It is usually impossible to repeat positive phase II results in the more rigorous setting of phase III, as Reata has just demonstrated in the Cardinal study of its lead asset, bardoxolone, in the rare kidney disease Alport syndrome.
That said, the efficacy data are undeniably still positive, a fact borne out by the group’s move to proceed with regulatory filings. This is not to say that approval is assured, of course, and a key question will be whether the latest results reignite concerns over hyperfiltration, a long-held Reata bear thesis.
This thesis holds that bardoxolone works by overworking the kidneys, causing hyperfiltration that results in a strong initial benefit. However, this then wanes, and eventually perhaps even leads to a speeding up of renal failure progression.
Leerink analysts, while remaining bullish on bardoxolone, accepted that more detailed proteinuria data might now be needed to disprove the potential for hyperfiltration. Bardoxolone is expected to sell $1.1bn in 2024, according to EvaluatePharma sellside consensus.
In the 30-subject, open-label phase II portion of Cardinal Reata appeared to score a resounding victory: bardoxolone treatment caused estimated glomerular filtration rate (eGFR) to increase by 10.4ml/min/m2 from baseline after 48 weeks, and this remained 4.1ml/min/m2 over baseline after a four-week washout.
At the time Reata said it was hoping to replicate this kind of benefit in the placebo-controlled, 157-patient, phase III part of Cardinal, specifying further that in the four-week withdrawal analysis it wanted to see a delta of at least 2.2ml/min/m2.
It has now managed to trump this, beating placebo at both time points with a high level of statistical significance (p value below 0.001). However, this has been achieved in part because placebo recipients experienced relatively large declines in eGFR.
Indeed, during the four-week withdrawal stage subjects on bardoxolone actually saw their eGFR decline from baseline, by almost 1ml/min/m2. This is what Reata bears will now latch on to.
|Two-stage Cardinal trial (NCT03019185) of bardoxolone|
|Phase II||Phase III|
|Chg in eGFR after 48wk||+10.40||+4.72||+9.50|
|Chg in eGFR after further 4wk withdrawal||+4.10||-0.96||+5.14|
|Source: Reata statements.|
Reata itself has provided fuel for the fire, pointing to tolvaptan, which was approved for chronic kidney disease on the basis of a small eGFR benefit over placebo, where both active and placebo cohorts experienced baseline declines. This, it argued on an analyst call today, indicated a mere slowing rather than stopping of eGFR decline.
The problem is that a bearish reading of the phase III Cardinal data can be construed as showing exactly the same thing, as after four weeks’ withdrawal both groups showed an eGFR decline. Reata argued that this decline was slight and “non-significant” versus baseline.
It also stressed that its analysis included all subjects, including low-dose patients and those who discontinued, and this might have depressed the absolute benefit. As for proteinuria, it said albuminuria was unchanged after the withdrawal and, while it increased at week 48, it was unchanged when adjusted for eGFR.
“The FDA doesn’t care about changes in albuminuria, they care about changes in eGFR,” it told analysts.
Reata stock initially fell 5% in the premarket, but by the open it was down just 1%. This is impressive, especially after its 45% surge last month when bardoxolone and omaveloxolone were bought back from Abbvie, and the latter scored in a Friedreich’s ataxia study, and considering the threat of a fund-raising.
There remains some risk that the US FDA might ask for a longer-term analysis of Cardinal to allay the risk of hyperfiltration, but for now investors are happy to live with it.