Bard|CTD-PAH

CTD-PAH

CTD-PAH results in a progressive increase in pulmonary vascular resistance, which ultimately leads to right heart ventricular failure and death. CTD-PAH patients make up approximately 30% of the overall PAH population, or approximately 12,000 individuals worldwide1,2.

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 diseases3. CTD-PAH patients treated with vasodilator therapies show 6MWD improvements only one-third as great as the improvements seen in I-PAH patients4. As a result, CTD-PAH patients represent a subset of the PAH population with a significant unmet medical need.

Pathophysiology


The primary CTDs underlying CTD-PAH include scleroderma, lupus, and mixed connective tissue diseases5. Patients with CTD-PAH are generally less responsive to existing therapies and have a worse prognosis than patients with other forms of PAH6,7. 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 years8. As described in a recent large meta-analysis, pulmonary vascular resistance, mean pulmonary arterial pressure, and right atrial pressure are lower in CTD-PAH patients as compared to I-PAH patients9. This may explain why CTD-PAH patients treated with vasodilator therapies show 6MWD improvements only one third as great as the improvements seen in I-PAH patients4.

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 related with fibrosis and tissue remodeling, and increase ATP production and cellular respiration10. Evidence potentially supporting the mitochondrial effects of the AIMS has been observed both pre-clinically and in clinical settings11,12. 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 have been characterized in preclinical studies with bardoxolone methyl and other AIMs13,14.
  • 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 macrophages14-17. We believe that bardoxolone methyl may, over an extended period of time, affect the synergistic effects of vasoconstriction, thrombosis, fibrosis, and vascular remodeling within the pulmonary arterial system, potentially improving patient outcomes14.
  • 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 patients18. 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 has initiated the Phase 3 CATALYST study. CATALYST is an international, randomized, double-blind, placebo-controlled trial examining the safety, tolerability, and efficacy of bardoxolone methyl in patients with WHO Group I CTD-PAH when added to standard-of-care vasodilator therapy. Patients will be on up to two background therapies and will be randomized one-to-one to bardoxolone methyl or placebo. Patients will be enrolled at 100 sites in the US, Canada, Australia, Japan, Mexico, Europe, Israel, and South America. Study drug will be administered once daily for 24 weeks. Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. The primary endpoint is the change from baseline in six-minute-walk distance (6MWD) relative to placebo at Week 24. The secondary endpoint is time to first clinical improvement as measured by improvement in WHO functional class, increase from baseline in 6MWD by at least 10%, or decrease from baseline in creatinine kinase (as a surrogate biomarker for muscle injury and inflammation) by at least 10%. The trial will enroll between 130 and 200 patients. Data from CATALYST are expected to be available during the first half of 2018.

References


  1. Badesch et al. Pulmonary arterial hypertension – Baseline characteristics from the REVEAL registry. Chest. 2010 Feb;137(2):376-87.
  2. McGoon et al. Pulmonary arterial hypertension – Epidemiology and registries. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D51-9.
  3. Overbeek et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009 Aug;34(2):371-9.
  4. Rhee et al. Comparison of treatment response in idiopathic and connective tissue disease-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015 Nov 1;192(9):1111-7.
  5. Galie et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus. 2005;14(9):713-7.
  6. Chung et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 2014 Mar;66(3):489-95.
  7. Chung et al. Clinical aspects of pulmonary hypertension in patients with systemic lupus erythematosus and in patients with idiopathic pulmonary arterial hypertension. Clin Rheumatol. 2006 Nov;25(6):866-72.
  8. Benza et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.Chest. 2012 Aug;142(2):448-56.
  9. Chung et al. Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL – Identifying Systemic Sclerosis as a Unique Phenotype. Chest. 2010 Dec;138(6):1383-94.
  10. 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.
  11. Reata Pharmaceuticals, Inc. Investigation of Serious Adverse Events in Bardoxolone Methyl Patients in BEACON. Presented at ERA-EDTA 2014.
  12. Reata Pharmaceuticals, Inc, internal data.
  13. Mainguy et al. Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension. Thorax. 2010 Feb;65(2):113-7.
  14. Kulkarni et al. The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis. PLoS One. 2013 May 31;8(5):e63798.
  15. 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.
  16. 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.
  17. 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.
  18. Oudiz. Initial Data Report from ‘LARIAT’: a Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy. Presented at CHEST 2015.