of PAH by the FDA. AIMs activate the biological transcription factor Nrf2, promoting the production of numerous antioxidant, detoxification, and anti-inflammatory genes, and inhibit NF-B, a gene that regulates many pro-inflammatory proteins. Nrf2 controls the body’s production of hundreds of antioxidative and cytoprotective molecules and is associated with protection against a broad range of diseases involving inflammation and oxidative stress. Activation of Nrf2 promotes the production of numerous anti oxidative, detoxifying, and anti-inflammatory genes and, moreover, inhibits NF-B, a gene that regulates many pro-inflammatory proteins. The pharmacology of the AIMs mimics that of endogenous prostaglandin metabolites that are responsible for the orchestrated resolution of inflammation. The anti-inflammatory, cytoprotective and energy metabolism effects of AIM pharmacology have been documented in more than 250 scientific papers and are potentially relevant to a wide range of diseases.
Bardoxolone methyl directly targets the bioenergetic and inflammatory components of PH. PH patients experience mitochondrial dysfunction, increased production of NF-B and related inflammatory pathways involved in ROS signaling, cellular proliferation, and fibrosis. Bardoxolone methyl, through the combined effect of Nrf2 activation and NF-B 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 respiration.
The LARIAT Study
LARIAT is a Phase 2 dose ranging study examining the safety, tolerability, and efficacy of bardoxolone methyl in patients with PAH on stable background therapy. To determine if bardoxolone methyl could complement approved PAH therapies, the Phase 2 study was designed to assess efficacy through exercise capacity.
This initial data report is from analysis performed on the initial 3 cohorts (24 patients). World Health Organization (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 bardoxolone methyl at doses of 2.5, 5, or 10 mg for 16 weeks. Each dosing 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 were included in the study. The primary efficacy variable, 6-minute walk distance (6MWD), was collected at baseline and every 4 weeks post-randomization. A Safety Review Committee monitored the study, and all eligible participants were offered open-label extension therapy after the initial 16 weeks. For more details on the LARIAT study visit:
More About PAH
The U.S. National Library of Medicine (NLM) describes pulmonary arterial hypertension as abnormally high blood pressure in the arteries of the lungs that makes the right side of the heart work harder than normal. The right side of the heart pumps blood through the lungs, where it picks up oxygen. Blood returns to the left side of the heart, where it is pumped to the rest of the body. When the small arteries (blood vessels) of the lung become narrowed, they cannot carry as much blood. When this happens, pressure builds up — called pulmonary hypertension. The heart needs to work harder to force blood through the vessels against this pressure, and over time, this causes the right side of the heart to become larger. Ultimately, heart failure affects the right side of the heart. This is called cor pulmonale.
In a Perspective paper published in the journal Cell Metabolism entitled “The Metabolic Basis of Pulmonary Arterial Hypertension” (Cell Metab. 2014 Apr 1;19(4):558-73. doi: 10.1016/j.cmet.2014.01.004. Epub 2014 Feb 60), Dr. Gopinath Sutendra and Professor of Medicine Evangelos D. Michelakis of the University of Alberta Department of Medicine in Edmonton, Canada, describe pulmonary arterial hypertension (PAH) as a vascular remodeling disease of the lungs resulting in heart failure and premature death, noting that, while until recently it was thought that PAH pathology is restricted to pulmonary arteries, it is now known that several extra-pulmonary organs are affected, with the mortality of severe PAH similar to that of metastatic breast cancer, and that the currently estimated cost of treatment for advanced PAH exceeds $200,000 per patient a year.
The NLM says pulmonary hypertension may be caused by autoimmune diseases that damage the lungs, such as scleroderma and rheumatoid arthritis; birth defects of the heart; blood clots in the lung (pulmonary embolism); heart failure; heart valve disease; HIV infection; low oxygen levels in the blood for a long time (chronic); lung disease, such as COPD or pulmonary fibrosis; medicines (for example, certain diet drugs); and obstructive sleep apnea, but in many patients, the cause of pulmonary hypertension is unknown. In this case, the condition is called “idiopathic pulmonary arterial hypertension (IPAH).”
Reata Pharmaceuticals, Inc.
The U.S. National Library of Medicine (NLM)
Annual-Meeting-2015 of the 2015 American College of Chest Physicians (CHEST)