What should have been a big win for Aurinia Pharmaceuticals Inc.’s stock (NASDAQ:AUPH) Monday on the back of positive phase IIb data in the particularly tough lupus nephritis (LN) indication turned into a drubbing for the shares, which plunged 56 percent as investor attention focused – perhaps unfairly – on the study’s death rate.

Admittedly, it was high. Data from the 265-subject AURA-LV study showed 13 deaths across all three trial arms – two in the arm receiving the high dose of calcineurin inhibitor voclosporin, 10 in the low-dose voclosporin arm and one in the control arm. All, however, were assessed by study investigators as being unrelated to treatment, said Neil Solomons, chief medical officer, during Aurinia’s investor call Monday morning.

Nor were the deaths wholly unexpected, Solomons added. “We know this is a serious and life-threatening illness.” He also pointed out that, of the 13 deaths, 11 occurred in Asia, a finding consistent with other LN studies and “probably related somewhat to patient management and severity of disease in this patient population.”

More Asian patients also were randomized into the low-dose voclosporin arm vs. the high-dose arm, Solomons later clarified.

The further details had little impact on Wall Street, as Aurinia’s stock continued trading low throughout the day, closing at $1.81, down $2.28, or 55.7 percent, on volume more than 152 times the average. Leerink analyst Joseph Schwartz, however, was encouraged after speaking with management, “which makes us incrementally more comfortable that the FDA will view the risk/benefit of voclosporin favorably,” he wrote in a research note. “We believe that [Aurinia] shares would not be trading down so precipitously [if at all] if this were made clearer.”

In addition to noting that all 13 deaths occurred in less-developed regions, where patients often have much more severe disease at the time they present for treatment, Schwartz said the rate of death in Aurinia’s AURA-LV study was similar to that seen the earlier induction trial for mycophenolate mofetil (MMF, Cellcept). Published data from that trial, called ALMS, showed a total of 14 patients died during the study, including nine in the MMF group, with seven deaths due to infection and no deaths attributed to lupus. In Aurinia’s study, four of the deaths reported in the low-dose group were due to infection, something Schwartz views as a similar pattern.

Infection is expected, given that LN patients have “a highly disordered immune system,” Aurinia’s Solomons said. The company continues to analyze the 13 deaths, but, at this time, “there is no one cause.” Some of the deaths even occurred “very, very soon” into the study start, “indicating that it was probably underlying disease.”

LN results from the inflammation of the kidney caused by systemic lupus erythematosus (SLE), a progressive, complex and often-disabling disease affecting about 500,000 patients in the U.S., predominately women, explained CEO Charlie Rowland. Roughly 60 percent of patients with SLE experience LN, a condition currently treated by off-label MMF and corticosteroids as the standard of care, though few patients actually achieve complete remission on that regimen.

Improving standard of care

Aurinia’s phase IIb study, launched in 2014, was designed to determine if adding voclosporin to standard of care could both improve remission rates and reduce the need for background steroid therapy, which carries significant side effects. The endpoints offered “straightforward disease outcomes,” Rowland said, measuring complete remission (CR) at 24 weeks defined as a protein/creatinine ratio of 0.5 mg/mg or less and normal stable renal function (estimated glomerular filtration rate, or eGFR, of 60 mL/min1.73m2 or less or no confirmed disease from baseline in eGFR of 20 percent or less).

All patients received an initial intravenous dose of steroids, from 500 mg to 1,000 mg, before being treated daily with 20 mg to 25 mg, gradually tapering down to a dose of 5 mg daily by week eight and to 2.5 mg daily by week 16.

Inclusion criteria for patients were stringent, Solomons said, requiring patients to have highly active LN, with biopsy-proven disease and severe proteinuria. While both treatment groups – 23.7 mg twice daily and 39.5 mg twice daily – were generally well-balanced for age, gender and race, disease severity was found to be greater in the low-dose group. Solomons gave the example of one patient who entered the study with a baseline proteinuria of 29 grams, a level that “really shocked me” and the study team. “I’ve been working in this disease for a while and I’ve never seen that.” During the trial, “this patient actually almost achieved complete remission, but this is an example of how sick these patients were.”

Top-line data from AURA-LV showed the study hit the primary endpoint, demonstrating statistically significant greater CR at 24 weeks (and confirmed at 26 weeks) in those receiving the low dose (p = 0.045). The intent-to-treat (ITT) analysis showed 32.6 percent of patients in the low-dose arm reached CR, while 27.3 percent in the high-dose arm (a numerical improvement that fell short of statistical significance) and 19.3 percent in the control arm achieved CR.

The odds ratio indicated that patients were twice as likely to achieve CR at 24 weeks compared to the control arm, Solomons said.

“This is the first global study and the only placebo-controlled study to ever meet its primary endpoint for the treatment of active lupus nephritis,” he said. “And this was done in the presence of low steroid exposure.”

Aurinia will be further analyzing the data. But some additional results were available Monday, including the fact that both voclosporin groups had a significantly faster time to CR than the control arm. On the secondary endpoint of partial response (PR), defined as 50 percent reduction in urine protein to creatinine ratio (UPCR) over baseline, both voclosporin arms in the ITT analysis, with 69.7 percent of patients in the low-dose arm achieving PR (p = 0.007) and 65.9 percent in the high-dose arm achieving PR (p = 0.024). Time to PR was similar – four weeks – in both treatment arms and shorter than that observed in the control arm (6.6 weeks).

Other secondary endpoints such as durability of remission and extra-renal lupus activity will be reported later. The study also is continuing through 48 weeks, with that analysis due in early 2017.

Next steps

Aurinia plans to take the AURA-LV data to the FDA in an end-of-phase II meeting in the fourth quarter to discuss plans for a pivotal trial and path for registration. Execs declined to reveal specifics of their phase III plan at this point, but Solomons said it will “incorporate much of our learnings” from earlier testing.

A pivotal trial is aimed to start in the early part of next year. Aurinia also plans to file for breakthrough therapy designation from the FDA. Fast track status was awarded for LN in March.

Voclosporin, designed to work by inhibiting calcineurin, which thereby blocks IL-2 expression and T-cell mediated immune responses, was created by the addition of one carbon molecule at the amino acid-1 residue of cyclosporine to strengthen the binding of the voclosporin/cyclophilin complex to calcineurin and allow the major metabolites of voclosporin eliminate more quickly. The result is higher potency and a lower metabolic load compared to cyclosporine.

The drug has been in development a number of years, previously in kidney transplant patients at Isotechnika Inc., a publicly listed firm that merged with privately held nephrology-focused Aurinia in 2013. Through an Isotechnika partner, Lux Biosciences Inc., the drug was studied in uveitis; however, despite promising early data, a phase III study in that indication failed to meet its endpoint. (See BioWorld Today, Dec. 28, 2012.)

Beyond AURA-LV, Aurinia also is testing voclosporin in a small LN study – the AURION trial – that offered preliminary data earlier this year, showing that 100 percent of the first seven patients to reach at least eight weeks of therapy achieved at least a 25 percent reduction in proteinuria compared to study entry.

Aurinia, of Victoria, British Columbia, ended the third quarter with about $12.1 million in cash, equivalents and short-term investments. In July, it entered an at-the-market facility in which it can raise, from time to time, up to $10 million.

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