Kezar Reports Four Deaths in Lupus Nephritis Study, Pauses Enrollment

Kezar Life Sciences announced on Monday that four patients have died during the Phase IIb PALIZADE trial, which is assessing the investigational immunoproteasome inhibitor zetomipzomib for active lupus nephritis. Due to these fatalities, the biotech company has decided to suspend both enrollment and dosing in this mid-stage study.

This voluntary suspension follows recommendations from an independent data monitoring committee, which identified the four fatal Grade 5 adverse events during a recent safety review. According to Kezar, three of these deaths showed a common pattern of symptoms closely linked to the dosing schedule. The company also highlighted additional serious but non-fatal toxicities that appeared to be similarly related to dosing times.

Kezar CEO Chris Kirk emphasized that patient safety is the company's highest priority. He stated, “Our top priority is the safety of every patient who participates in our clinical trials.” Kirk assured that the biotech would collaborate with site investigators, the data monitoring committee, and regulatory bodies to thoroughly investigate the patient deaths and determine the best course of action for zetomipzomib in treating lupus nephritis.

In addition, Kezar is actively exploring potential risk mitigation strategies for zetomipzomib. The FDA has not yet issued a formal clinical hold on the drug candidate. Kirk mentioned that further information regarding the investigation and the development program for zetomipzomib would be provided at an appropriate time.

The recent announcement does not impact Kezar’s ongoing Phase IIa PORTOLA study of zetomipzomib in autoimmune hepatitis, which has recently completed enrollment. According to the company, no Grade 4, fatal, or serious adverse events, including severe opportunistic infections, have been documented in the PORTOLA study or in any prior clinical trials involving zetomipzomib.

Zetomipzomib is designed to be administered via subcutaneous injection and serves as a potentially first-in-class inhibitor of immunoproteasome proteins. Under normal conditions, these proteins help maintain the proper function of the immune system. By inhibiting immunoproteasomes, zetomipzomib also suppresses various inflammatory pathways, including cytokine production and immune effector cell activity.

The PALIZADE trial, which is randomized, placebo-controlled, and conducted globally, has so far enrolled 84 patients to assess the efficacy and safety of zetomipzomib in treating lupus nephritis. The investigational drug was administered in doses of 30 mg and 60 mg.

Kezar previously conducted the Phase II MISSION trial for zetomipzomib in lupus nephritis. In November 2022, the company released comprehensive data from this study, reporting an 88.2% overall renal response rate, defined as at least a 50% reduction in proteinuria from baseline over a 37-week period. The MISSION trial also demonstrated significant anti-inflammatory effects, which lasted up to 12 weeks after discontinuation of treatment.

At that time, Kezar stated that zetomipzomib had a “favorable safety and tolerability profile,” with no indications of immunosuppression.

William Blair analyst Matt Phipps commented that although deaths possibly linked to treatment are always concerning, the overall data for zetomipzomib from both the MISSION and PRESIDIO studies, as well as an open-label extension, indicate a favorable safety profile. There were no deaths in either study, and the rate of severe Grade 3 toxicities or worse was low.

Phipps acknowledged that the setback in the PALIZADE trial is disappointing but suggested that there might still be a viable path forward for developing zetomipzomib to treat lupus nephritis. He also sees potential for the drug in the treatment of autoimmune hepatitis.