Kezar reports the deaths of four patients in a study of intermediate-stage lupus nephritis and suspends enrollment

Kezar Life Sciences announced this on Monday four patients died in the Phase IIb PALIZADE trial evaluating its investigational immunoproteasome inhibitor zetomipzomib in active lupus nephritis, forcing the biotech to pause enrollment and dosing in the mid-stage of the trial.

Kezar said the voluntary pause is consistent with the recommendations of an independent data monitoring committee that documented the four fatal Grade 5 adverse events as part of a recent safety review. Three of the four deaths showed “a common pattern of symptoms and proximity to dosage,” the company announced, while it pointed to other non-fatal serious toxicities that “showed similar proximity to dosage.”

“Our top priority is the safety of every patient participating in clinical trials,” Kezar CEO Chris Kirk said in a statement, noting that the biotech company will work with local investigators, the data monitoring board and regulators to better understand patient deaths and determine the best route for zetomipzomib in lupus nephritis.

Kezar is also working on potential risk reduction strategies for zetomipzomib. The FDA has not yet issued a formal clinical hold for the drug candidate.

“We will provide further information on this investigation and the zetomipzomib development program in due course,” Kirk said.

Monday’s announcement does not impact Kezar’s Phase IIa PORTOLA trial of zetomipzomib in autoimmune hepatitis, which recently completed enrollment and is ongoing. The biotech said it did not document any fatal or serious Grade 4 adverse events – including serious opportunistic infections – in PORTOLA or other previous clinical trials with zetomipzomib.

Zetomipzomib, developed for subcutaneous injection, is a potentially first-in-class blocker of immunoproteasome proteins, which help maintain normal immune system function under healthy circumstances. By inhibiting immunoproteasomes, zetomipzomib also suppresses various inflammatory pathways, including cytokine production and immune effector cell activity, according to Kezar website.

PALIZADE, a global, placebo-controlled, randomized trial, has enrolled 84 patients to date to evaluate the efficacy and safety of zetomipzomib in lupus nephritis. The investigational therapy was administered at a dose of 30 mg and 60 mg.

Kezar also led the Phase II MISSION trial for zetomipzomib in lupus nephritis. In November 2022, the biotech company reported the full data from the study and praised a 88.2% overall renal response rate– defined as a decrease in proteinuria of at least 50% from baseline – after 37 weeks. Zetomipzomib also demonstrated strong anti-inflammatory activity in MISSION, an effect that lasted up to 12 weeks after discontinuation of treatment.

At the time, Kezar said zetomipzomib had a “favorable safety and tolerability profile” and showed no signs of immunosuppression.

Matt Phipps, an analyst at William Blair, acknowledged in a note to investors that deaths that may be related to treatment are “always concerning.” However, Phipps wrote, “We believe that the totality of the data for zetomipzomib from both the MISSION and PRESIDIO trials and.” [open-label extension] “Highlight the favorable safety profile” of the drug candidate. There were no deaths in either study and overall rates of grade 3 or worse toxicities were low.

“Although the setback for PALIZADE is disappointing, we believe there may still be a path forward for the development of zetomipzomib.” [lupus nephritis] and also see an opportunity for zetomipzomib in autoimmune hepatitis,” said Phipps.