Reata Pharmaceuticals announced plans to initiate a study using the drug bardoxolone methyl in the treatment of chronic kidney disease caused by Alport syndrome. The clinical trial (CARDINAL) will study how bardoxolone methyl affects the chronic inflammation and decline in kidney function that are key features of Alport syndrome.
Almost all patients with Alport syndrome develop end-stage renal disease (ESRD), and approximately 50% of male patients with the predominant form require dialysis or kidney transplant by the age of 25. Women are also impacted, often experiencing delayed symptoms, although some are impacted similarly to men. There are currently no approved therapies for Alport syndrome.
What is a Phase 2/3 trial?
Before testing a new drug on patients with a specific condition, any new therapy is first tested on healthy individuals to look for side effects and determine the ideal dosage. This has already been completed for bardoxolone methyl.
In a Phase 2 trial, the drug is administered to a small number of patients over an extended period. Researchers watch to see if patient health improves and if there are any safety concerns.
Once a Phase 2 trial shows the drug benefits patients, it is administered to a larger group of patients during a Phase 3 trial. Researchers continue to evaluate the safety and effectiveness of the medication.
Reata Pharmaceuticals has already completed prior studies of the drug for patients with chronic kidney disease (CKD) caused by type 2 diabetes with favorable results. They are now testing its effectiveness on patients with Alport syndrome. Because of the other data on CKD patients, the FDA has approved a Phase 2/3 study. This means that instead of running back-to-back, the Phase 2 and Phase 3 studies will run concurrently (or at the same time). This shortens the overall period the drug is in clinical trial, and thus how long before the drug could potentially be available to patients.
Both phases of the trial will be international and involve multiple sites. Genetic testing and baseline (or beginning) estimated glomerular filtration rate (eGFR) will be completed as part of the trial enrollment intake process. Both phases will run for two years, with a 4-week withdrawal at the one-year point, before the treatment will be resumed. Patients who are currently using an ACE inhibitor or ARB will be allowed to continue this medication in addition to study participation medication.
What is the Phase 2 trial design?
The Phase 2 portion of the study will involve up to 30 patients who will all receive the active drug. The trial will enroll patients from age 12 to 60 with eGFR values between 30 and 90.
What is the Phase 3 trial design?
The Phase 3 portion will enroll up to 180 patients using the same criteria as the Phase 2 study, except 50% of patients will receive the active drug and 50% will receive a placebo. A placebo is a version of medication that looks like the active drug but contains no active ingredient. Researchers will observe changes from the baseline eGFR in patients receiving the active drug compared to the same changes in patients receiving a placebo.
Placebos are an important part of the research process. A double-blind, randomized trial means the decision on who gets the active drug vs. the placebo is completely random. This way neither the researchers nor the patients know if a specific participant is receiving the active medication or not. This is important because the researchers need to be able to identify normal changes vs. changes because of the drug they are testing.
What do we know about bardoxolone methyl?
Bardoxolone methyl is a once-daily oral medication that promotes normal mitochondrial function and potentially reduces kidney inflammation. It has been studied in seven studies involving approximately 2,600 patients, including a Phase 3 international study of patients with severe (Stage 4) CKD from type 2 diabetes. In these studies, bardoxolone methyl treatment significantly increased eGFR and creatinine clearance compared to baseline and placebo.
Reata terminated its development program in CKD caused by type 2 diabetes when the Phase 3 study was stopped for a safety concern. The concern involved a small percentage of patients who experienced an increase in heart events because of fluid retention, which resolved upon patients receiving diuretics. Further analysis revealed that these patients all had prior history of heart failure risk factors. Patients without these risk factors showed no changes in heart failure events, which is consistent with Phase 2 study findings.
Knowledge of these risk factors has informed ongoing clinical trials by Reata’s Asian development partner, Kyowa Hakko Kirin (KHK), in studying bardoxolone methyl to treat CKD in patients with type 2 diabetes, and Reata’s own Phase 3 study in patients with connective tissue disease associated with pulmonary arterial hypertension. Neither of these studies has shown an increased risk for adverse heart events from fluid retention associated with use of the drug.
When will this trial begin enrolling?
Reata plans to start their Phase 2/3 study, called CARDINAL, in the first half of 2017.
Will there be a study site near me?
While it is too soon to announce actual study sites, Reata is already working with nearly 40 potential study sites in the United States. The aim is to have coverage across all regions of the country and to cover the cost of travel for any patients who participate in the study and need to travel to the research center.
International sites will also be announced when the study opens. The study will be listed on clinicaltrials.gov in the coming weeks. That listing will provide full detail on the sites/physicians who will be conducting the study.
Reata may share more specific information during upcoming patient web conferences, the first of which will take place in December. If you’d like to join one of the web conferences, please email Hanh Nguyen with Reata.
Who is Reata Pharmaceuticals?
Reata Pharmaceuticals, Inc., is a clinical-stage biopharmaceutical company that develops novel therapeutics for patients with serious or life-threatening diseases by targeting molecular pathways involved in regulating mitochondrial function, oxidative stress, and inflammation. Their two most advanced clinical candidates (bardoxolone methyl and omaveloxolone) target important transcription factors, called Nrf2 and NF-κB, to restore mitochondrial function, reduce oxidative stress, and resolve inflammation.
What is ASF’s role in the clinical trial?
As a patient advocacy group, the Alport syndrome Foundation provides the patient perspective as researchers design details of the study. ASF provides patients with information regarding all clinical studies involving Alport syndrome. ASF will not tell patients which study to join nor advocate for one study over another. Each research study has different, often non-competing, goals that are all beneficial to the Alport syndrome community. Patients and their families are encouraged to discuss clinical studies with their doctor(s) to determine which study provides the best fit for them.
Reata Pharmaceuticals and Alport syndrome
Note: This article has been revised to include additional information received from Reata Pharmaceuticals after the initial article was posted. The article was originally published November 14, 2016.