Kidney Effects in the MOXIe Trial: Presentation at ERA-EDTA 2020

In Part 2 of the Phase 2 MOXIe study of omaveloxolone in patients with Friedreich’s ataxia, a rapid, continuous decline in kidney function as measured by eGFR was observed in the placebo group. Omaveloxolone treatment for 48 weeks was associated with an increase in eGFR. These increases were durable and sustained throughout one year of treatment, similar to results observed with its analog, bardoxolone methyl, in clinical trials for various forms of CKD.

  • The rate of eGFR decline in patients with FA was equal to or greater than many forms of CKD.
  • Rapidly progressive loss of kidney function in patients without traditional risk factors for CKD highlight the role of mitochondrial dysfunction in progression of CKD.
  • Placebo-corrected increases in patients treated with omaveloxolone were durable through one year of treatment.

KIDNEYCODE: A Genetic Testing Program for Patients with Chronic Kidney Disease: Presentation at ERA-EDTA 2020

Reata and Invitae are sponsoring KIDNEYCODE, a no-charge genetic testing program, to help nephrologists identify patients with genetic forms of CKD.

  • Seventy-eight percent of patients with eGFR below normal, a family history of CKD, and hematuria have been found to have Alport syndrome in the KidneyCode program including variants of uncertain significance in COL4A3, COL4A4, and COL4A5 genes.
  • Of the tests that have results that we can access, approximately half have been positive for Alport syndrome, and half of these patients were previously misdiagnosed with other forms of CKD including variants of uncertain significance in COL4A3, COL4A4, and COL4A5 genes.

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.

Data Presentation: Topline Results from Year One of the CARDINAL Study of Bardoxolone Methyl in Alport Syndrome

Phase 3 Year 1 portion of the CARDINAL study of bardoxolone methyl in patients with chronic kidney disease caused by Alport syndrome met its primary and key secondary endpoints. 

  • After 48 weeks of treatment, patients treated with bardoxolone methyl had a statistically significant improvement compared to placebo in mean estimated glomerular filtration rate (eGFR).
  • After 48 weeks of treatment and a four-week withdrawal period, patients treated with bardoxolone methyl had a statistically significant improvement compared to placebo in mean off-treatment eGFR.
  • Bardoxolone methyl treatment was generally reported to be well-tolerated and showed a similar safety profile to the Phase 2 portion of the CARDINAL study.

Data Presentation: Positive Topline Pivotal MOXIe Data

Reata announced that the registrational Part 2 portion of the MOXIe Phase 2 trial of omaveloxolone in patients with Friedreich’s ataxia met its primary endpoint of change in the modified Friedreich’s Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment.

  • Part 2 of MOXIe, an international, multi-center, double-blind, placebo-controlled, randomized registrational Phase 2 trial, enrolled 103 patients with FA.
  • Omaveloxolone treatment met the primary endpoint of the study producing a statistically significant, placebo-corrected 2.40 point improvement (decrease) in mFARS (n=82; p=0.014).
  • Omaveloxolone was generally reported to be well tolerated in this study.

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.

Analyses from a Phase 2 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): The PHOENIX Study: Presentation at ASN KidneyWeek 2018

PHOENIX was a Phase 2, open-label, multi-center, US-only trial with four separate cohorts of patients with ADPKD, IgAN, T1D CKD, or FSGS. Bardoxolone methyl treatment in patients with ADPKD resulted in significant increase in kidney function as measured by eGFR at Week 12 from baseline.

  • ADPKD affects approximately 400,000 people and is leading inheritable cause of kidney failure in the US.
  • Bardoxolone methyl significantly improved eGFR (+9.3 mL/min/1.73 m²) from baseline in patients with ADPKD that historically declined ~4.8 mL/min/1.73 m² annually.
  • Bardoxolone methyl was well-tolerated without any drug-related SAEs, changes in blood pressure, or evidence of fluid overload.

Analyses from a Phase 2 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with IgA Nephropathy: The PHOENIX Study: Presentation at ASN Kidney Week 2018

PHOENIX was a Phase 2, open-label, multi-center, US-only trial with four separate cohorts of patients with ADPKD, IgAN, T1D CKD, or FSGS. Bardoxolone methyl treatment in patients with IgA nephropathy resulted in significant increase in kidney function as measured by eGFR at Week 12 from baseline.

  • IgAN is the most prevalent primary chronic glomerular disease and affects approximately 120,000 patients in the US.
  • Bardoxolone methyl treatment resulted in a significant eGFR increase of 8.0 mL/min/1.73 m² at Week 12 from baseline in patients with IgAN. 
  • Bardoxolone methyl was well-tolerated without any drug-related SAEs, changes in blood pressure, or evidence of fluid overload.

Analyses from a Phase 2 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Type 1 Diabetes (T1D CKD): The PHOENIX Study: Presentation at ASN KidneyWeek 2018

PHOENIX was a Phase 2, open-label, multi-center, US-only trial with four separate cohorts of patients with ADPKD, IgAN, T1D CKD, or FSGS. Bardoxolone methyl treatment in patients with T1D CKD resulted in significant increase in kidney function as measured by eGFR at Week 12 from baseline.

  • Type 1 diabetes (T1D) affects an estimated 1.25 million people in the US and CKD affects approximately 10-20% of patients with T1D or roughly 150,000 people in the US.
  • Bardoxolone methyl significantly improved eGFR (+5.5 mL/min/1.73 m²) from baseline in patients with T1D CKD.
  • Bardoxolone methyl was well-tolerated without any drug-related SAEs, changes in blood pressure, or evidence of fluid overload.

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.

Data Presentation: Reata Announces Improvements in Kidney Function with Bardoxolone Methyl Maintained for Two Years in PAH Patients from LARIAT Trial

Reata announced results from the long-term follow up portion of the LARIAT study demonstrating that pulmonary arterial hypertension patients treated with bardoxolone methyl experienced kidney function improvements that were durable for two years and not associated with adverse outcomes.

  • Patients in the placebo-controlled, double blind phase of LARIAT had impaired kidney function upon study entry with an eGFR averaging 75.6 mL/min/1.73 m². Patients who received treatment with bardoxolone methyl (n=71) had significantly increased eGFR compared to placebo (n=30) by 10.6 mL/min/1.73 m² (p<0.0001) after 16 weeks of treatment.
  • After 56 weeks of treatment, patients experienced a significant, mean increase in eGFR of 10.7 mL/min/1.73 m² from baseline (p<0.0001), and after 104 weeks of treatment, patients experienced a significant, mean increase in eGFR of 11.3 mL/min/1.73 m² from baseline (p<0.0001).
  • 88% of patients on bardoxolone methyl who reached week 104 maintained increases in eGFR above baseline after two years of 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.