Historical Development with Bardoxolone Methyl

On June 2, 2014, Dr. Colin Meyer presented a Late-Breaking Presentation at the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Congress in Amsterdam. For Dr. Meyer's presentation, titled "Investigation of Serious Adverse Events in Bardoxolone Methyl Patients in BEACON", clickhere.

As Reata Pharmaceuticals' first clinical development candidate from the Antioxidant Inflammation Modulators class of synthetic triterpenoids, bardoxolone methyl (also known as RTA 402 or CDDO-Me) has been extensively studied in the clinic. Given the long-standing research describing the chemo- and radio-protective effects of Nrf2 activation and the anti-cancer activity of bardoxolone methyl and its analogs in preclinical models (see Reata's current program inImmuno-Oncology), bardoxolone methyl's clinical history began with a phase 1 first-in-human trial in patients with advanced solid tumors and lymphomas1.

First-In-Human Study

From April 2006 through March 2008, forty-seven patients with a variety of advanced cancers were enrolled and the safety of the bardoxolone methyl in a standard dose escalation scheme was evaluated.

Key Efficacy and Safety Findings:

  • Bardoxolone methyl was well tolerated at doses up to 900 mg/day.
  • Pharmacodynamic biomarkers indicated Nrf2 pathway activation (e.g., NQO1 mRNA levels) were increased in PBMCs.
  • Tumor biopsies showed decreased levels of NF-κB and cyclin D1 and increased frequencies of apoptosis, demonstrating positive anti-proliferative effects.
  • Ten patients with a variety of tumor pathologies experienced disease stabilization for 4 to 10 months.

Additionally, an increase in the estimated glomerular filtration rate (eGFR), an indicator of kidney function, was also observed1. The observation of improved eGFR in the phase 1 oncology trial led to further studies on the potential for efficacy of bardoxolone methyl in chronic kidney disease (CKD).

Phase 2a CKD Studies

The first CKD trial was a phase 2a study to test the effect of bardoxolone methyl on kidney function in patients with type 2 diabetes (T2D) and stage 3b-4 CKD2. Beginning in 2008, a small study of 18 eligible patients, 16 of which completed the study according to protocol, were treated with increasing doses of bardoxolone methyl for 56 days. The study achieved its primary efficacy endpoint, as demonstrated by a significant increase in eGFR from baseline.

Key Efficacy and Safety Findings:

  • Improvements in eGFR were seen in approximately 90% of patients and a dose- and time-dependent increase in eGFR was observed.
  • The eGFR change paralleled a significant reduction in serum creatinine and blood urea nitrogen, along with an increase in creatinine clearance, without a change in the 24-hour creatinine excretion rate.
  • Markers of vascular injury and inflammation were improved by treatment with bardoxolone.
  • No life-threatening adverse events or drug-related serious adverse events were reported2.

BEAM Study

To further characterize the effects of bardoxolone methyl on kidney function in patients with CKD and T2D, Reata initiated a phase 2 randomized, placebo-controlled 52-Week study (BEAM,NCT00811889) in patients with T2D and stage 3b-4 CKD3. Two hundred twenty-seven patients were assigned in a 1:1:1:1 ratio to receive placebo or one of three doses of bardoxolone methyl once daily.

Key Efficacy and Safety Findings:

  • Patients receiving bardoxolone methyl had significant increases in eGFR, as compared with placebo, at 24 weeks (p<0.001). The eGFR increases were maintained through week 52.
  • Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related and were not associated with markers of muscle damage.
  • Hypomagnesemia and mild increases in alanine aminotransferase levels were more common among patients receiving bardoxolone methyl.
  • Weight reduction was observed in all the study groups but was more pronounced in patients with an increased body-mass index BMI3.

The results of the BEAM trial supported further development of bardoxolone methyl in CKD and laid the foundation for the initiation of a larger, multi-national phase 3 program.

BEACON Study

From June 2011 through September 2012, a total of 2,185 patients underwent randomization in the phase 3 clinical trial, "Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events" (BEACON) to test the hypothesis that daily treatment with bardoxolone methyl reduces the risk of end-stage renal disease (ESRD) or death from cardiovascular causes among patients with T2D mellitus and stage 4 CKD4.

In October 2012, Reata, in consultation with the BEACON Steering Committee, decided to terminate the BEACON trial, based upon a recommendation of the Independent Data Monitoring Committee (IDMC). The precipitating factor in this decision stemmed from an increase in heart failure in the bardoxolone methyl group.

Key Efficacy and Safety Findings:

  • A total of 96 patients (8.8%) in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 (5.0%) in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). This excess in observed heart failure events in the bardoxolone methyl group was observed within the first four weeks after randomization4.
  • Bardoxolone methyl statistically significant increased eGFR above baseline through 48 weeks of treatment. In contrast, placebo-treated patients had mean decreases from baseline.
  • Fewer than 4% of bardoxolone methyl experienced post-baseline transaminase values that exceeded three times the upper limit of normal. Notably, no Hy's Law cases were observed, and the incidence of hepatobiliary disorder SAEs in the bardoxolone methyl group was approximately half the number observed in the placebo group.
  • Pharmacological effects on muscle cramps, magnesium levels, weight, and blood pressure were consistent with prior clinical experience.

After termination of the trial, completion of data collection, and database lock, Reata sought to better understand the cause of these events. Additional investigation of the BEACON data identified prior hospitalization for heart failure and baseline B-type natriuretic peptide (BNP), a marker of fluid retention, as predictors of heart failure hospitalizations in BEACON5. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo- treated patients was similar (at only 2% in each arm). Post-hoc analysis revealed thatexclusion of patients with these risk factors would have balanced the number of serious adverse events between treatment groups. In addition, bardoxolone methyl-treated patients in a BEACON sub-study had a statistically significant reduction in urine volume and sodium excretion at Week 4 relative to baseline5. These reductions were not observed in the placebo group, and a separate study revealed that decreased sodium excretion and urine output occurred in bardoxolone methyl patients with stage 4 CKD but not those with stage 3b CKD. These data suggest that bardoxolone methyl treatment may differentially affect sodium and water volume handling according to the clinical condition of subjects, having no clinically detectable effect in healthy volunteers or early-stage CKD patients, while apparently promoting fluid retention in patients with stage 4 CKD5. Thus, the pharmacologic promotion of acute fluid retention in patients with more advanced renal dysfunction, baseline fluid retention, cardiovascular disease history likely contributed to the increased risk for heart failure and fluid-related serious adverse events with bardoxolone methyl treatment observed in BEACON.

Notably, the clinical phenotype of fluid overload and heart failure associated with bardoxolone methyl treatment in BEACON was similar to that observed with endothelin receptor antagonists (ERAs) in advanced CKD patients. Importantly, preclinical data demonstrated that bardoxolone methyl modifies endothelin signaling6. While some ERAs have unacceptable risk-benefit profiles in late-stage CKD patients, they are safe and efficacious as approved therapies for patients with pulmonary arterial hypertension (PAH). Furthermore, the bardoxolone methyl-mediated hemodynamic effects on renal function, which preclinical data support are caused by improvements in endothelial dysfunction and suppression of smooth muscle cell contraction7, are potentially beneficial to PAH patients. Consequently, while a path forward in CKD is uncertain, these analyses have prompted additional clinical studies to test bardoxolone methyl in patients with PAH. In November 2013, Reata filed an IND for a phase 2 study ofbardoxolone methyl in PAH. The FDA allowed the study to proceed; it is currently underway (see Reata's current programs inCardiovascular).

Pharmacological Profile of Bardoxolone Methyl

The totality of data from preclinical and clinical studies demonstrate that bardoxolone methyl pharmacologically modulates the following clinical characteristics:

  • Serum Magnesium:Patients treated with bardoxolone methyl have mean decreases in serum magnesium levels that appear to be attenuated after 8 to 12 weeks of therapy. Moreover, these decreases do not correlate with QTcF increases and are not associated with increased risk for fatal or heart failure events. Analysis of serum and urinary magnesium from an open-label pharmacokinetic study in patients with Stage 3b and 4 CKD and type 2 diabetes (402-C-1102) showed that decreases in serum magnesium levels were not associated with changes in total urinary magnesium excretion, suggesting the decreases in serum magnesium levels are not secondary to renal loss8.
  • Liver Function Tests:In clinical studies of bardoxolone methyl, almost all patients had transient increases of transaminase enzymes upon initiation of treatment, which followed a consistent pattern and were not associated with elevations in bilirubin levels or other signs of liver toxicity. Bardoxolone methyl also increases ALT and AST protein levels in cell lines derived from non-hepatic tissues, such as colon, skeletal muscle, and kidney. These data indicate that bardoxolone methyl regulates transcription of ALT and AST in multiple organs, and suggest that the increases in transaminase levels observed in humans are related to the pharmacology of the drug and not due to liver toxicity.
  • Metabolic Effects:Decreases in weight have been observed following treatment with bardoxolone methyl in patients with CKD. The weight reduction is more pronounced in patients with increased body-mass index at baseline than in other patients. In addition, unchanged 24-hour urinary creatinine excretion suggests that weight loss is not associated with muscle wasting. Although the mechanism of the weight loss associated with bardoxolone methyl treatment in humans is not fully understood, it is hypothesized that bardoxolone methyl increases beta-oxidation and lipolysis of peripheral lipid stores, as has been observed with other AIMs in animals9.
  • Muscle Effects:Muscle spasms are the most frequently reported adverse event in clinical trials of bardoxolone methyl in patients with CKD and type 2 diabetes. Prominent laboratory findings associated with muscle toxicity, such as increased levels of serum markers, including creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), uric acid, phosphorus, and potassium levels, were not increased in bardoxolone methyl subjects. Notably, in BEACON and several Phase 2 studies, bardoxolone methyl decreased creatine kinase, which is associated with muscle inflammation and turnover. Muscle spasms may result from improved insulin sensitivity and glucose uptake.

References

  1. Hong, D.S., Kurzrock, R., Supko, J.G., He, X., Naing, A., Wheler, J., Lawrence, D., Eder, J.P., Meyer, C.J., Ferguson, D.A., et al. (2012). A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas. Clin. Cancer Res.18, 3396-3406.
  2. Pergola, P.E., Krauth, M., Huff, J.W., Ferguson, D.A., Ruiz, S., Meyer, C.J., and Warnock, D.G. (2011a). Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am. J. Nephrol.33, 469-476.
  3. Pergola, P.E., Raskin, P., Toto, R.D., Meyer, C.J., Huff, J.W., Grossman, E.B., Krauth, M., Ruiz, S., Audhya, P., Christ-Schmidt, H., et al. (2011b). Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. N. Engl. J. Med.365, 327-336.
  4. De Zeeuw, D., Akizawa, T., Audhya, P., Bakris, G.L., Chin, M., Christ-Schmidt, H., Goldsberry, A., Houser, M., Krauth, M., Lambers Heerspink, H.J., et al. (2013). Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med.369, 2492-2503.
  5. Chin, M.P., et al. (2014a). Risk Factors for Heart Failure in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl. Journal of Cardiac Failure.
  6. Chin, M.P., et al. (2014c). Mechanisms Contributing to Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease treated with Bardoxolone Methyl. Am. J. Neprhol.
  7. Aminzadeh, M., et al. (2013). The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease. Redox Biology. 1, 527-531.
  8. Chin, M.P., et al. (2014b). Patient PK Study manuscript.Planned.
  9. Saha, P., et al. (2010). The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Lepr db/db mice. J Biol Chem.285, 40581-40592.

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