Currently, there are no approved therapies for PH-ILD patients. While vasodilators approved for PAH 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.
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 (ROS) in ILD trigger hypoxic pulmonary vasoconstriction, which is one of the major causes of PH in ILD patients2. 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 Nrf2 activators 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:
In the third quarter of 2017, Reata completed enrollment of 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 – Sarc (sarcoidosis)
- Pulmonary Hypertension – ILD – IPF (idiopathic pulmonary fibrosis)
- Pulmonary Hypertension – ILD – CTD (connective tissue disorder)
- Pulmonary Hypertension – ILD – IIP (idiopathic interstitial pneumonia).
Data are anticipated in the first quarter of 2018.
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- Behr J and JH Ryu. Pulmonary hypertension in interstitial lung disease. Eur Respir J 2008; 31: 1357–1367.
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- 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.
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