William Blair analyst Matt Phipps in a note to investors wrote that despite the patient deaths, the totality of the data still leans in favor of Kezar Life Sciences’ investigational immunoproteasome inhibitor zetomipzomib.
Kezar Life Sciences on Monday announced that four patients have died in the Phase IIb PALIZADE trial, evaluating its investigational immunoproteasome inhibitor zetomipzomib in active lupus nephritis, forcing the biotech to suspend enrollment and dosing in the mid-stage study.
The voluntary pause is in line with the recommendations of an independent data monitoring committee, which documented the four fatal Grade 5 adverse events during a recent safety review, according to Kezar. Three of the four deaths demonstrated “a common pattern of symptoms and proximity to dosing,” the company announced, while flagging other non-fatal serious toxicities that “showed a similar proximity to dosing.”
“Our top priority is the safety of every patient who participates in or clinical trials,” Kezar CEO Chris Kirk said in a statement, noting that the biotech will work with site investigators, the data monitoring committee and regulators to better understand the patient deaths and determine the best path forward for zetomipzomib in lupus nephritis.
Kezar is also working on potential risk mitigation strategies for zetomipzomib. The FDA has yet to issue a formal clinical hold for the drug candidate.
“We will provide additional information regarding this investigation and the zetomipzomib development program at the appropriate time,” Kirk said.
Monday’s announcement does not affect Kezar’s Phase IIa PORTOLA study of zetomipzomib in autoimmune hepatitis, which recently completed enrollment and remains ongoing. The biotech said that it has not documented Grade 4, fatal or serious adverse events—including severe opportunistic infections—in PORTOLA or in other prior clinical studies of zetomipzomib.
Designed to be administered via a subcutaneous injection, zetomipzomib is a potentially first-in-class blocker of immunoproteasome proteins, which under healthy circumstances help maintain the normal function of the immune system. By inhibiting immunoproteasomes, zetomipzomib also suppresses various inflammatory pathways, including cytokine production and immune effector cell activity, according to Kezar’s website.
PALIZADE, a global, placebo-controlled and randomized trial, has so far enrolled 84 patients to evaluate the efficacy and safety of zetomipzomib in lupus nephritis. The investigational therapy was given at a 30-mg and 60-mg dose.
Kezar also ran the Phase II MISSION trial for zetomipzomib in lupus nephritis. In November 2022, the biotech reported complete data from the study, touting an 88.2% overall renal response rate—defined as at least a 50% drop in proteinuria from baseline—at 37 weeks. Zetomipzomib also demonstrated strong anti-inflammatory activity in MISSION, an effect that persisted up to 12 weeks after discontinuing treatment.
At the time, Kezar said that zetomipzomib had a “favorable safety and tolerability profile,” showing no signs of immunosuppression.
William Blair analyst Matt Phipps in a note to investors conceded that deaths possibly linked to treatment are “always concerning.” However, Phipps wrote that “we believe the totality of the data for zetomipzomib across both the MISSION and PRESIDIO study and [open-label extension] highlight the favorable safety profile” of the drug candidate. There were no deaths in either study and overall low rates of grade 3 toxicities or worse.
“While the setback for PALIZADE is disappointing, we believe there may still be a path forward to develop zetomipzomib in [lupus nephritis] and also see opportunity for zetomipzomib in autoimmune hepatitis,” according to Phipps.
