Investors in Aurinia Pharmaceuticals Inc. breathed a sigh of relief, and moved shares (NASDAQ:AUPH) higher, after learning that both study doses in the phase IIb AURA-LV (Aurinia Urine Protein Reduction in Active Lupus Nephritis) study of lupus nephritis (LN) candidate, voclosporin – added to standard-of-care mycophenolate mofetil and a forced oral corticosteroid taper – met 24-week pre-specified secondary endpoints compared to control.
AURA-LV enrolled 265 patients at centers in more than 20 countries. Entry criteria required patients to have a diagnosis of LN according to established diagnostic criteria (American College of Rheumatology) and clinical and biopsy features indicative of highly active nephritis.
In August, the company reported top-line data from AURA-LV showing that voclosporin, dosed at 23.7 mg twice daily, met the primary endpoint of complete remission (CR) at 24 weeks. That disclosure was marred, however, by the revelation that 13 deaths occurred in the 265-subject study: two in the high-dose (39.5 mg) voclosporin arm, 10 in the low-dose arm and one in the control arm. With investors focused more on the deaths than the CR, despite Aurinia’s explanation that investigators deemed the deaths unrelated to treatment, the company’s shares nose-dived 56 percent. (See BioWorld Today, Aug. 16, 2016.)
As the fuller picture emerged Friday, shares rebounded, gaining as much as 40 percent before settling back to close at $3.01 for a gain of 37 cents, or 14 percent. Volume of 31.6 million shares was more than 30 times the company’s three-month moving average.
Secondary endpoints included partial remission (PR) – measured by a ≥50 percent reduction in urinary protein creatinine ratio (UPCR) without concomitant use of rescue medication – of 70 percent (p=0.007) in the voclosporin 23.7 mg dose cohort and 66 percent (p=0.024) in the 39.5 mg high-dose cohort vs. 49 percent in the control group. Time to PR was 4.1 weeks (p=0.002) and 4.4 weeks (p=0.003) in the low- and high-dose cohorts, respectively, compared to 6.6 weeks in the control group, while time to CR was 19.7 weeks (p<0.001) and 23.4 weeks (p=0.001), respectively, in the voclosporin groups and was not met in the control group.
The company also reported that patients on voclosporin saw a reduction in the Systemic Lupus Erythematosus Disease Activity Index, or SLEDAI, score of 6.3 percent and 7.1 percent, respectively, in the low- and high-dose groups (p=0.003 for both) vs. a reduction of 4.5 percent in the control group. Over the 24-week treatment period, reduction in UPCR was 3.769 mg/mg (p<0.001) in the low-dose group and 2.792 mg/mg (p=0.006) in the high-dose group over the 24-week treatment period compared to 2.216 mg/mg for the control group.
An immunosuppressant, voclosporin is designed with a dual mechanism of action that offers the potential to improve near- and long-term outcomes in LN when added to standard of care. By inhibiting calcineurin, voclosporin blocks IL-2 expression and T-cell mediated immune responses.
Aurinia unveiled details of the phase IIb data at a key opinion leader breakfast in New York. The nearly two-hour presentation, which was simultaneously webcast, included a review of the LN space and of historical mortality in the indication by prominent nephrologists, a thorough vetting of the safety and efficacy data by company officials and a compelling LN patient testimony.
AURA-LV became the first global active LN study to meet its primary endpoint and 24-week pre-specified secondary endpoints, according to Aurinia officials, who offered a painstaking review of mortality in the study designed to reassure the Street that patient deaths were unrelated to voclosporin and consistent with complications of LN, as initially maintained in August.
The mortality analysis, in particular, struck a chord with some observers, according to Charles Rowland, Aurinia’s CEO, who observed during his introduction that the patient population “was a sicker and more severe population” than enrolled in any previous study, “and all of those studies failed.”
Speaking directly to the feeding frenzy that occurred in August, Rowland promised to deliver “more [mortality] data than you probably wanted to see, but we’re going to put this behind us.”
‘WE'LL DO THE GLOBAL WORK TO GET THE APPROVAL’
The company revealed that the AURA-LV trial deaths occurred in Bangladesh, Sri Lanka, the Philippines and Russia, where patient access to comprehensive medical care was compromised. In some cases, officials said, patients were enrolled as a last-ditch effort to save their lives rather than sending them home to die.
“When we showed the mortality analysis that had been done in our study as well as three other global studies that had been done in the States, it really illustrated to investors that the deaths were not related to the drug,” Rowland told BioWorld Today.
During the company’s presentation, David Jayne, director of the vasculitis and lupus clinic at the University of Cambridge, pointed out that LN patients are diagnosed, on average, in their late 20s. Most die prematurely, generally when the complex interaction among disease activity, immunosuppression and infection risk leads to cardiovascular events and active infections. Subsequent organ damage drives mortality.
“We don’t tend to have an oncology mindset when we look at lupus nephritis, but in fact the outcomes are worse than in many malignancies,” he said, noting that the outlook for LN patients is relatively unchanged over the past 20 years.
The infective severe adverse events (SAEs), other SAEs and mortality in AURA-LV were consistent with other global studies in LN, including the phase III ALMS study of mycophenolate mofetil by Roche Holdings AG, Genentech Inc.’s phase III BELONG study of ocrelizumab and Bristol-Myers Squibb Co.’s pivotal study of abatacept.
“You could say these are fairly predictable data,” Jayne concluded.
Leerink Partners analyst Joseph Schwartz seemed to agree, writing in a flash note, “An important reminder for investors to consider is that the AURA-LV study is still ongoing, with a 48-week endpoint readout expected early next year; if there was a reasonable doubt that voclosporin was responsible for these patient deaths, this would not be the case.”
With the pattern of deaths shown in AURA-LV comparable to that observed in the ALMS induction study for mycophenolate mofetil (Cellcept) in LN, which is now the standard of care, “we maintain that mortality rates shown to date will not preclude continued development,” Schwartz added.
The addition of positive secondary endpoints helps to hit home that “this drug works,” Neil Solomons, Aurinia’s chief medical officer, told BioWorld Today. “To me, that was always clear because our primary endpoint was constructed to show that, but I think that came across more today.”
The AURA-LV study is continuing to its 48-week endpoint, which is expected to report in the first quarter of next year.
In the meantime, officials from the Vancouver, British Columbia-based company expect to hold an end-of-phase-II meeting with the FDA this month to discuss the AURA-LV findings and the design of two – or perhaps one – phase III trial.
“Neil has a two-study design in his pocket,” Rowland said. “He’s got a one-study design. Both are on the table. We’re also going to ask about endpoints – should it be 48, 24 or eight [weeks], based on some other data we have.”
With guidance expected by year-end and a phase III expected to begin in the first half of 2017, the company also is mulling partnering prospects.
“At a minimum, Asia-Pacific doesn’t make sense on our own,” Rowland said, though Aurinia is determined to complete its pivotal program and show that voclosporin works equally well in patients in the region.
“We’ll do the global work to get the approval,” he maintained.
The bigger opportunities are in the U.S. and Europe, where the company could partner or go to market on its own, largely depending on the direction of its shares, Rowland acknowledged.
“If I don’t believe that I can get the capital I need on good terms, we may make the decision to out license Europe to fund the phase III study,” he said. “We haven’t made a firm decision, but we’ve done all the analysis – the pricing work, the work with the physicians, the burden of the disease. They’re all complete.”