Lupus Nephritis Drug Voclosporin Meets Primary Endpoint in Phase 2 Study––But Deaths Cause Concern

Company to discuss next steps with FDA

Mixed results have been reported from a phase 2b trial of voclosporin (Aurinia Pharmaceuticals) in patients with active lupus nephritis (LN). The trial achieved its primary endpoint, demonstrating a significantly greater complete remission (CR) rate in patients treated with voclosporin 23.7 mg twice daily (BID) plus current standard of care compared with placebo plus standard of care (P = 0.045). However, 12 deaths occurred in voclosporin-treated patients during the 24-week study.

Voclosporin is an immunosuppressant calcineurin inhibitor that blocks the expression of interleukin-2 and T-cell–mediated immune responses. It is made by modifying a single amino acid of the cyclosporine molecule.

The Aurinia Urine Protein Reduction in Active Lupus Nephritis (AURA–LV) trial compared the efficacy of voclosporin added to current standard of care (mycophenolate mofetil [MMF]; CellCept, Genentech) with that of placebo and standard of care in achieving CR in patients with active LN. The trial enrolled 265 patients at centers in more than 20 countries. To be enrolled into the study, patients were required to have a diagnosis of LN, according to established American College of Rheumatology diagnostic criteria, along with clinical and biopsy features indicating highly active LN.

The patients were randomly assigned to one of two dosages of voclosporin (23.7 mg BID or 39.5 mg BID) or placebo, with all patients also receiving MMF and oral corticosteroids as background therapy. All of the patients were given an initial intravenous dose of steroids (500 mg to 1,000 mg) and were then started on voclosporin or placebo 20 mg to 25 mg daily, which was tapered down to a low dose of 5 mg daily by week 8 and 2.5 mg daily by week 16.

The study’s primary endpoint was the number of patients who achieved CR at 24 weeks (confirmed at 26 weeks). CR was defined as a protein/creatinine ratio of less than or equal to 0.5 mg/mg as well as stable renal function (i.e., an estimated glomerular filtration rate [eGFR] of greater than or equal to 60 mL/min/1.73 m2 or no confirmed decrease from baseline in the eGFR of greater than or equal to 20%).

The primary endpoint of CR was met in the low-dose voclosporin group (23.7 mg BID) compared with the placebo group (P = 0.045). CR was achieved by 33% of patients receiving low-dose voclosporin compared with 27% of the high-dose group (39.5 mg BID) and 19% of the placebo arm. The odds ratio (OR) indicated that patients treated with voclosporin were twice as likely to achieve CR at 24 weeks compared with the placebo group (OR = 2.03).

Thirteen deaths occurred during the trial: 10 in the low-dose voclosporin arm, two in the high-dose voclosporin arm; and one in the placebo arm. Most of the deaths (11 of 13) occurred in Asia. All of the deaths were assessed by the investigators as being unrelated to study treatment.

According to FierceBiotech, Aurinia Pharmaceuticals’ stock dropped on news of the patients’ deaths and the unexpectedly low response rates. The company explained that the deaths were due to the severe underlying nature of LN and not to its drug, even though only one of the 13 deaths occurred during placebo treatment.

Aurinia plans to meet with the FDA in the fourth quarter of 2016 to discuss the subsequent clinical development of voclosporin and the path to registration in LN. The study will continue through 48 weeks, and those data will be available for release in early 2017.

Sources: Aurinia Pharmaceuticals; August 15, 2016; and FierceBiotech; August 15, 2016.