Overview

Executive Summary

    • PH is a multi-organ condition characterized by abnormally high pressure in the network of arteries and veins that lead to and from the lungs, which is caused by narrowing of the pulmonary vasculature as a result of inflammation, remodeling, proliferation, and endothelial dysfunction. Mitochondrial dysfunction has also been implicated in PH. PH patients experience increased pressure on the right side of the heart, ultimately leading to right ventricular failure and death.
    • Reata is conducting a Phase 3 trial (CATALYST) in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). Data from this trial will be available in the first half of 2018.
    • Reata is conducting a Phase 2 trial (LARIAT) in four etiologies of pulmonary hypertension associated with interstitial lung disease (PH-ILD). The four etiologies include PH-ILD associated with connective tissue disease, idiopathic pulmonary fibrosis, sarcoidosis, and other idiopathic interstitial pneumonias.

PH is a multi-organ condition characterized by an abnormally high pressure in the network of arteries and veins that lead to and from the lungs due, in part, to narrowing of the pulmonary vasculature as a result of inflammation, remodeling, proliferation, and endothelial dysfunction1-4. Mitochondrial dysfunction has also been implicated in PH. PH patients experience increased pressure on the right side of the heart, ultimately leading to right ventricular failure and death3,4. PH shares some features with cancer, including hyperproliferation and resistance to apoptosis (or programmed cell death) of vascular smooth muscle and other cells5,6. Further, impaired energetics of skeletal muscle is a common feature of PH1,6.

Bardoxolone methyl was initially tested in pulmonary arterial hypertension (PAH) patients in a Phase 2 trial (LARIAT). Initial results were presented at the CHEST meeting in 2015, and additional data were released when we announced the first patient enrolled in our Phase 3 trial (CATALYST) studying patients with connective tissue associated PAH (CTD-PAH).

Because initial data show that bardoxolone methyl was active in patients with CTD-PAH (a fibrotic disease), we believe that it may be effective in patients with other forms of PH that also involve fibrosis. We are conducting an expansion of the Phase 2 LARIAT trial studying four etiologies of PH associated with interstitial lung disease.

PH can be caused by a number of different underlying defects, which have been classified into five groups by the World Health Organization, or WHO. In the graphic below, the detailed boxes under the WHO groups represent patient populations in which bardoxolone methyl is being studied7.

Pathophysiology


Pulmonary Arterial Hypertension

PAH, like PH more generally, results in a progressive increase in pulmonary vascular resistance, which ultimately leads to right ventricular heart failure and death. PAH has a number of different etiologies, with approximately 72% of PAH cases being associated with either connective tissue disease, or CTD, or being idiopathic8.

Patients with CTD-PAH are generally less responsive to existing therapies and have a worse prognosis than patients with other forms of PAH10,11. The primary CTDs underlying CTD-PAH include scleroderma, lupus, and mixed connective tissue diseases12. CTD-PAH patients make up approximately 30% of the overall PAH population8,13. In comparison to patients with idiopathic PAH, or I-PAH, patients with CTD-PAH have a higher occurrence of small vessel fibrosis and greater incidence of pulmonary veno-obstructive diseases14. In the United States, the five-year survival rate for CTD-PAH patients is approximately 44%, with a median survival rate of approximately four years, whereas I-PAH patients have a median survival rate of approximately seven years9.

Pulmonary Hypertension in Interstitial Lung Disease (ILD)

Interstitial lung disease, or ILD, patients experience extensive pulmonary vascular remodeling, which ultimately leads to PH-ILD in approximately 30% to 40% of ILD patients16. PH-ILD is classified under both WHO Groups III and V PH, and bardoxolone methyl is currently being studied in the subset of ILD patients with idiopathic pulmonary fibrosis, CTD that has affected the lung tissue, and IIP, or idiopathic interstitial pneumonia, which are all classified under WHO Group III PH. In addition, bardoxolone methyl is being studied in ILD patients with sarcoidosis, which is classified under WHO Group V PH1. PH-ILD patients have a one-year survival rate of approximately 63%, as compared to approximately 92% for ILD patients without PH17. Recent studies have demonstrated that mitochondrial abnormalities are key contributors to PH-ILD5.

Mechanism of Action



Bardoxolone methyl directly targets the bioenergetic and inflammatory components of PH. PH patients experience mitochondrial dysfunction, increased activation of NF-κB and related inflammatory pathways involved in ROS signaling, cellular proliferation, and fibrosis. Bardoxolone methyl, through the combined effect of Nrf2 activation and NF-κB suppression, has the potential to inhibit inflammatory and proliferative signaling, suppress ROS production and signaling, reduce the production of enzymes involved in fibrosis and tissue remodeling, and increase ATP production and cellular respiration18. Evidence supporting the mitochondrial effects of the AIMS has been seen both pre-clinically and in clinical settings where more frequent weight loss was observed in the treatment groups19,20. By addressing a novel pathway in PH, we believe that bardoxolone methyl may provide additional benefits beyond current PAH therapies, including:

  • Increased functional capacity: We believe the bioenergetic effects of bardoxolone methyl may result in increased functional capacity, the ability to perform everyday functions, for PH patients, due to its effects on energy production and cellular respiration, as characterized in preclinical studies with bardoxolone methyl and other AIMs21,22.
  • Potential effects beyond functional improvements: Bardoxolone methyl has potential anti-inflammatory, anti-proliferative, and anti-fibrotic effects and targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages22-25. We believe that bardoxolone methyl may, over an extended period of time, affect the synergistic processes of vasoconstriction, thrombosis, fibrosis, and vascular remodeling within the pulmonary arterial system, potentially improving patient outcomes22.
  • Broader applicability: Bardoxolone methyl may be useful in treating earlier stage PAH patients, CTD-PAH patients, and PH-ILD patients, all of whom are underserved by existing PAH therapies, likely because vasoconstriction is not as prominent a feature in these patients as it is in idiopathic and other PAH patients14,15,26.
  • Potential as a combination therapy: To date, it has been observed that bardoxolone methyl does not induce systemic hemodynamic effects or drug-to-drug interactions in PH patients26. This may provide clinicians with greater flexibility in dosing, ultimately result in a more favorable safety profile, and allow for use in combination with other therapies with a greater incremental effect than an additional vasodilator.

Development Program

Reata is enrolling patients in the CATALYST study, a placebo controlled, international, multi-center Phase 3 study of bardoxolone methyl in CTD-PAH.

Reata is enrolling patients in the LARIAT study, a placebo-controlled, multi-center Phase 2 study of bardoxolone methyl in PAH and four different etiologies of PH-ILD, which include:

  • Pulmonary Hypertension – ILD – CTD (connective tissue disorder)
  • Pulmonary Hypertension – ILD – IPF (idiopathic pulmonary fibrosis)
  • Pulmonary Hypertension – ILD – Sarc (sarcoidosis)
  • Pulmonary Hypertension – ILD – IIP (idiopathic interstitial pneumonia).

Initial results in PAH from the LARIAT study were presented at the CHEST meeting in Montreal in October 2015 and additional results in CTD-PAH patients were released at the time we enrolled the first patient in our CATALYST trial.

AIMs have potential applications in many other cardiovascular diseases, including cardiomyopathies, vasculitis, and vascular complications of diabetes.

References


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  20. Reata Pharmaceuticals, Inc, internal data.
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