Reata Pharmaceuticals Inc.'s chief medical officer, Colin Meyer, told BioWorld Today that an earlier phase III trial in chronic kidney disease (CKD) was stopped because of "a very specific safety finding that we did not understand at the time," and the company's more recently informed confidence – along with a blessing from the FDA – is fueling another attempt with bardoxolone methyl (bard).

Irving, Texas-based Reata began patient screening for a phase II/III trial to test the compound in patients with CKD caused by Alport syndrome, a rare genetic disease due to mutations in the genes encoding type IV collagen, a major structural component of the glomerular basement membrane in the kidney.

In 2012, Reata ended the BEACON trial testing bard in patients with stage IV CKD and type 2 diabetes after an independent data monitoring committee pointed to safety signals in the treatment arm. Abbvie Inc., of North Chicago, had paid $450 million in up-front and near-term cash payments to gain rights to bardo, an antioxidant inflammation modulator (AIM), in late 2010. The deal excluded U.S. rights, retained by Reata. (See BioWorld Today, Sept. 24, 2010, and Oct. 19, 2012.)

"There was a concern [in BEACON] that the drug had direct cardiotoxicity that was causing an increase in heart failure events," Meyer said. "We now know that's not the case." Instead, a subset of sick patients had acute fluid overload. Bard turned up "no evidence of any direct cardiotoxicity," he said, adding that "if we had known that fluid retention was a risk, we could have excluded patients who are at risk, watched their volume status, given them optimal diuretics. That's what we do now. It's not like an idiosyncratic toxicity that you cannot predict."

At the time of the Abbvie deal, bard had demonstrated significantly improved kidney function in CKD type II diabetics in phase II testing. Shortly afterward, Reata reported phase IIb results showing that 60 percent of diabetes patients given the drug turned up a reduction in the classification of the severity of their disease after 24 weeks of treatment. Efficacy signals were good in BEACON, too. "The trial was powered to show a difference in dialysis and end-stage renal disease [ESRD] events," Meyer said. "We stopped it before we could answer that question" but kidney function was improving. With Alport CKD, "while its etiology is distinct from diabetic CKD, the underlying pathophysiology that causes loss of kidney function is very similar," he said.

Reata more recently changed its focus to orphan diseases such as Alport where the company can undertake "studies with tractable endpoints in a reasonable period of time," Meyer said. The phase II part of the Alport study is open-label and will enroll up to 30 patients from 12 to 60 years old with estimated glomerular filtration rates (eGFR) between 30 to 90 mL/min/1.73 m2. Fifteen patients with microalbuminuria will receive up to 20 mg of bard once daily and 15 patients with macroalbuminuria will receive up to 30 mg of bard once daily. The primary endpoint in phase II is change in eGFR at week 12 compared to baseline. Data from the phase II portion are expected by the end of the year, at which point Reata will decide about phase III.

The phase III part of the experiment is designed to support regulatory approval of bard, will be double-blind and placebo-controlled and will randomize about 180 patients on a 1-to-1 basis to once-daily oral bard or placebo. Similar to phase II, the study will assess dose escalation of bard from 5 mg to a maximum daily dose of 20 mg or 30 mg based on baseline proteinuria at randomization. The primary efficacy endpoint is the on-treatment change from baseline in eGFR in bardo-treated patients relative to placebo after 48 weeks. The key secondary endpoints will be the change from baseline in eGFR following a four-week withdrawal of drug after one and two years of treatment. 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.

OPT-IN CLAUSE SIMILAR TO OMAVELOXOLONE

"The FDA said they would like to see once that drug is removed, after one year of treatment, that there's a significant difference between the drug and placebo," Meyer said. "That's important to them because it would indicate that the drug is having an effect on the structure of the kidney, which means that it would likely affect progression to ESRD." Data from BEACON make Reata "bullish for what we may see in Alport syndrome," he said, noting that the company's partner in Tokyo, Kyowa Hakko Kirin Co. Ltd., conducted work validating eGFR as a measure of better kidney function. "It's a very technical point, and a very technically laborious study they had to conduct, but there was some skepticism in the community about our drug's ability to actually improve kidney function," he said. "They clearly demonstrated using a gold-standard technique that it was a true improvement."

What's more, "whereas [in BEACON] we had to study stage IV diabetic CKD patients using a dialysis and transplant endpoint, we've been given a path to registration in earlier-stage patients in a much broader range, kidney function from 30 to 90. The BEACON trial was 15 to 29," he said.

Bardo is an oral, once-daily activator of Nrf2, a transcription factor that induces molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling. It's undergoing a phase III trial called CATALYST for the treatment of connective tissue disease-associated pulmonary arterial hypertension.

In the pipeline is another AIM, omaveloxolone for melanoma, mitochondrial myopathies, Friedreich's ataxia and post-surgical corneal endothelial cell loss. Reata was responsible for a certain initial amount of early development costs before Abbvie began sharing development costs equally in that program. As of April 2016, the company had incurred all of those initial costs, after which payments from Abbvie with respect to research and development costs incurred by the company were recorded as a reduction in research and development expenses, notes the annual report filed with the SEC. Reata's expenses were reduced by $773,000 and about $1.4 million for Abbvie's share of research and development costs for the three months and nine months ended Sept. 30, 2016. The company collected $661,000 from Abbvie in October 2016.

Last September, the pair agreed that Reata would continue unilateral development of omaveloxolone, so Abbvie no longer co-funds the exploratory development costs of that program, but retains the right to opt back in at certain points in development.

Depending upon what point, if any, Abbvie takes the option, it may retain its right to commercialize a product outside the U.S., or Reata may be responsible for commercializing the product worldwide.

Upon opting back in, Abbvie would be required to pay an agreed-upon amount of all development costs accumulated up to the point of exercising the right, after which development costs and product revenue worldwide would be split equally. The deal for bard has a similar opt-in structure, Meyer said.

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