Alport syndrome is a rare and serious hereditary disease that affects approximately 12,000 children and adults in the United States and 40,000 globally. Patients with Alport syndrome are normally diagnosed with the disease in childhood to early adulthood and have average GFR declines of 4.0 mL/min/1.73 m2 per year1. The progressive decline of the kidney’s ability to filter blood in Alport syndrome inexorably leads to renal failure and end-stage renal disease (ESRD). In males with the most prevalent subtype of Alport syndrome, approximately 50% require dialysis or kidney transplant by the age of 25. The incidence of renal failure increases to 90% by age 40 and nearly 100% by age 60 for these patients2. Similar to patients with other forms of chronic kidney disease (CKD), Alport patients receiving dialysis are at increased risk for cardiovascular disease and infections, which are the most common causes of death.
Currently, there are no approved therapies for the treatment of Alport syndrome. In July 2017, Reata received orphan drug designation for bardoxolone methyl for the treatment of Alport syndrome and announced initial data from the ongoing Phase 2 portion of the Phase 2/3 CARDINAL trial. We are enrolling patients in the Phase 3 portion and expect data in the second half of 2019.
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. The GBM is the primary filtration barrier in the kidney. The abnormal expression of type IV collagen causes loss of GBM integrity, which leads to abnormal leakage of proteins through the GBM and excessive reabsorption of protein in the proximal tubules of the kidney.
The GBM defects and leaked proteins in Alport syndrome, as in other forms of CKD, including hyperglycemia in diabetes and hypertension in cardiovascular disease, all activate pro-inflammatory signaling pathways. Excessive reabsorption of protein in the tubules activates pro-inflammatory signaling pathways, which induces mitochondrial dysfunction in which production of cellular energy, or ATP, is impaired in favor of production of mitochondrial reactive oxygen species (ROS). Overproduction of ROS is a central feature of inflammation and activates additional pro-inflammatory signaling complexes. This cascade of events induces chronic inflammation in multiple types of kidney cells, while also recruiting activated macrophages and other inflammatory effector cells to the renal interstitium.
Chronic inflammation in the kidney contributes to declining glomerular filtration rate (GFR) by at least three mechanisms:
- Inflammation-associated ROS cause endothelial cell dysfunction in the blood vessels of the glomerulus. This results in damage to the kidney vasculature and decreases the overall surface area of the glomerulus that is available for filtration.
- Inflammation-associated ROS cause contraction of mesangial cells in the kidney and reduces the overall surface area of the glomerulus that is available for filtration.
- Inflammation-associated ROS leads to fibrosis and structural changes within the kidney, including thickening of the GBM, further contributing to decline of GFR.
Mechanism of Action
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. Bardoxolone methyl binds to Keap1 and activates Nrf2, a transcription factor that increases cellular antioxidant content and promotes normal mitochondrial function by making reducing equivalents available for ATP production. This reduces mitochondrial ROS production and ROS-mediated activation of inflammatory signaling complexes. Through these effects, bardoxolone methyl restores mitochondrial production of ATP, increases production of antioxidants, reduces oxidative stress, and reduces pro-inflammatory signaling.
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 disease3,4,5. 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.
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, in response to high protein, as well as pressure overload in the setting of hyperfiltration, or increased kidney filtration driven by higher blood pressure in the organ, and dyslipidemia, or an abnormal amount of lipids in the blood.
Prior to initiating the current clinical development programs in PH and CKD caused by Alport syndrome, bardoxolone methyl was evaluated in multiple trials, enrolling 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 (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 and creatinine clearance, and significantly reduced uremic solutes (BUN, uric acid, and phosphate) in inverse correlation to eGFR increases.
In addition, Reata’s Asian development partner, Kyowa Hakko Kirin (KHK), is conducting a Phase 2 study of patients with Stage 3 and 4 CKD from type 2 diabetes (TSUBAKI) using the gold-standard technique to directly measure GFR, the inulin clearance method. KHK recently announced interim results from TSUBAKI demonstrating that bardoxolone methyl treatment resulted in a significant improvement 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 validate eGFR as a clinical endpoint for measuring improvement in renal function from bardoxolone methyl treatment. Taken together, the Reata and KHK CKD studies suggest that bardoxolone methyl treatment has the potential to produce consistent and meaningful improvements in renal function, as measured by inulin clearance, creatinine clearance, and eGFR.
The data from BEAM and BEACON demonstrate that eGFR improvements 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.
In both BEAM and BEACON, bardoxolone methyl markedly reduced the proportion of patients with clinically-meaningful loss of kidney function. In BEACON, at 48 weeks, bardoxolone methyl significantly reduced the proportion of patients with an eGFR loss of approximately 13%, 22%, and 33% of baseline eGFR. The proportion of patients with a loss of eGFR of 30% from baseline at any visit was reduced by 67% (p<0.001).
In both BEAM and BEACON, 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 increase in eGFR through one year of treatment and the presence of a sustained eGFR improvement 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.
During a meeting with the FDA in October 2016, we 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. We initially proposed a Phase 2 trial in Alport patients; however, the FDA suggested to us that there could be a more efficient path to registration utilizing a single trial with eGFR-based endpoints at one and two years.
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 CARDINAL. The study 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 patients will be followed for two years with eGFR measurements, including at weeks 48 and 100 on drug and 52 and 104 after withdrawal of drug for four weeks, and will not be included in the Phase 3 portion of the trial. In July 2017, Reata received orphan drug designation for bardoxolone methyl for the treatment of Alport syndrome and announced initial data from the ongoing Phase 2 portion of the study.
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 on 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.
Enrollment in the Phase 3 portion of CARDINAL began in August 2017. We expect to have the one year withdrawal data that could support accelerated approval in the second half of 2019.
- Rheault M, Gross O, Appel G, et al. Change in glomerular filtration rate and renal biomarkers in patients with chronic kidney disease due to Alport syndrome: interim results from the ATHENA study, a prospectively designed natural history study. Nephrol Dial Transplant 2016;31:i126.
- Jais J, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 2000;11:649-57.
- 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.
- Aminzadeh MA, Reisman SA, Vaziri ND, et al. The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease. Redox Biol 2013;1:527-31.
- Camer D, Yu Y, Szabo A, et al. Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fed diet. Chem Biol Interact 2016;243:10-18.