Kezar Life Sciences has been hit by its second clinical hold from the FDA in as many months.
The agency has placed a partial hold on the phase 2a PORTOLA trial evaluating the selective immunoproteasome inhibitor zetomipzomib in 24 patients with autoimmune hepatitis. The FDA’s decision means that the four patients still being evaluated as part of the 24-week double-blind treatment period cannot continue on to an additional 24-week open-label extension (OLE) portion of the study.
The patients who have already reached the OLE stage can continue to receive their zetomipzomib treatment, but their dose of the steroid prednisone must not fall below 5 mg/day, Kezar explained in its third-quarter earnings release.
The FDA issued the partial hold in the wake of the agency’s full hold last month on the PALIZADE trial, which was investigating zetomipzomib as a treatment for lupus nephritis. That study was initially paused after a review of emerging safety data revealed the death of four patients in the Philippines and Argentina.
A safety review by the trial’s independent monitoring committee's safety had already revealed that three of the four deaths showed a “common pattern of symptoms” and a proximity to dosing, Kezar said at the time.
Later that month, Kezar decided to terminate the PALIZADE lupus trial and focus its efforts solely on zetomipzomib in autoimmune hepatitis.
William Blair analysts added some extra context to the FDA’s latest decision, pointing out in a Nov. 13 note that Kezar’s management had explained that the partial hold on PORTOLA was due to “potential concerns of some placebo patients among the four patients yet to roll over in the OLE, who could be subject to safety risk upon initiating zetomipzomib treatment.”
Regarding the continued use of prednisone, the analysts said that Kezar’s execs had “noted the FDA is cautiously concerned about the risk of systemic injection site reactions, and therefore believes maintaining a level of steroid dosage may reduce this risk.”
“Systemic injection reactions have been reported in previous trials with zetomipzomib, but in general, seemed to be more frequent in the earlier cycles of treatment and manageable,” the analysts added.
The biotech was keen to stress in yesterday’s release that no grade 4 or 5 serious adverse events—with grade 5 referring to a fatality—had been observed in the PORTOLA trial, which is being conducted in the U.S. The study’s independent data monitoring committee had also recommended that the PORTOLA trial proceed without modification, Kezar added.
“The team at Kezar has made great progress towards completing the double-blind portion of the PORTOLA trial as we prepare for a data release in first half of 2025,” CEO Chris Kirk, Ph.D., said in the release. “There are currently no approved drugs for the treatment of autoimmune hepatitis, and we are focused on bringing zetomipzomib to patients living with this life-threatening disease.”
“In addition, we are working to understand the safety events that occurred in the PALIZADE trial in lupus nephritis, including deaths that occurred in both the placebo and drug arms, so that we can provide patients and physicians appropriate guidance during our ongoing and future clinical trials,” Kirk added.
The discontinuation of the PALIZADE trial means there is “clearly significant dependence” on a positive outcome from the PORTOLA study to “spur a reversal” in Kezar’s share price, the William Blair analysts said in this morning’s note.
The pair of clinical holds are only the latest disruptions for Kezar, which shrank its workforce by 41% and significantly trimmed its pipeline a year ago to save up enough cash to cover the PALIZADE readout. More recently, the company dropped a solid tumor asset that had originally survived the pipeline culls; and, only a few weeks ago, the biotech turned down an acquisition bid from Concentra Biosciences.
Even zetomipzomib has not been immune to the changes, with a phase 2 miss in a rare autoimmune disease derailing plans to pitch the drug as an inflammatory disease pipeline-in-a-product.