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 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.
Alport Syndrome is caused by mutations in the genes encoding type IV collagen, a major structural component of the glomerular basement membrane, or 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. This leads to abnormal leakage of proteins through the GBM, and excessive reabsorption of protein in the proximal tubules of the kidney.
As in other forms of CKD, excessive reabsorption of protein in the tubules activates pro-inflammatory signaling pathways, which induce mitochondria to produce less cellular energy, or ATP, and increase the production of 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, or 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. This also reduces the overall surface area of the glomerulus that is available for filtration.
- Inflammation-associated ROS lead 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 underlying 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.
These anti-inflammatory and tissue-protective effects suppress the three processes detailed above that promote GFR loss. Bardoxolone methyl reverses endothelial dysfunction and pathogenic 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 scarring of the vasculature in the kidney. 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 in a number of animal models of renal injury and disease3,4,5. Bardoxolone methyl and related AIMs have also been shown to reduce inflammation and inhibit fibrosis in animal models of liver, skin, and lung injury or disease.
In addition to preclinical models of chronic renal disease, bardoxolone methyl has been evaluated in seven studies of patients with CKD caused by type 2 diabetes that enrolled approximately 2,600 patients. 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 (see table below).
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. Table 2 below shows the change in eGFR for both placebo and bardoxolone methyl patients in the BEAM (mid-dose) and BEACON trials.
In both BEAM and BEACON, bardoxolone methyl markedly reduced the proportion of patients with clinically-meaningful loss of kidney function. As shown in the table below, 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.
We are in the process of designing the Phase 2/3 trial. The clinical study will be an international, multi-center, double-blind, randomized, placebo-controlled Phase 2/3 trial studying the safety and effectiveness of bardoxolone methyl in slowing, halting, or reversing renal function decline in patients with Alport syndrome. The trial will enroll 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 will be open-label, and the primary endpoint will assess eGFR change at 12 weeks. These patients will be followed for two years and will not be included in the Phase 3 portion of the trial.
The Phase 3 portion will be designed to support registration and will randomize patients evenly to either bardoxolone methyl or placebo. The Phase 3 primary efficacy endpoint will be the change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo after one year. The eGFR change after one year 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 (off treatment) after one and two years. 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. Based on FDA guidance, if the trial is positive, the year one off treatment data could support accelerated approval under subpart H of the Food, Drug, and Cosmetic Act, and the year two off treatment data could support full approval. Reata plans to initiate the Phase 2 portion of the integrated Phase 2/3 trial in the first half of 2017.
- 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.