As Aurinia Pharmaceuticals Inc. marches ahead with the phase III trial testing what could become the first approved lupus nephritis (LN) therapy, company backers are watching with interest another, lesser known indication where the cyclosporine analogue voclosporin might also work: focal segmental glomerular sclerosis (FSGS), a glomerular disease that can cause nephrotic syndrome. A phase II experiment is slated to start next month. Both conditions involve high amounts of protein in the urine, or proteinuria.
CEO Richard Glickman said Victoria, British Columbia-based Aurinia remains "very pleased with how this [lupus nephritis] trial is going forward," and the experiment has been designed to ensure quality control at sites, which number more than 200. The company spent much time training trial personnel and, "very importantly, when you look at the outcome measures that we use in this study, they're very objective outcome measures, which is, for us, the reason we choose to work within LN, rather than just lupus. I believe the calcineurin inhibitor has promise in both areas, but specifically in lupus nephritis. Having those very clear endpoints [and] having central laboratories really makes a difference in our ability to execute a program like this."
Extensive monitoring of patients with contract research organizations [CROs] adds to his confidence, he said earlier this month during a conference call on earnings.
Two years ago, Aurinia suffered a setback when phase IIb data, though positive, included 13 deaths across 265 patients. The AURA-LV (Aurinia Urinary Protein Reduction Active-Lupus with Voclosporin) study included two fatalities in the arm receiving the high dose of voclosporin, 10 in the low-dose drug arm, and one in the control arm. But all were assessed by study investigators as unrelated to treatment. Of the 13 deaths, 11 occurred in Asia, a finding consistent with other LN studies. More Asian patients were randomized into the low-dose voclosporin arm than the high-dose arm. (See BioWorld Today, Aug. 16, 2016.)
The phase III trial called AURORA (Aurinia Renal Response in Active Lupus with Voclosporin) is a 52-week global, double-blind, placebo-controlled experiment intended to demonstrate that voclosporin added to the current standard of care of mycophenolate mofetil (Cellcept, Roche Holding AG) can increase overall renal response rates in the presence of extremely low steroids. The primary endpoint is complete renal response at 52 weeks. The trial will recruit about 320 patients and is intended to support full marketing approval of voclosporin for patients with LN in multiple regulatory jurisdictions, Aurinia said.
By inhibiting calcineurin, voclosporin blocks interleukin-2 expression and T-cell-mediated immune responses. The drug is made by a modification of a single amino acid of the cyclosporine molecule, which means a more predictable pharmacokinetic and pharmacodynamic relationship with potential for flat dosing. Voclosporin boasts more potency, and has an improved metabolic profile vs. cyclosporine. Aurinia said that if the drug wins approval, patent protection for voclosporin will be extended in the U.S. and certain other major markets, including Europe and Japan, until at least October 2027 under the Hatch-Waxman Act and in accordance with similar laws in other countries.
Chief medical officer Neil Solomons noted that Aurinia has two CROs involved in overseeing AURORA. "But also, remotely, we have experienced medical staff monitoring every single data point, and that really helps us to be reassured that the key elements and protocol are adhered to, and as [Glickman] said, our endpoints are laboratory-driven by central laboratory readings. There's no dispute as to the results that are collected from each patient at each site."
Glickman said the advantage of doing the trial at so many sites "really comes down to educating large numbers of physicians about our clinical program, but also a realization over the years [that] you never know which sites are actually going to produce patients. We've learned from experience that, if you, let's say, choose 50 sites you think are the best performers, you often are wrong, and then you have all that extra time in gearing up the next sites. We spent the additional money and educated more sites, so that we could actually see who really are the producers. If a site doesn't produce for us, we can close down that site."
Also due to start in June is a phase II study with voclosporin in dry eye syndrome. This will be a head-to-head study with the ophthalmic solution vs. Restasis (cyclosporine ophthalmic emulsion 0.05 percent, Allergan plc), and data are expected from the four-week, 90-patient effort by the end of the year.
Retrophin in the mix as well
RBC Capital Markets analyst Douglas Miehm said in a report that the LN market is "underpenetrated," since no drugs are approved in the U.S. or EU. "The current treatment paradigm is comprised of off-label medication and has significant room for improvement, with complete remission rates only in the mid-teens," he noted. "Phase II trials [with] voclosporin demonstrated a statistically significant improvement in patient outcomes when added to the current standard of care, with complete remission rates of about 50 percent."
He predicted success for the phase III experiment, followed by marketing clearance in the U.S., EU and Japan, and forecast that the drug could hit peak global sales of $930 million.
Leerink analyst Joseph Schwartz also saw good things ahead for Aurinia, predicting that the company would be first to market in the LN indication, worth about $1.4 billion. With 212 sites activated in the phase III study, researchers should complete enrollment in the fourth quarter of this year and provide investors with top-line data in 2019. In the second half of this year, the firm will submit the first module of the rolling NDA – nonclinical data – and the chemistry, manufacturing and controls piece will follow in the first half of 2019. The clinical module goes to gatekeepers in the second half of 2020. He expects voclosporin to reach patients in 2021.
And what of FSGS? On the earnings call, Schwartz wanted to know about talks with the FDA, especially with regard to the regulators' view regarding the importance of estimated glomerular filtration rate (EGFR). Solomons noted that a number of companies have announced that they've come to agreements on their accelerated approval pathway, "whereby they have to not only reproduce the short-term reductions in proteinuria, but also continue to follow the patients up for long-term clinical outcomes. That's not necessarily the approach we're taking.
"It's certainly our understanding from our pre-R&D discussions with the FDA that the short-term remission endpoints, on their own, may be adequate to support approval further down the line." The EGFR factor is important, he said, "but this is just a secondary endpoint in our study. We believe that we have a broad agreement with the FDA," but the outcome of the phase II experiment will largely determine what happens next.
Another player in FSGS, San Diego-based Retrophin Inc., made news last month when regulators cleared a phase III interim endpoint that could improve the chances for accelerated approvals in the U.S. and the EU with sparsentan. The trial, called Duplex, will build on encouraging data seen in the phase II study, known as Duet, in which sparsentan appeared to reduce proteinuria. Duplex will report an interim outcome following 36 weeks of treatment: the proportion of patients on sparsentan achieving a modified partial remission of proteinuria, a readout expected to arrive in the second half of 2020. (See BioWorld Today, Sept. 8, 2016.)
FSGS is described as a rare malady characterized by proteinuria and progressive scarring of the glomeruli. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, steroids and immunosuppressant agents help manage some cases of the condition, but not all. In the U.S., where about 40,000 people have FSGS, Retrophin estimates that about half are candidates for sparsentan.