A Sad Halt to a Promising CKD drug

In my research I found studies on Bardoxolone Methyl to treat serious CKD in Stage 3-4. From 2010 the drug looked extremely positive and trial findings showed a dose of 75 mg a day (vs 25 or 150) provided a great rise in eGFR and kidney function. in 2011 a larger trial was begun.
[I have Bolded and broken up paragraphs to make it easier to skim and understand]

GOOD NEWS STEP 1: New Findings Confirm Bardoxolone's Efficacy 2011
http://www.renalandurologynews.com/era-edta-congress/new-findings-confirm-bardoxolones-efficacy/article/206071/

MORE GOOD NEWS 2 Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes
http://www.nejm.org/doi/full/10.1056/NEJMoa1105351

Superior eGFR at 52 weeks

Patients' eGFR increased within one month of starting the drug, peaked at 12 weeks, and was relatively stable through 52 weeks, Dr. Warnock reported. At 24 weeks, all doses of bardoxolone were associated with a statistically significant increase in eGFR compared with placebo. The 75 mg dose produced significantly greater improvement in eGFR compared with the 25 mg dose, but there was no significant difference between the groups on 75 or 150 mg of bardoxolone.

At 52 weeks, every dose of bardoxolone was associated with more improvement in eGFR compared with placebo, which produced no significant improvements at 24 or 52 weeks compared with baseline. At 52 weeks, the 25, 75, and 150 mg doses were associated with increases in eGFR of 5.8, 10.5, and 9.3 mL/min/1.73 m2, respectively. Earlier in the study, at 24 weeks, fewer patients (2%) in the combined bardoxolone groups showed a significant eGFR reduction of 25% or more compared with the placebo group (13%).

AND THE BAD NEWS: Reata and Abbott Halt Phase 3 BEACON Trial For Bardoxolone Methyl Amid Serious Safety Concerns
http://diatribe.org/issues/48/new-now-next/1 THIS REPORT IS ALARMIST..the finding are shown in the next report below

On October 18, Reata and Abbott stopped their phase 3, 2,000-patient BEACON trial for the drug bardoxolone methyl, the most promising candidate in development for the treatment of chronic kidney disease (CKD). The trial was terminated due to an excessive number of serious adverse effects, including death, among those taking bardoxolone in the study.

This is shocking and deeply disappointing news, particularly because the earlier phase 2 results for bardoxolone had been so encouraging – the drug showed the potential to both ease the symptoms of CKD and to actually reverse it through anti-inflammatory mechanisms. The stakes were very high for bardoxolone since nothing of its kind is currently available, and it would have offered a sorely needed treatment for a very ill group of patients. As context for how grave a condition stage 4 CKD is (the disease state being tested in this trial), a 2004 study found that the five-year mortality rate of patients with stage 4 CKD was 46% – worse than many cancers.

The companies have not released further information about why these safety problems arose, the magnitude of the problems, or the next steps with the drug. While it is possible that bardoxolone is simply not safe for use as a CKD treatment, these adverse events may be the result of unfortunate statistical variance or perhaps due to flaws in the study design.

In particular, BEACON focused on patients with type 2 diabetes and stage 4 CKD, the most advanced stage of CKD before dialysis is needed. As a result, it’s possible that the participants were too ill to handle the treatment. Given that no glaring safety signals were apparent in the smaller phase 2 study (BEAM) with stage 3 and 4 CKD patients (though we note this was a much smaller study of 227 patients), we wonder if Reata and Abbott will still attempt to develop the drug for less severe forms of CKD. In any case, we will continue to monitor this story for more information on what went wrong in the BEACON trial. –AW/AB -

After a taste of disaster, Reata plans a comeback for bardoxolone
July 9, 2014 | By John Carroll
http://www.fiercebiotech.com/story/after-taste-disaster-reata-plans-comeback-bardoxolone/2014-07-09

(this is about funding) "AbbVie signed up to partner on its chronic kidney disease drug bardoxolone by dangling $450 million in quick cash, and then came back a year later to get the full portfolio of follow-up drugs at Reata for another $400 million upfront.

The deals quickly soured in one gut-wrenching moment in 2012, though, when Reata had to suddenly terminate its clinical work on the drug after the monitoring board tracked signs that the CKD patients in the drug arm were experiencing a higher rate of heart-related adverse events, including heart failure, hospitalizations and deaths.

In an interview with FierceBiotech, Reata CEO Warren Huff says the company first had to slash its employee roster in half--scrapping efforts to build up a marketing arm in anticipation of a U.S. launch--and now operates with a staff of about 60. Researchers went back to the drawing board to figure out what had gone wrong.

What happened, he explained, was that the drug caused fluid retention to spike in the first few weeks of treatment for the advanced, stage 4 CKD patients recruited for the study…... In earlier studies, the company had recruited a mix of stage 3 and stage 4 patients, which softened the AE profile. "We really didn't see it until we got into a trial with thousands of patients," says Huff.

That pointed Reata to PAH, a disease in which narrowed arteries in the lung forces one side of the heart to work overtime, triggering effects that include mitochondrial dysfunction and profound fatigue. The new Phase II dose-ranging study, which wraps in 2015, has its eye on demonstrating an improved performance in the 6-minute walk test. Significantly, Reata is hoping that bardoxolone can work as a complementary treatment to the roster of new drugs recently approved for PAH, a lineup that include's Bayer's Adempas (which delivered an average 36-meter improvement in a 6-minute walk test), Actelion's ($ATLN) Opsumit and others.
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LATEST UPDATE 2015: Reata Pharmaceuticals Receives Orphan Drug Designation For Bardoxolone Methyl

http://www.pharmpro.com/news/2015/04/reata-pharmaceuticals-receives-orphan-drug-designation-bardoxolone-methyl

Reata Pharmaceuticals, Inc., a biopharmaceutical company dedicated to the development of breakthrough medicines for difficult-to-treat diseases, today announced that the FDA Office of Orphan Products Development (OOPD) has granted orphan drug designation for bardoxolone methyl for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease involving endothelial dysfunction, pulmonary vasoconstriction, vascular remodeling, pulmonary fibrosis, and right ventricular hypertrophy. Additionally, PAH involves skeletal muscle dysfunction that contributes to the exercise intolerance observed in PAH patients. In preclinical studies, bardoxolone methyl has demonstrated potent antioxidant, anti-inflammatory, and bioenergetic properties, which may lead to improved exercise tolerance in patients.

The primary efficacy endpoint is a six minute walk test. For more information on this study, visit: http://clinicaltrials.gov/show/NCT02036970.

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This encourages me more than ever to captain my own health and make changes to maintaining kidney function. If you REVIEW the TENGION Corp. post under Pre-Dialysis Topic you will see a NEO-KIDNEY enhancement with $$$$ millions also invested has just failed clinical trials in 12/2014 for bankruptcy. So Sad.