Publication: Omaveloxolone and TX63682 Are Hepatoprotective in the STAM Mouse Model of NASH

Omaveloxolone and novel Nrf2 activator TX63682 decreased hepatic fat deposition, hepatocellular ballooning, hepatic inflammatory cell infiltration, nonfasting blood glucose and glycated hemoglobin A1C concentrations, and liver and serum triglycerides in the STAM mouse model of nonalcoholic steatohepatitis (NASH).

  • Omaveloxolone and TX63682 demonstrated significant hepatoprotection in a rodent model of NASH in conjunction with improvements in glucose control and lipid handling, which is consistent with the overall phenotype of improved mitochondrial function that is associated with Nrf2 activation.
  • Mild increases in serum transaminases were observed in conjunction with improvements in hepatic histology and without major changes in serum bilirubin suggesting that they are a pharmacological and not toxic effect.
  • Overall, these data suggest that changes in serum chemistries and other blood based markers observed with our Nrf2 activators are likely a pharmacologic effect of Nrf2 activation associated with restoration of lipid metabolism and suppression of inflammation.

Publication: TSUBAKI, a Study of Bardoxolone Methyl in Patients with Diabetic CKD

The Phase 2 study of bardoxolone methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) met its primary efficacy endpoint and, using the inulin clearance method, demonstrated that bardoxolone methyl treatment significantly increased measured GFR.

  • Bardoxolone methyl treatment was associated with an increase in measured GFR, as determined by inulin clearance.
  • Treatment with bardoxolone methyl was associated with improvements in eGFR and creatinine clearance.
  • There was no change in 24-hour excretion of creatinine suggesting that bardoxolone methyl does not affect muscle metabolism of creatinine.
  • Data confirm that serum creatinine based eGFR is an appropriate measure to assess kidney function in response to bardoxolone methyl treatment.

Publication: Bardoxolone Methyl Analog Attenuates Proteinuria-Induced Tubular Damage by Modulating Mitochondrial Function

Dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, significantly reduced proteinuria-induced tubular cell mitochondrial damage in a model of diabetic kidney disease.

  • Treatment with bardoxolone methyl analog improved mitochondrial function, suppressed inflammatory signaling, and reduced oxidative stress.
  • Treatment with bardoxolone methyl analog was protective of the renal tubular interstitium, decreased fibrosis, and preserved kidney function despite not improving proteinuria.

Publication: Effect of Bardoxolone Methyl on the Urine Albumin-To-Creatinine Ratio in Patients With Type 2 Diabetes and Stage 4 Chronic Kidney Disease

In patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria were directly related to changes in eGFR.

  • Relative to placebo, bardoxolone methyl treatment resulted in a significant decrease in albuminuria when indexed to eGFR.
  • Mean increases in eGFR from baseline at both week 48 and 4 weeks off treatment were not different in the highest and lowest quartiles of patients stratified by week 12 UACR changes.

Publication: Effects of Bardoxolone Methyl on Body Weight, Waist Circumference and Glycemic Control in Obese Patients with T2DM and Stage 4 Chronic Kidney Disease

Bardoxolone methyl treatment resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.

  • Bardoxolone methyl treatment resulted in significant reductions in body weight in a generally overweight patient population with T2DM and stage 4 CKD.
  • The magnitude and rate of weight reductions were more pronounced in patients with higher baseline BMI. The loss in body weight was accompanied by a significant reduction in waist circumference, with declines proportional to both baseline body weight and BMI.
  • In a subset of patients who provided timed urine collections, there was no reduction in 24-hour urinary creatinine excretion, suggesting that bardoxolone methyl does not adversely affect creatinine production and serum creatinine-based eGFR is therefore an appropriate measure of kidney function in response to bardoxolone methyl treatment.

Publication: Post-Hoc Analyses from the BEACON Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and T2DM

In BEACON, post hoc analyses demonstrated that treatment with bardoxolone methyl significantly reduced the risk of experiencing a composite renal endpoint consisting of ≥30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m², and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation) compared to placebo.

  • Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p < 0.0001).
  • Patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48 and 4 weeks after cessation of treatment.