Overview

  • AS is the second most common inherited cause of renal failure after ADPKD and affects as many as 60,000 people in the US1
  • AS is caused by a genetic defect in type IV collagen, a component in building the glomerular basement membrane (GBM), the kidney’s filtering system. Type IV collagen mutations can alter the GBM’s structure, impair its function, and ultimately, lead to end-stage renal disease (ESRD)2
  • With no approved therapies to stop the progressive loss of kidney function, AS represents a disorder with a significant unmet need3,4
  • Early and accurate diagnosis is critical since many patients, including women who are rarely tested, can develop kidney failure at a young age5-7
  • As in other forms of CKD, mitochondrial dysfunction and chronic inflammation play important roles in the pathophysiology and progression of AS8,9
  • Reata is developing bardoxolone methyl, which has the potential to prevent long-term consequences and improve the symptoms of many diseases, by correcting the underlying pathologic processes associated with mitochondrial dysfunction, inflammation, and oxidative stress
  • Reata is conducting the pivotal, registrational, phase 2/3 CARDINAL study to evaluate the efficacy and safety of bardoxolone methyl in individuals with CKD caused by AS
  • Reata received orphan drug designation from the FDA for bardoxolone methyl for the treatment of AS

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Pathophysiology

Although AS is caused by mutations in the genes encoding type IV collagen, a major structural component of the GBM in the kidney, mitochondrial dysfunction and chronic inflammation play a central role in the progression of AS. Mitochondrial dysfunction in AS is associated with the genetic insult and results in the development of chronic inflammation in the kidney. The activation of proinflammatory pathways promotes kidney tissue remodeling, tubular atrophy, interstitial scarring, and fibrosis, which manifests clinically as progressive loss of kidney function that can eventually lead to ESRD.8,9

Bardoxolone Methyl Mechanism of Action

Through Nrf2 induction and inhibition of NF-κB, bardoxolone methyl activates molecular pathways that promote the resolution of inflammation by restoring mitochondrial function and redox balance and inhibiting proinflammatory signaling. In preclinical models, bardoxolone methyl reverses endothelial dysfunction and chronic, disease-related mesangial cell contraction, resulting in an increased surface area of the glomerulus and increased glomerular filtration rate (GFR). Bardoxolone methyl also inhibits activation of proinflammatory and profibrotic pathways that lead to structural remodeling and glomerulosclerosis. Thus, bardoxolone methyl targets multiple pathways that contribute to GFR loss in AS.

Pivotal Programs

The CARDINAL Trial

Study Design

CARDINAL is an international, multicenter, phase 2/3 study. The phase 2 portion of CARDINAL is open-label and enrolled 30 patients. The phase 3 portion of CARDINAL is double-blind, placebo-controlled, and is fully enrolled with 157 patients randomized on a 1:1 basis to once-daily, oral bardoxolone methyl or placebo. A dose-titration scheme will be used to reach a goal dose of 20 mg or 30 mg. All patients in the study will have the same visit and assessment schedule and will be followed for two years.

Cardinal-study-design

Key Eligibility Criteria:

  • Ages 12 to 60 years
  • Confirmed genetic or histological diagnosis of AS
  • Baseline estimated GFR (eGFR) values between 30 to 90 mL/min/1.73 m2

Primary Efficacy Endpoint:

The phase 2 primary efficacy endpoint is the change from baseline in eGFR after 12 weeks of treatment.

The phase 3 primary efficacy endpoint is the on-treatment eGFR change from baseline in bardoxolone methyl-treated patients relative to placebo at week 48. The key secondary endpoint of the phase 3 portion of the trial is the change from baseline in retained eGFR benefit after 48 weeks on-treatment and 4 weeks off-treatment relative to placebo and is designed to demonstrate that bardoxolone methyl has disease-modifying activity in patients with AS.

References
  1. Alport Syndrome Foundation. What is Alport syndrome? http://alportsyndrome.org/what-is-alport-syndrome/. Accessed November 7, 2018.
  2. Kashtan CE, Ding J, Gregory M, et al. Clinical practice recommendations for the treatment of Alport syndrome: A statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol. 2013;28(1):5-11.
  3. Gross O, Kashtan CE. Treatment of Alport syndrome: Beyond animal models. Kidney Int. 2009;76(6):599-603.
  4. Gross O, Kashtan CE, Rheault MN, et al. Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: Report from the 2015 International Workshop on Alport Syndrome. Nephrol Dial Transplant. 2017;32(6):916-924.
  5. Savige J, Colville D, Rheault M, et al. Alport syndrome in women and girls. Clin J Am Soc Nephrol. 2016;11(9):1713-1720.
  6. Alport Syndrome Foundation. Alport syndrome fast facts. http://alportsyndrome.org/wp-content/uploads/2015/09/Fast-Facts-About-AS-Rev-9-14-15.pdf. Accessed November 7, 2018.
  7. Romagnani P, Remuzzi G, Glassock R, et al. Chronic kidney disease. Nat Rev Dis Primers. 2017;3:17088.
  8. Noone D, Licht C. An update on the pathomechanisms and future therapies of Alport syndrome. Pediatr Nephrol. 2013;28(7):1025-1036.
  9. Savige J. Alport syndrome: Its effects on the glomerular filtration barrier and implications for future treatment. J Physiol. 2014;592(18):4013-4023.
View References