– Conference call and webcast
- Received Guidance from the
FDAon Key Design Aspects of a Single, Pivotal Trial in Alport Syndrome with an eGFR-Based Endpoint
- Alport Syndrome is an Orphan Disease that Affects Children and Adults and has No Approved Therapy
- Alport Syndrome and Diabetic Chronic Kidney Disease have Similar Characteristics
- Reata Expects Data From Prior CKD Program of 2,600 Patients to Translate to Alport Syndrome
“We approached the
Alport syndrome is a rare and serious hereditary disease with no approved therapies that affects approximately 12,000 people in
“The Alport Syndrome Foundation works to encourage the development of therapies to meet patients’ needs. We are grateful to Reata for engaging us in this process and recognizing the crucial role of the patient perspective,” said
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
Bardoxolone methyl is currently being studied in a Phase 3 registrational study (“CATALYST”) in patients with connective tissue disease-associated pulmonary arterial hypertension (“CTD-PAH”). Although Alport syndrome and CTD-PAH have different etiologies and inflammatory stimuli, at a molecular level, mitochondrial dysfunction, inflammation, and proliferative signaling are common to the pathophysiology of both diseases. The anti-inflammatory and anti-fibrotic properties of bardoxolone methyl may therefore be relevant to preventing remodeling of the pulmonary vasculature in CTD-PAH as well as inhibiting structural alterations and glomerulosclerosis in Alport syndrome.
Alport Syndrome and the Pharmacological Rationale for Treatment with Bardoxolone Methyl
Patients with Alport syndrome are usually 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 GFR in Alport syndrome inexorably leads to renal failure and the need for dialysis or kidney transplant. In males with the most prevalent subtype of Alport syndrome, the median age at onset of ESRD is 25 years. The incidence of renal failure increases to 90% by age 40 and nearly 100% by age 60 for these patients2. Currently, there are no approved therapies for the treatment of Alport syndrome.
Alport Syndrome is a rare, genetic disease caused by mutations in the genes encoding type IV collagen, a major structural component of the glomerular basement membrane (“GBM”) in the kidney. The abnormal expression of type IV collagen causes loss of GBM integrity, abnormal leakage of proteins (such as albumin) through the GBM, and excessive reabsorption of protein in the proximal tubules of the kidney. Like other forms of CKD, excessive reabsorption of protein in the tubules induces oxidative stress, chronic inflammation in kidney cells, and renal interstitial inflammation and fibrosis.
Reata believes 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 multiple cellular processes that conspire to promote GFR loss. Bardoxolone methyl and closely related structural analogs have been shown to improve renal function, reduce inflammation, and prevent injury, remodeling, and fibrosis in many animal models of renal injury and disease3,4,5.
Development History of Bardoxolone Methyl in Patients with CKD from Type 2 Diabetes
The pathogenic role of inflammation and declining renal function in CKD from Alport syndrome is similar to that of CKD caused by type 2 diabetes. Because of this, in designing the Phase 3 trial, Reata has relied upon the clinical trial experience of bardoxolone methyl in patients with CKD from diabetes to estimate the potential treatment effect in Alport syndrome.
Bardoxolone methyl has been tested 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, significantly reduced uremic solutes (BUN, uric acid, and phosphate) in inverse correlation to eGFR increases, and numerically reduced renal SAEs and ESRD events.
Reata’s Asian development partner,
Table 1: Overview of Bardoxolone Methyl Studies Demonstrating Significant Improvements in Renal Function
|Study||Phase/Country||Patient Population||Mean Placebo-corrected ∆eGFR (mL/min/1.73m2)a|
|402-C-0903 (BEACON)||3/Global||CKD/Diabetes||6.4 (p<0.001 vs PBO)c|
|402-C-0804 (BEAM)||2/US||CKD/Diabetes||8.6 (p<0.001 vs PBO)|
|RTA402-005 (TSUBAKI)||2/Japan||CKD/Diabetes||Data not yet publicly disclosed|
|402-C-0801 (Stratum 1)||2a/US||CKD/Diabetes||6.7 (p<0.001)b|
|402-C-0801 (Stratum 2)||2b/US||CKD/Diabetes||7.2 (p<0.001)b,c|
|402-C-1302 (LARIAT)||2/US||Pulmonary hypertension||14.7 (p<0.001 vs PBO)|
a) Unless noted, data are differences between mean eGFR changes from baseline for bardoxolone methyl versus placebo groups and p-values calculated comparing the difference in means between bardoxolone methyl and placebo groups.
b) Data are mean eGFR changes from baseline for bardoxolone methyl patients and p-values are calculated from two-sided paired t-tests comparing eGFR change to 0.
c) Study also demonstrated a significant increase in creatinine clearance.
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.
Table 2: Changes from Baseline in eGFR After One Year in BEAM and BEACON
eGFR ± SD
|Change from Baseline in eGFR|
|BEACON||498||22.9 ± 4.3||7.2||6.8|
|BEAM||92||31.9 ± 6.6||11.6||15.5|
Notably, in both BEAM and BEACON, bardoxolone methyl markedly reduced the proportion of patients with clinically-meaningful loss of kidney function. For example, 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 (Table 3). The proportion of patients with a loss of eGFR of 30% from baseline at any visit was reduced by 67% (p<0.001).
Table 3: Percentage of Patients with Large Losses of Kidney Function in BEACON
|∆eGFR < -3.0 by WK48||20||%||67||%||p<0.001|
|∆eGFR < -5.0 by WK48||14||%||37||%||p<0.001|
|∆eGFR < -7.5 by WK48||8||%||16||%||p<0.01|
|∆eGFR < -30% (any visit)||4||%||12||%||p<0.001|
Most importantly, in both BEAM and BEACON, bardoxolone methyl treatment increased eGFR relative to both baseline and placebo after cessation of drug for four weeks (Table 4). 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.
Table 4: Retained eGFR Benefit After Withdrawal of Bardoxolone Methyl
Termination of Diabetic CKD Program and Transition to PAH and Alport Syndrome Indications
Reata terminated its development program in CKD caused by type 2 diabetes in 2012 when the Phase 3 BEACON study was stopped for a safety concern. After the trial was terminated, analysis revealed that there was a small but significant imbalance in heart failure events (placebo-corrected excess of 3.8% or 1 in 26 patients). The reason for the increase in heart failure events was fluid overload that occurred only in the first four weeks after randomization. There was no increase in risk for fluid overload (as compared to placebo) after the first four weeks of treatment, and patients with fluid overload events who were treated with intravenous diuretics resolved their symptoms.
Importantly, the analysis demonstrated that three risk factors were predictors of fluid retention events and could be used to exclude patients at risk in future trials: severe (Stage 4) CKD, prior hospitalization for heart failure, and baseline elevation in B-type natriuretic peptide (BNP) a blood-based measure of fluid overload. In effect, patients with severe CKD near ESRD with a history of heart failure, and who were already retaining excess fluid and were in or near heart failure prior to receiving bardoxolone methyl, were at risk of retaining additional fluid. Patients without these risk factors showed no imbalance in heart failure events or mortality, which is consistent with the Phase 2 studies conducted by Reata (including BEAM) that primarily enrolled Stage 3 CKD patients and did not show a risk of fluid overload.
Following termination of BEACON, Reata transitioned development of bardoxolone methyl to pulmonary arterial hypertension. Reata communicated its analysis of the BEACON risk factors and its risk mitigation strategy for managing acute fluid retention to the
Conference Call Information
Reata will host a conference call at
Analysts and investors can participate in the conference call by dialing toll-free (844) 348-3946 for domestic callers and (213) 358-0892 for international callers, using the conference ID 19858093.
The webcast link is http://edge.media-server.com/m/p/fn4m7g6a.
About Bardoxolone Methyl
Bardoxolone methyl is an experimental, oral, once-daily antioxidant inflammation modulator that 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, a protein that is activated during the resolution of a healthy inflammatory response once the pathogenic threat or tissue damage is resolved. Binding to Keap1 activates Nrf2, a transcription factor that promotes normal mitochondrial function, increases production of antioxidant and detoxification enzymes, reduces oxidative stress, and reduces pro-inflammatory signaling.
For more information on the Foundation and Alport Syndrome, please visit www.alportsyndrome.org.
This press release includes certain disclosures which contain “forward-looking statements,” including, without limitation, statements regarding the success, cost and timing of our product development activities and clinical trials, our plans to research, develop and commercialize our product candidates, our ability to obtain and retain regulatory approval of our product candidates, estimates of our expenses and our needs for additional financing, and our ability to obtain additional financing for our product development activities and existing and future clinical trials and pre-clinical programs. You can identify forward-looking statements because they contain words such as “believes,” “will,” “may,” “aims,” “plans” and “expects.” Forward-looking statements are based on Reata’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements are set forth in Reata’s filings with the
1 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.
2 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.
3 Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria.
4 Aminzadeh MA,
5 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.
Reata Pharmaceuticals, Inc.(972) 865-2219 email@example.com http://news.reatapharma.com Investor Relations: The Trout Group Lee M. Stern, CFA (646) 378-2922 IR@reatapharma.com