Overview

  • PAH, which impairs the heart’s ability to pump blood throughout the body, is a chronic, progressive, and often fatal lung disease1
  • Approximately 30% of patients with PAH have an underlying connective tissue disease, such as scleroderma or lupus erythematosus2
  • In the US, the 5-year survival for CTD-PAH is approximately 44%, while the survival of PAH from other causes is substantially greater3
  • As a result, patients with CTD-PAH represent a subset of the PAH population with a significant unmet medical need
  • Reata is conducting the phase 3 CATALYST trial, an international, randomized, double-blind, placebo-controlled study examining the safety, tolerability, and efficacy of bardoxolone methyl when added to standard of care in patients with WHO Group 1 CTD-PAH
  • The FDA has granted orphan drug status to bardoxolone methyl for the treatment of PAH

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Pathophysiology

Several factors are involved in the pathogenesis and progression of CTD-PAH. Chronic activation of the transcription factor NF-κB, which controls several genes involved in immune response inflammation results in a perpetual state of mitochondrial dysfunction and inflammation.4 This promotes vascular proliferation, and ultimately, the chronic cardiac remodeling in CTD-PAH.5

chronic-inflammation-in-PAH-goal

Bardoxolone Methyl Mechanism of Action

Bardoxolone methyl targets several factors involved in CTD-PAH by activating Nrf2, a key regulator of cellular responses to oxidative damage due to inflammation and injury. Bardoxolone methyl acts by releasing Nrf2 from Keap1, allowing it to suppress NF-κB and activate transcription of many anti-inflammatory and antioxidant genes. Evidence potentially supporting the mitochondrial effects of the Nrf2 activators has been observed both preclinically and in clinical settings.

Pivotal Program

CATALYST Trial12

CATALYST is an international, randomized, double-blind, placebo-controlled trial examining the safety, tolerability, and efficacy of bardoxolone methyl in patients with WHO Group 1 CTD-PAH.

CATALYST: Study Design

  • Enrolling patients with WHO Group I CTD-PAH receiving up to two background therapies
  • Patients are randomized to receive bardoxolone methyl at a starting dose of 5 mg, that will be increased to 10 mg at week 4, unless contraindicated clinically

CATALYST-study-design

Study Endpoints

Primary

  • Change from baseline in 6MWD relative to placebo at week 24

Secondary

  • Time to first clinical improvement, as measured by:
    • Improvement in WHO functional class
    • ≥10% increase from baseline in 6MWD or
    • ≥10% decrease from baseline in creatinine kinase (as a surrogate biomarker for muscle injury and inflammation)

By addressing a novel pathway in PAH, bardoxolone methyl may provide additional benefits beyond current PAH therapies.

LARIAT Trial13

LARIAT was a phase 2 trial to assess the safety and efficacy of bardoxolone methyl. Specifically, LARIAT was designed to determine the recommended dose range, the change from baseline in 6MWD, and the effect of bardoxolone methyl on pulmonary hypertension in patients with conditions including CTD, interstitial lung disease, and unknown causes.

LARIAT-trial-design

References
  1. Pulmonary Hypertension Association. Types of pulmonary hypertension. https://phassociation.org/patients/aboutph/types-of-ph/. Accessed November 7, 2018.
  2. McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension: Epidemiology and registries. J Am Coll Cardiol. 2013;62(25 suppl):D51-D59.
  3. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL registry. Chest. 2012;142(2):448-456.
  4. Park MH, Hong JT. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016;5(2):pii:E15.
  5. Galiè N, Manes A, Farahani KV, et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus. 2005;14(9):713-717.
  6. Bello-Klein A, Mancardi D, Araujo AS, Schenkel PC, Turck P, de Lima Seolin BG. Role of redox homeostasis and inflammation in the pathogenesis of pulmonary arterial hypertension. Curr Med Chem. 2018;25(11):1340-1351.
  7. Scott TE, Kemp-Harper BK, Hobbs AJ. Inflammasomes: A novel therapeutic target in pulmonary hypertension [published online May 30, 2018] Br J Pharmacol. doi:10.1111/bph.14375.
  8. Cho J, Lee A, Chang W, Lee MS, Kim J. Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction. Front Immunol. 2018;9:294.
  9. Plecitá-Hlavatá A, D’Alessandro A, El Kasmi K, et al. Metabolic reprogramming and redox signaling in pulmonary hypertension. Adv Exp Med Biol. 2017;967:241-260.
  10. Liu N, Parry S, Xiao Y, Zhou S, Liu Q. Molecular targets of the Warburg effect and inflammatory cytokines in the pathogenesis of pulmonary artery hypertension. Clin Chim Acta. 2017;466:98-104.
  11. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165-175.
  12. US National Institutes of Health. US National Library of Medicine. Bardoxolone methyl in patients with connective tissue disease-associated pulmonary arterial hypertension – CATALYST. http://clinicaltrials.gov/ct2/show/NCT02657356. Updated September 2018. Accessed November 7, 2018.
  13. US National Institutes of Health. US National Library of Medicine. Bardoxolone methyl evaluation in patients with pulmonary hypertension (PH) – LARIAT. https://clinicaltrials.gov/ct2/show/NCT02036970. Updated June 2018. Accessed November 7, 2018.