Juno’s lead CAR-T drug is killing more patients, and this time it may have reached the end of the clinical road.
Four months after the biotech was forced to scramble to save the program in the wake of three patient deaths, Juno says that two more patients have died of cerebral edema out of only 12 more patients treated in the study.
Juno has voluntarily put the study back on clinical hold and informed regulators at the FDA, who may not be so quick to allow this study to resume this time around.
Juno’s stock $JUNO immediately cratered after trading was resumed, plunging 45%.
Investigators have been treating adult patients with relapsed or refractory B cell acute lymphoblastic leukemia in the “ROCKET” trial. “The clinical hold was initiated after two patients suffered cerebral edema earlier this week,” Juno said in a statement. “One patient died and as of last night the other is not expected to recover.”
Juno is now considering its “options.”
In a call with analysts, Juno execs said that one of those options is dropping the JCAR015 trial and moving on to JCAR017 and other drugs in the pipeline, which would put them even further behind.
In July, the company firmly pinned the first deaths on fludarabine, a drug used to condition patients in this and many other studies. Pulling flu from the treatment regimen, they insisted, would prevent further deaths.
That did not happen. And today Juno’s team was forced to deal with a simple question: “Do we know what’s really going on?”
CMO Mark Gilbert handled that question gingerly, noting that the company continues to learn more about CAR-T over time. These new cases occurred very recently, he adds. And cerebral edemas have been associated with a number of CAR-Ts.
“I do think we understand that there’s a strong correlation of rapid expansion of CAR-T cells seem to correlate directly on cerebral edema,” he added. “That’s the big focus for us.”
I queried the FDA on its decision to quickly green-light the resumption of the trial back in July and whether they were going to reinstitute the hold, but in a lengthy response a spokesperson didn’t answer my questions, or even refer to Juno, JCAR015 or cerebral edema.
While no decision on JCAR015’s future has been made at Juno, execs quickly focused on JCAR017 as its next lead program to turn to.
“We’ve not seen any severe cases of severe CRS” with JCAR017, said Juno CEO Hans Bishop on the call. There was also a lower neurotoxicity rate and no treatment-related mortalities. “We’re encouraged by the safety and efficacy profile of JCAR017.”
Back in July the FDA took only a few days to respond positively to Juno’s plan to resume the study, dropping the use of fludarabine, which is commonly used to prep patients for these cell therapies. The company pinned the first three deaths from cerebral edemas — along with a fourth in a separate study — on its mix of JCAR015 and the combo that was used to improve its chances of success.
This new setback will force the FDA to review its own role in getting the program restarted after just a few days of review — a rare occurrence at the agency which stunned a number of observers at the time.
While the last hold was brief, it held serious consequences for Juno, throwing it off track and pushing any new drug application back to 2018. That gave the edge to Kite, which has so far reported no unusual adverse events related to its use of fludarabine. Kite now expects to complete its first application in Q1 2017, and Novartis is also shooting for a 2017 filing for its rival CAR-T.
These drugs work by extracting T cells from patients and then equipping them with chimeric antigen receptors, which then zero in on cancer cells. This first generation of CAR-Ts, which is likely to be eclipsed by early-stage efforts, has been known to trigger harsh side effects. But regulators have been willing to put up with the added risk for trials that involve very sick volunteers.
Was never convinced about fludarabine being at fault for earlier JCAR15 problems. If these events are w/o then they have big problems here
— Sally Church (@MaverickNY) November 23, 2016
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