Pulmonary Hypertension – ILD: CTD, IPF, Sarc, IIP
Interstitial lung disease, or ILD, patients experience extensive pulmonary vascular remodeling, which ultimately leads to PH-ILD in approximately 30% to 40% of ILD patients1. PH-ILD is categorized under both WHO Groups III and V PH, and we are initially targeting the use of bardoxolone methyl in the subset of ILD patients with idiopathic pulmonary fibrosis, CTD that has affected the lung tissue, and other types of idiopathic interstitial pneumonia, which are classified under WHO Group III PH, as well as sarcoidosis, which is classified under WHO Group V PH2.
Currently, there are no approved therapies for PH-ILD patients. While approved vasodilators are sometimes used off-label, given the degree of remodeling and fibrosis present in the lung tissue and vasculature of PH-ILD patients, they are minimally effective. Several current PAH therapies have been tested in PH-ILD patients and have resulted in little to no clinical improvement3.
PH-ILD patients have a one-year survival rate of approximately 63%, as compared to approximately 92% for ILD patients without PH4. Recent studies have demonstrated that mitochondrial abnormalities are key contributors to PH-ILD5.
ILD represents a heterogeneous group of diseases that are characterized by fibrotic remodeling of the pulmonary interstitium, which results in irreversible structural changes and ultimately death. A common feature of all ILDs is the decline of pulmonary function and impairment of gas exchange6,7.
Mitochondrial dysfunction and increased oxidative stress and reactive oxygen species in ILD trigger hypoxic pulmonary vasoconstriction, which is one of the major causes of PH in ILD patients. Additionally, vascular remodeling, perivascular fibrosis and vascular destruction, hypoxemia, and microvascular inflammation and injury also contribute to increased pulmonary vascular resistance and PH in ILD8.
PH contributes significantly to functional impairment in patients with ILD and PH-ILD patients commonly complain of shortness of breath on exertion and, in severe cases, at rest. This limitation can severely compromise the quality of the patient’s life. PH also substantially worsens the prognosis of ILD patients and has been shown to be a predictor of mortality in patients with ILD9-12.
Mechanism of Action
Bardoxolone methyl directly targets the bioenergetic and inflammatory components of PH-ILD. PH-ILD 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 related with fibrosis and tissue remodeling, and increase ATP production and cellular respiration13. Evidence potentially 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 groups14,15. By addressing a novel pathway, we believe that bardoxolone methyl may provide benefits, 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 AIMs16,17.
- 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 macrophages17-20. 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 outcomes17.
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).
- Behr and Ryu. Pulmonary hypertension in interstitial lung disease. Eur Respir J. 2008 Jun;31(6):1357-67.
- Paulin and Michelakis. The metabolic theory of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):148-64.
- Cottin V. Treatment of pulmonary hypertension in interstitial lung disease: do not throw out the baby with the bath water. European Respiratory Journal 2013; 41:781-783.
- Andersen et al. Pulmonary hypertension in interstitial lung disease: Prevalence, prognosis and 6 min walk test. Respir Med. 2012 Jun;106(6):875-82.
- Cottrill and Chan. Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect. Eur J Clin Invest. 2013 Aug;43(8):855-65.
- Behr J and JH Ryu. Pulmonary hypertension in interstitial lung disease. Eur Respir J 2008; 31: 1357–1367.
- Chung F and E Dean. Pathophysiology and cardiorespiratory consequences of interstitial lung disease–review and clinical implications: a special communication. Phys Ther 1989; 69: 956–966.
- Ryu J, Kroka M, Swanson KL. Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clin Proc 2007; 82 (3): 342-350.
- Shorr AF, Davies, DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung transplantation. Chest 2003; 124(3):922-8.
- Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003; 11:2398-23405.
- Lettieri CJ Nathan SD, Barnett SD, et al. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129: 746-752.
- Anderson CU, Mellemkjær S, Hillberg O, et al. Pulmonary hypertension in interstitial lung disease: Prevalence, prognosis and 6 min walk test. Respiratory Medicine 2012; 106:875-882.
- Neymotin et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO triﬂuoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med. 2011 Jul 1;51(1):88-96.
- Reata Pharmaceuticals, Inc. Investigation of Serious Adverse Events in Bardoxolone Methyl Patients in BEACON. Presented at ERA-EDTA 2014.
- Reata Pharmaceuticals, Inc, internal data.
- Mainguy et al. Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension. Thorax. 2010 Feb;65(2):113-7.
- Kulkarni et al. The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis. PLoS One. 2013 May 31;8(5):e63798.
- Bynum et al. Cytoprotection of human endothelial cells from oxidant stress with CDDO derivatives: network analysis of genes responsible for cytoprotection. Pharmacology. 2015;95(3-4):181-92.
- Vannini et al. The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3139-46.
- Liby et al. The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice. Cancer Res. 2007 Mar 15;67(6):2414-9.