Success for Aurinia has arrived with phase IIb data on its main asset, voclosporin, with one of the two doses meeting the primary endpoint of complete remission of active lupus nephritis. Not so fast. The dose that met the primary endpoint was the lower of the two tested.
Despite management trying to explain away the reverse dose-response as patients being unable to tolerate the higher dose, and trialists in the two arms having different disease characteristics, there was also the matter of a much higher death rate in the low-dose group. Investors took flight: the group’s shares rose 24% pre-market, but opened 56% down at $1.80.
In the low-dose group 10 of 89 patients died, compared with two in the high-dose group, and one given placebo. Aurinia’s management was adamant that the deaths were not related to voclosporin, attributing them to infections and the underlying lupus itself.
11 of the 13 deaths occurred in Asia, with the company saying that this might be more to do with “patient management and the severity of the underlying disease in this population”.
The company also suggested that patients in the low-dose group had more severe disease than the others based on biomarkers: baseline proteinuria was higher in the low-dose patients, and EGFR lower in the low-dose patients.
Lupus nephritis is a potentially life-threatening complication of systemic lupus erythematosus, and affects around 60% of SLE patients. The 265-patient Aura-LV trial tested voclosporin at 23.7mg or 39.5mg twice daily on top of the standard of care, Roche’s CellCept and steroids, versus placebo and the standard therapy.
The primary endpoint was the number of patients who achieved complete remission, defined as a protein/creatinine ratio of no more than 0.5mg/mg in addition to normal stable renal function, at week 24. It was met by 32.6% of patients in the low-dose voclosporin arm with a p value of 0.045.
19.3% of placebo recipients met the endpoint, as did only 27.3% of high-dose patients, which missed statistical significance.
“It is likely that some patients… were not able to tolerate the high dose,” said Mr Solomons, seeking to explain the discrepancy. That said, patients who dropped out were not considered in the final analysis.
A problem of geography
Analysts from Leerink wrote that the reverse dose response was surprising “particularly since this would have been pulled down by accounting for the relatively high number of deaths in the drug arm”.
They also offered an explanation for the death rate itself: that the patients were treated at many sites with differing practice patterns in Asia, “some of which we believe were in much less developed places”.
Which, if any, of this suite of explanations proves to be correct will perhaps become clearer when a more detailed analysis of the results emerges in a couple of months. The project's prospects for approval, and hence Aurinia’s as a business, will become clearer then, too.