Aurinia Pharmaceuticals’ voclosporin has experts on guard for a potential high death rate in its Phase III lupus nephritis (LN) trial as seen in its Phase IIb study.
Despite the prior deaths in the active drug arm described by Aurinia as not being treatment-related, and company risk mitigation strategies for the Phase III, experts said their concerns are not completely allayed yet. That said, the fact the data and safety monitoring board (DSMB) has not halted the trial is at least somewhat reassuring, they said.
Analysts remained optimistic on voclosporin’s prospects, noting that the company’s determination that the deaths are not treatment-related should put concerns at ease. Some experts noted that should the death rate in AURORA be as high as it was in the Phase IIb, it would not likely be approved, even if efficacy reads out strongly. Having no deaths in the trial would be unlikely given that the disease has inherent mortality risks, but reducing that rate in the active drug arm at 11% to that observed in the placebo arm at about 1% would be amenable for approval, experts said.
Some noted that even a marginally higher death rate than placebo could still be approvable, given the lack of approved treatments in the space.
Analyst reports stated that the lack of approved LN treatments, strong response and remissions seen in the Phase IIb trial promote optimistic outcomes in voclosporin approval and uptake.
Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus (SLE).
Some experts had concerns that should the Phase III trial recruit a high proportion of Asian patients — as did the Phase IIb — it would be hard to translate the efficacy results to non-Asian patients. They noted that there might be ethnic differences in response to LN treatments and a high Asian recruitment would limit the usefulness of that data.
Voclosporin is being evaluated in the double-blind, 358-patient Phase III trial AURORA (NCT03021499), with topline results expected in 4Q19, according to a September 2018 press release. On July 23 it was reported that, according to an investigator, data would not be unblinded in time for the American Society of Nephrology annual meeting in November.
Voclosporin has projected sales of $2.2bn in 2026. Aurinia has a market capitalisation of CAD 751m ($570m). The company did not respond to request for comment.
Mortality risk closely watched
The deaths disproportionately occurred in Bangladesh and Sri Lanka, and it was mentioned in the published data that the deaths likely occurred as a result of patients being unable to access timely medical care during complications, said AURA-LV investigator Dr David Isenberg, professor of rheumatology, University College London.
The 265-patient Phase IIb trial AURA-LV (NCT02141672) saw 10 deaths in the low-dose arm (11.2%), two deaths in the high-dose arm (2.3%) and one in the placebo arm (1.1%) (Rovin, et al, Kidney Int. 2019 Jan;95(1):219-231).
The deaths seemed unlikely to be random, given that the rates were much higher in the low-dose arm than placebo, noted Dr Vladimir Tesar, head of the Department of Nephrology at the General University Hospital, Prague, Czech Republic. The Phase IIb deaths could have been due to patient cohort makeup based on where they were enrolled, Tesar said.
While the company has publicly said the high death rate seen in the Phase IIb trial was not treatment-related, and that adequate steps have been taken to reduce that risk, it is not clear that risk is “out of the woods yet,” said Dr Richard Glassock, emeritus professor of medicine at the University of California, Los Angeles. Isenberg welcomed the mitigation strategies but noted they are no guarantees for bringing down the death rate to acceptable levels and that they warrant a close watch.
Aurinia has employed mitigation strategies including stricter vetting of sites and better training of investigators, noted an AURORA investigator. Bangladesh and Sri Lanka have been omitted as Phase III sites, according to ClinicalTrials.gov.
However, the investigator acknowledged that there are still some AURORA sites where medical access is not typically as comprehensive as in developed countries, spelling some risk, though he noted that these sites typically recruit faster.
The fact that the DSMB has not halted the trial or raised any red flags is an encouraging sign for AURORA, said Tesar and the investigator. A DSMB is a group of independent individuals, external to the trial, who review the accumulated data from one or more ongoing clinical trials on a regular basis and advise the sponsor about continued safety of the trial participants.
Should the high death rate of 11% return in AURORA, it is unlikely voclosporin will be approvable, said Glassock. A 1–3% death rate as observed in the placebo arm in AURA-LV might be more palatable for approval, Isenberg said. The investigator said AURORA’s death rate should not repeat that seen in AURA-LV, and while it would be ideal to have no deaths, some are likely to occur, given the disease’s severity. Even if the mortality rate of the treatment arm is higher than placebo’s, voclosporin could still eke out an approval given the lack of approved treatment, though its uptake potential is likely to be curbed, said the investigator.
Nonetheless, the Phase IIb voclosporin efficacy was very promising since it suggested that calcineurin inhibitors (CNIs), especially voclosporin, could be a significant contribution for LN, said Tesar. Complete renal remission (CRR) was achieved by 29 (32.6%), 24 (27.3%) and 17 (19.3%) patients in the low-dose, high-dose and placebo groups, respectively.
High Asian enrolment precludes translatability
The AURA-LV study had a high Asian patient enrolment that is not reflective of the US LN patient population, Glassock said. Given that there might be ethnic differences to response and remission, should AURORA maintain high Asian enrollment, it will be hard to perceive how voclosporin might fare in non-Asian patients, he noted. The majority of CNI studies in LN that have generally been successful were conducted in Asia, while studies with Caucasian and African-origin patients have tended to be small, Glassock said.
Of 265 patients, AURA-LV had 60 Asian-Indian (22.6%) and 72 Asian-other (27.2%) patients, 108 (40.8%) white, 14 black (5.3%) and 11 others (4.2%), according to published results.
A high Asian data set would preclude translatability especially in the US, where LN might be more common and severe in African-American patients, Glassock said. The investigator agreed that African-American patients tend to present more severe disease and a high Asian data set might not pertain as much to the former.
Isenberg noted that there might be ethnic differences in response to treatment, though he was not sure that the differences would be significant enough to matter within a clinical trial. The investigator and Isenberg said it is not clear what the AURORA enrolment breakdown is, though both suspect Asian enrolment will continue to be high. AURORA has sites in Japan, South Korea, Malaysia, Philippines, Taiwan, Thailand and Vietnam, according to ClinicalTrials.gov.
by Shuan Sim and Manasi Vaidya in New York
Shuan Sim and Manasi Vaisya are Senior Reporters for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.