Alport Syndrome and Other Kidney Diseases
Reata is conducting a single, pivotal registrational Phase 2/3 study named CARDINAL to evaluate the safety and efficacy of bardoxolone methyl in patients with chronic kidney disease (CKD) caused by Alport syndrome. Alport syndrome is a rare and serious hereditary disease that affects approximately 12,000 people in the United States and 40,000 people globally. Alport syndrome is caused by mutations in the genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM) in the kidney.
Patients with Alport syndrome are normally diagnosed with the disease in childhood to early adulthood and have average glomerular filtration rate (GFR) declines of 4.0 mL/min/1.73 m2 per year30. The progressive decline of GFR in Alport syndrome patients leads to renal failure and end-stage renal disease (ESRD). Fifty percent of males with the most prevalent subtype of Alport syndrome require dialysis or kidney transplant by age 25. The incidence of renal failure in these patients increases to 90% by age 40 and nearly 100% by age 6031. Similar to patients with other forms of CKD, Alport syndrome patients receiving dialysis are at increased risk for cardiovascular disease and infections, which are the most common causes of death in these patients. Currently, there are no approved therapies for the treatment of Alport syndrome.
Reata recently announced primary endpoint and other 12-week data from the ongoing open-label Phase 2 portion of the CARDINAL trial (click here for data presentation). The Phase 2 portion of the trial enrolled 30 patients, and available data demonstrate that bardoxolone methyl significantly increased kidney function in Alport syndrome patients as measured by estimated GFR (eGFR). From a mean baseline eGFR of 54 mL/min/1.73 m2, data from patients showed a mean increase of 13.4 mL/min/1.73 m2 at Week 12 (p<0.000000001). All patients demonstrated increases in eGFR, with 87% of patients demonstrating a clinically meaningful increase in eGFR of at least 4.0 mL/min/1.73 m2 by Week 12, and 63% of patients demonstrated an increase in eGFR of at least 10.0 mL/min/1.73 m2. Additionally, 73% of patients had an improvement in CKD stage, and none worsened. As of the 12-week primary endpoint visit for the Phase 2 portion, no discontinuations or serious adverse events (SAEs) were reported, and reported adverse events (AEs) were generally mild to moderate in intensity.
In August 2017, Reata began enrolling patients in the Phase 3 portion of CARDINAL, and the company expects data from the study in the second half of 2019. Reata recently received orphan drug designation for bardoxolone methyl for the treatment of Alport syndrome. Bardoxolone methyl’s novel anti-inflammatory mechanism of action and clinical activity in Alport syndrome and diabetic CKD encourage the study of bardoxolone methyl in additional, rare kidney diseases. In October 2017, Reata began activating sites for a Phase 2 trial called PHOENIX of bardoxolone methyl in various rare forms of CKD, including autosomal dominant polycystic kidney disease, IgA nephropathy, type 1 diabetic CKD, and focal segmental glomerulosclerosis. The company anticipates that data from the individual cohorts of PHOENIX will be released throughout the second half of 2018 and 2019.
For an overview of Reata’s development program in CKD see this presentation.
How does bardoxolone methyl target pathogenic pathways in CKD?
Bardoxolone methyl was originally considered for development in cancer patients, and in two Phase 1 studies in cancer, bardoxolone methyl reduced serum creatinine levels, corresponding to an increase in eGFR. Since then, Reata and collaborators have extensively characterized the effects of bardoxolone methyl on the kidney (150+ published papers). Both acute and chronic kidney disease, regardless of initiating cause (infection, diabetes, hypertension, autoimmunity), have inflammation and immune activation in common1. Bardoxolone methyl targets these common inflammatory pathways that are implicated in CKD.
Bardoxolone methyl activates molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling. Bardoxolone methyl binds to Keap1 and consequently activates Nrf2, a transcription factor that promotes normal mitochondrial function by making reducing equivalents available for ATP production, and increases cellular antioxidant content. This reduces mitochondrial reactive oxygen species (ROS) production and ROS-mediated activation of inflammatory signaling complexes. Binding to Keap1 and activation of Nrf2 also inhibit NF-κB, the primary transcription factor producing proteins that promote inflammation and the production of ROS.
In the kidney, the first stage of the blood filtering process takes place in the glomerulus, which consists of a small tuft of capillaries containing endothelial cells, between which are large pores, and mesangial cells which are modified smooth muscle cells that lie between the capillaries. Tight coordination between these cell types is necessary for proper filtration. The pores between the endothelial cells allow for the free filtration of fluid, plasma solutes, and protein. When endothelial cells become dysfunctional, due to oxidative stress or other reasons, the pores can become more permeable and increase spillage of protein, which can drive further inflammatory signaling and oxidative stress. The mesangial cells regulate blood flow by their contractile activity, and contraction of the cells reduces surface area for filtration of the blood. Mesangial cells also remove proteins and other molecules trapped in the glomerular basement membrane, or filtration barrier.
In preclinical models, bardoxolone methyl reverses endothelial dysfunction and chronic, disease-related mesangial cell contraction, resulting in increased surface area of the glomerulus and increased GFR. Additionally, bardoxolone methyl inhibits activation of inflammatory and pro-fibrotic pathways that lead to structural remodeling and glomerulosclerosis.
As a result, bardoxolone methyl and closely related structural analogs have been shown to improve renal function, reduce inflammation, and prevent injury, remodeling, and fibrosis, or the thickening and scarring of connective tissue, in a number of animal models of renal injury and disease2-6. Specifically, bardoxolone methyl and analogs reverse endothelial dysfunction and mesangial cell contraction in response to angiotensin II, a hormone that causes vasoconstriction and subsequent increase in blood pressure, thereby increasing the surface area of the glomerulus and increasing GFR. Importantly, these increases in GFR were not due to effects on blood pressure, renal plasma flow, or pressure within the kidney in animals5.
Further, data from animal models relevant to chronic renal disease demonstrate that the compounds are anti-fibrotic and have protective effects on the renal interstitium, part of the extravascular space of the kidney responsible for modulating exchange among the tubular and vascular elements of the organ. Bardoxolone methyl and related analogs are protective in response to high protein, pressure overload in the setting of hyperfiltration2, increased kidney filtration driven by higher blood pressure, and dyslipidemia7, an abnormal amount of lipids in the blood.
How is it known that the increases in eGFR with bardoxolone methyl are reflective of true increases in GFR?
Prior to initiating the current clinical development program in CKD caused by Alport syndrome, bardoxolone methyl was evaluated in multiple trials. These trials enrolled approximately 3,100 people, of which approximately 1,900 received bardoxolone methyl, including patients with CKD caused by diabetes, patients with solid tumors or lymphoma, and healthy volunteers. These studies included a randomized, placebo-controlled 52-week Phase 2b study in Stage 3b/4 CKD patients (BEAM) and a large, multinational Phase 3 study (BEACON) that enrolled only patients with severe (Stage 4) CKD. In these studies, bardoxolone methyl treatment significantly increased eGFR, which is commonly used to assess kidney function and is determined by measuring the amount of creatinine that is filtered by the kidneys. Other measures of improved kidney function were also observed with bardoxolone methyl treatment, including increased creatinine clearance and significant reductions in uremic solutes (BUN, uric acid, and phosphate) that inversely correlated with eGFR increases.
Most important, Reata’s Asian development partner, Kyowa Hakko Kirin (KHK), conducted a Phase 2 study of patients with Stage 3 and 4 CKD from type 2 diabetes (TSUBAKI) using the gold-standard inulin clearance method to directly measure GFR. KHK recently announced interim results from TSUBAKI demonstrating that bardoxolone methyl treatment resulted in a significant increase in measured GFR, as assessed by inulin clearance, after 16 weeks of treatment compared to placebo. The increase in inulin clearance is similar in magnitude to the changes in eGFR reported in other studies with bardoxolone methyl and demonstrates that the eGFR increases with bardoxolone methyl reflect true increases in GFR.
Are the increases in eGFR from bardoxolone methyl sustained?
The data from BEAM and BEACON demonstrate that increases in eGFR from bardoxolone methyl can be sustained for at least one year on treatment. BEAM and BEACON included approximately 600 patients treated for one year or longer.
Moreover, bardoxolone methyl treatment increased eGFR relative to both baseline and placebo after cessation of drug for four weeks as shown below. Sub-therapeutic concentrations of drug are achieved within approximately 10 days after drug withdrawal. The sustained eGFR response through one year of treatment and the presence of an eGFR increase after withdrawal of drug suggest that the maladaptive structural deficits that contribute to declining kidney function may be improved over the course of longer-term treatment with bardoxolone methyl.
Importantly, the profile of eGFR increases with bardoxolone methyl is inconsistent with pressure-mediated hyperfiltration, which accelerates glomerular damage. Agents that increase eGFR solely through increases in intraglomerular pressure, such as certain types of calcium channel blockers (e.g., amlodipine in the AASK study8), would be expected to cause a rapid decline in kidney function below placebo rates after withdrawal of drug due to pressure-mediated injury. By contrast, the withdrawal data from BEAM and BEACON showed a residual eGFR increase from baseline after cessation of treatment for four weeks, while an eGFR decline from baseline was observed in placebo patients. As noted above, in animals, a bardoxolone methyl analog prevents fibrosis, preserves kidney function, and slows CKD progression in the 5/6 nephrectomy model of hyperfiltration-induced chronic kidney failure2. Thus, the withdrawal data with bardoxolone methyl may be indicative of disease-modifying remodeling that leads to partially retained benefit after cessation of study drug.
Despite early termination of the BEACON study as discussed below, bardoxolone methyl increased eGFR and reduced kidney failure outcomes in BEACON. Bardoxolone methyl significantly increased eGFR (p<0.0001) and the increases were durable through at least Week 489. Further, bardoxolone methyl treatment was associated with a decreased risk of adverse kidney outcomes in BEACON, as assessed by kidney serious adverse events and ESRD events. Post-hoc analyses showed that bardoxolone methyl significantly decreased the likelihood of a kidney failure event in a composite consisting of two events that have recently been established as surrogate endpoints for progression to kidney failure in clinical trials of CKD14,15, ≥30% decline in eGFR and eGFR < 15 mL/min/1.73 m2, as well as adjudicated ESRD events in BEACON.
How can bardoxolone methyl affect kidney function in patients with Alport syndrome?
Bardoxolone methyl has the potential to address the causes of GFR loss in Alport syndrome patients because it activates molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting ROS-mediated pro-inflammatory signaling. There are no currently approved therapies for the treatment of CKD caused by Alport syndrome. The goal of current disease management is to slow the progression of CKD, beginning with anti-hypertensives, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, aldosterone, and diuretics, all of which are intended to reduce the levels of protein found in patient urine. Once patients reach ESRD, they require dialysis or renal transplantation.
During 2016, we sought and received guidance from the FDA on key elements of a single, pivotal Phase 2/3 clinical trial that would study the safety and efficacy of bardoxolone methyl in patients with CKD caused by Alport syndrome. Our clinical study in chronic kidney disease caused by Alport syndrome, named CARDINAL, was initiated in February of 2017, and is enrolling patients in the Phase 3 portion of the study. CARDINAL is an international, multi-center, double-blind, randomized, placebo-controlled Phase 2/3 trial studying the safety and effectiveness of bardoxolone methyl in patients with Alport syndrome. The trial is enrolling patients from age 12 to 60 with eGFR values between 30 to 90 mL/min/1.73 m2. The Phase 2 portion of the study is open-label, and the primary endpoint assesses eGFR change at 12 weeks. These Phase 2 patients will not be included in the Phase 3 portion of the trial.
The Phase 2 portion of the study met its primary efficacy endpoint and showed that bardoxolone methyl increased eGFR by 13.34 mL/min/1.73 m2 (n=30, p<0.0000000015, 95% CI 10.54 to 16.3) after 12 weeks of treatment. All patients completed the treatment period without any discontinuations. The increases in eGFR were consistent across multiple subgroups, including age, gender, baseline albuminuria, and CKD stage, and all patients had increases from baseline. Notably, 87% had an increase of at least 4 ml/min/1.73 m2, which is the approximate annual rate of decline in kidney function in patients with Alport syndrome. The improvements in eGFR translated to an improvement in CKD stage for 22/30 (73%) patients. No serious adverse events or discontinuations were reported, and adverse events were generally mild to moderate in intensity.
The Phase 3 portion of CARDINAL is designed to support registration and will randomize approximately 150 patients evenly to either bardoxolone methyl or placebo. The Phase 3 primary efficacy endpoint is the change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo after one year. The eGFR change after 48 weeks will be measured while the patients are on treatment, and the key secondary endpoints will be the change from baseline in eGFR after withdrawal of drug for four weeks (retained eGFR) after one year. After the initial withdrawal, patients will be restarted on study drug with their original treatment assignments and will continue study drug for a second year. The eGFR change at two years will also be measured after 100 weeks while the patient is on treatment and after withdrawal of drug for four weeks (retained eGFR). Based on FDA guidance, if the trial is positive, the year one retained eGFR data could support accelerated approval under subpart H of the Food, Drug, and Cosmetic Act, and the year two retained eGFR data could support full approval.
What happened in BEACON and how can the risk of acute fluid retention be managed?
BEACON was a large Phase 3 trial designed to meet FDA requirements that bardoxolone methyl delay the time to ESRD or death. It was conducted in only advanced (Stage 4) CKD patients because earlier stage patients would not have contributed to the ESRD endpoint. The BEACON trial was terminated in 2012 for safety concerns in response to a recommendation from the independent data monitoring committee, which identified a significant increase in the risk of heart failure hospitalizations or death from heart failure with bardoxolone methyl treatment (96 [8.8%] bardoxolone methyl-treated patients versus 55 [5.0%] placebo patients)9.
After BEACON was terminated, analyses revealed the following:
(a) the primary reason for the increase in adjudicated heart failure events in the treatment group was fluid overload (not direct cardiotoxicity),
(b) patients at risk, on average, were in subclinical heart failure prior to randomization (mean baseline BNP 550 pg/mL), and
(c) the imbalance in events occurred only in the first four weeks after randomization10.
The profile of fluid overload in BEACON was similar to that previously observed in CKD patients with the endothelin receptor antagonist, avosentan (ASCEND study). Urinary protein induces endothelin signaling and vasoconstriction in Stage 4 and 5 CKD patients and bardoxolone methyl has been shown to modulate endothelin signaling in kidneys10. Because endothelin signaling is dysregulated in the kidneys of patients with lower eGFR values, acute modulation of this pathway by bardoxolone methyl in a Stage 4 CKD patient population may have promoted acute sodium and water retention, which translated to frank fluid overload in susceptible patients. Urinary data from BEACON and a separate Phase 2 study showed sodium and volume retention in Stage 4 but not Stage 3 CKD patients10.
Post hoc analysis identified two risk factors that are predictors of fluid overload events: elevated baseline B-type natriuretic peptide (BNP) and prior hospitalization for heart failure11. Patients in BEACON without these risk factors showed no imbalance in heart failure events or mortality, which is consistent with early Phase 1 and Phase 2 clinical studies that primarily enrolled CKD stage 3 patients who had better baseline kidney function and less cardiovascular disease12,13. Exclusion of at-risk patients also improved the distribution of ESRD, primary composite events, and SAEs in BEACON11. (See Late-Breaking Presentation at the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Congress in Amsterdam in June 2014, Investigation of Serious Adverse Events in Bardoxolone Methyl Patients in BEACON, that discusses the clinical profile, risk factors, and likely mechanistic explanation of key adverse events uncovered in the BEACON trial.)
Using the identified risk factors for heart failure from BEACON, patients with elevated BNP and prior history of heart failure are excluded from ongoing and future studies of bardoxolone methyl. In addition, more frequent visits during the first few weeks of treatment, additional assessment of BNP, and daily monitoring of weight is used to assess for signs and symptoms of fluid overload. These risk mitigation features have been implemented in clinical programs with bardoxolone methyl that have enrolled approximately 500 patients, which have not shown increased risk for fluid overload to date.
What other findings have been observed in clinical trials with bardoxolone methyl?
Throughout the on-going clinical development of bardoxolone methyl, some clinical observations have been observed repeatedly in multiple studies. Preclinical studies have been conducted to investigate and help understand these clinical findings, and a summary of clinical observations and supporting preclinical data is provided below.
- Decreased body weight
Some patients in prior clinical trials of bardoxolone methyl have lost weight during the trials. When observed, weight reduction with bardoxolone methyl tended to be more pronounced in patients with higher body mass index (BMI)19 and correlated with reductions in waist circumference20. Multiple preclinical studies have demonstrated that bardoxolone methyl reduces fat production and promotes break-down (beta-oxidation) of fat to be used as fuel for energy production. These effects are associated with improved blood sugar control, reduced fat, and preservation of muscle mass in animals16-18. We hypothesize that similar effects may be associated with the weight loss observed in some clinical trial participants. Moreover, creatinine is a by-product of muscle metabolism, and its excretion is associated with muscle wasting. In clinical trials with bardoxolone methyl, urinary creatinine levels were generally unchanged, suggesting that the observed weight loss was not caused by muscle wasting12.
- Increased proteinuria
Increases in urinary protein have been observed in CKD patients treated with bardoxolone methyl in previous clinical trials. In CKD, damage to the glomerular filtration barrier results in loss of selectivity, increased filtration of protein, and subsequent proteinuria. When GFR increases, the increased flow delivers more albumin to proximal tubules and decreases protein reabsorption in tubules21. Because most water is reabsorbed and urine volume is generally constant, the increased protein is shunted to the same urinary volume, thereby increasing the urinary albumin concentration in a manner that does not reflect further loss of filtration selectivity. The increases in urinary protein that have been observed in CKD patients treated with bardoxolone methyl in clinical trials are consistent with the increases in flow and GFR9. The increases in proteinuria are significantly correlated with eGFR increases. Moreover, when normalized by eGFR, the amount of excreted urinary protein is unchanged from baseline22. The increases in proteinuria with bardoxolone methyl have not been associated with other signs of kidney injury. These clinical observations are consistent with data from animal models of protein overload-induced secondary nephropathy, where bardoxolone methyl has shown a protective effect4.
- Increases in transaminases (LFT)
In clinical trials, transaminase increases with bardoxolone methyl have been observed that are transient and reversible, with a clinical pattern that is distinct from that observed with liver injury. The transaminases ALT and AST are enzymes that are measured in the blood to assess liver function and are often referred to as LFTs. Transaminases, including ALT and AST, also play a critical role in cellular energy metabolism, and are produced in many organs, including the liver, kidney, muscle, and others23. The biological target of bardoxolone, Nrf2, has been shown to regulate cellular production of transaminases in liver and other tissues, such as kidney, muscle, and colon tissue, and their production is increased in response to bardoxolone methyl24. In clinical trials, bardoxolone methyl was not associated with any other signs of liver injury, and there have been no reports of severe liver injury or failure (Hy’s Law cases). In animal models, bardoxolone methyl and close analogs are protective against liver injury25-27.
- Decrease in serum magnesium
Decreases in the levels of the enzyme creatine kinase have been observed with bardoxolone methyl in some clinical trials. Magnesium is an element that is used in tissues for energy metabolism, and it is also found at much lower concentrations in the blood. Both creatine kinase and magnesium are necessary in the conversion of ATP to ADP for the production and maintenance of the body’s energy supply. We hypothesize that decreases in magnesium in the blood may reflect an intracellular shift to higher energy-demanding cells, such as muscle cells. Correlations between magnesium and creatine kinase decreases in patients may therefore reflect improved muscle metabolism.
Importantly, unchanged excretion of magnesium in the urine and excretion of other electrolytes suggest that decreases in serum magnesium are not due to kidney problems (i.e., renal magnesium wasting or tubular toxicity). Unchanged magnesium levels in sublingual epithelial cells also support the hypothesis that total body magnesium depletion does not occur. Decreases in magnesium have not been associated with increased stomach or cramping side effects28. Decreases in magnesium with bardoxolone have also not been associated with irregular heart rhythms (as assessed by changes in the QT interval). In a cardiovascular safety study, bardoxolone methyl did not increase the QT interval at doses as high as 80 mg.
- Muscle spasms
Muscle spasms are the most commonly reported side effect reported in clinical trials with bardoxolone methyl. Similar muscle spasms have been reported with insulin treatment in diabetics. In vitro, a bardoxolone methyl analog increased the conversion of glucose to energy in cultured muscle cells29. Thus, the etiology and clinical profile of the muscle spasms in patients treated with bardoxolone methyl may be similar to exercise-induced muscle cramps. Importantly, the spasms observed in clinical trials have not been associated with increased markers of muscle toxicity, such as lactate dehydrogenase, which is released during tissue damage, or increases in other serum electrolytes such as phosphorous or potassium levels. Instead, decreases in the levels of the enzyme creatine kinase have been observed in multiple trials with bardoxolone methyl, which is consistent with improved muscle metabolism.
Is bardoxolone methyl being studied in other forms of CKD?
The inflammatory processes that promote disease progression in diabetic CKD and Alport syndrome are similar to those underlying other forms of CKD. Bardoxolone methyl’s novel anti-inflammatory mechanism of action and clinical activity in Alport syndrome and diabetic CKD therefore encourage the study of bardoxolone methyl in additional, rare kidney diseases. Site activation is currently underway for the PHOENIX program studying bardoxolone in four additional rare causes of CKD. Similar to the Phase 2 portion of the CARDINAL study of bardoxolone in CKD caused by Alport syndrome, PHOENIX will be an open-label trial of bardoxolone orally-administered once-daily for 12 weeks, with a primary efficacy endpoint of change from baseline in the eGFR at week 12. The PHOENIX study will enroll patients with autosomal dominant polycystic kidney disease, IgA nephropathy, CKD associated with type 1 diabetes and focal segmental glomerulosclerosis, with approximately 20 to 30 patients enrolled per cohort. The company anticipates that data from the individual cohorts of PHOENIX will be released throughout the second half of 2018 and 2019.
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- Hisamichi, M. et al. Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury. Hypertens. Res.(2017).
- Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria. Poster (TH-PO717) American Society of Nephrology Meeting, 2010. Reproduced here with permission of ASN.
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