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My thoughts on opportunity for $FGEN's roxadustat in non-dialysis anemia (NDD) in light of $AKBA's failure with vadadustat in their trial. First I'll deal with the comparison of the two drugs in this indication, and in second thread talk about impact on approval and market size
Vada failed very badly here - not just failed to show inferiority to an ESA, but actually stat sig *inferior* to drug w/ black box warning for MACE: HR 1.17, (95% CI: 1.01, 1.36). (MACE is composite of all-cause mortality, non-fatal myocardial infarction, & non-fatal stroke)
Note that in the vada trial, they treated to a somewhat lower Hgb - only 10.4, compared with target of 11.0 in comparable roxa trial. It's notable that they didn't disclose response rate, which is perhaps an even more significant number than average Hgb.
Here is comparable (but smaller) $FGEN NDD trial vs active comparator. The key takeaway here is not just non-inferiority to an ESA, but strong trend to better MACE (HR 0.81).
Also note response rate stat sig *superior* to active comparator.
Also note response rate stat sig *superior* to active comparator.
So the results here for the two drugs could not have been more different. I was very surprised by AKBA results - I thought this trial should have been a layup based on the results of the FGEN Dolomites trial. So what is the explanation?
First the drugs are quite different. Roxa is about 10x more potent than vada, and has a quite different balance of activity between the three prolyl hydroxylase enzymes PHD1, PHD2 and PHD3. Next, daily dosing by vada (and $GSK competitor) is different than the TIW for roxa.
FGEN has demonstrated preclinically two disadvantages of daily dosing - first many more genes get turned on with daily dosing, raising spectre of more non-anemia effects and second you get a feedback loop in an enzyme that potentially causes tachyphylaxis with prolonged dosing.
I believe vada is being dosed near the top of its dose curve, while roxa is very much on steep part. In DD trial you saw more variability in effect size with vada, suggesting that for some pts you can't dose high enough. So bottom line for me is that roxa simply superior drug.
