Three Deaths In Trial Mean Clinical Hold For Juno’s Lead CAR-T Therapy

Juno Therapeutics Inc. planned to win US FDA approval in 2017 for its chimeric antigen receptor T cell (CAR-T) cell therapy JCAR015, but the company has reached another significant milestone that may delay that goal: its Phase II ROCKET clinical trial in the treatment of adults with relapsed or refractory B cell acute lymphoblastic lymphoma (ALL) has been put on clinical hold due to three deaths.

Juno recently instituted a new pre-conditioning regimen in ROCKET that added fludarabine to cyclophosphamide chemotherapy, which was administered before the company's engineered T cells were injected back into recently enrolled patients. The addition of fludarabine may have caused the three cases of cerebral edema that killed three people – two in the last week of June and one in May – but Juno executives conceded during a July 7 conference call to discuss the clinical hold that there are many variables that will have to be reviewed.

The FDA clinical hold notice was issued in response to the two patients who died during the week before the July 4 holiday in the US. To inform the agency's decision about whether to let the trial proceed, and to support the company's request to continue ROCKET without the use of fludarabine, Juno must submit: a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the company's July 6 presentation to FDA staff.

Juno Chief Medical Officer Mark Gilbert said during the company's conference call that it expects the agency's review to occur in "an expedited fashion," but he acknowledged that the FDA has 30 days to issue a decision after it receives Juno's documents. The requested information will be submitted to the agency within the next few days.

But removing fludarabine from the ROCKET protocol, while potentially protecting patients, also could lead to less positive results for JCAR015 in the study. The chemotherapy drug, when added to cyclophosphamide, has been touted by Juno and other CAR-T therapy developers as necessary to improve the persistence of engineered cells.

A CAR-T Class Risk?

During the American Society of Clinical Oncology (ASCO) meeting in early June, Juno presented data showing higher response rates as well as better disease-free survival and overall survival rates for patients who received fludarabine in their pre-conditioning treatments without significantly higher neurotoxicity or cytokine release syndrome (CRS) rates.

Gilbert said during the company's call that fludarabine "augments the expansion of these cells. Following pre-conditioning with the chemotherapy drug Juno has observed "rapid expansion [of CAR-T cells] in those patients that is distinct from other trials and other conditioning regimens."

However, he and Juno CEO Hans Bishop noted during their call that JCAR015 and the company's other product candidates have shown strong efficacy following both cyclophosphamide-only and fludarabine plus cyclophosphamide pre-conditioning therapy.

It is possible that the FDA will investigate the potential for CAR-T therapies in general to cause severe and deadly cerebral edema, since neurotoxicity has been a concern for the immune system-harnessing cell therapies in the past. In fact, Gilbert noted that the FDA already has a CAR-T safety database in place. As for Juno's own safety data, he said the three deaths after cerebral edema in ROCKET represent "the first safety signal we've seen." (Also see "ASH 2015: As CAR-T Players Vie For 1st Place, Will Efficacy Trump Safety?" - Scrip, 11 Dec, 2015.)

Investors certainly seemed to view a class-wide review of CAR-T products as a distinct possibility. While Juno plunged 27.3% in after-hours trading on July 7 to $29.66 per share, the company's other main biotech competitor Kite Pharma Inc. fell 10.4% to $46.70.

Bellicum Pharmaceuticals Inc., which is developing CAR-T therapies as well as a "safety switch" for the treatments, declined 4.8% to $14. bluebird bio Inc. fell 5.7% to $46.05.

Among big pharma, Novartis AG – a neck-and-neck contender with Juno and Kite – was essentially unchanged, moving only 0.1% lower to $81.73. Meanwhile, Celgene Corp. – the big biotech that invested $1bn up front in Juno a year ago under a 10-year collaboration agreement – fell 1.4% to $102.91. (Also see "Celgene shows CAR-T confidence with $1bn Juno investment" - Scrip, 30 Jun, 2015.)

Can Patients Be Protected From Harm?

As for heading off severe reactions to CAR-T therapy following a fludarabine-containing chemotherapy regimen, Gilbert hinted that it may be too difficult to stop that from happening.

He said during Juno's conference call that when patients in the company's studies develop a fever following administration of the cells, which could be a sign of CRS, investigators administer an interleukin-6 (IL-6) receptor antagonist, like Genentech Inc.'s Actemra (tocilizumab), or a steroid.

However, the fever comes on much faster in fludarabine-conditioned patients – in a few days rather than a week for those who were pre-treated with cyclophosphamide alone.

"These cerebral edema cases come on quite rapidly, such that these fatal cases are happening in under a week," Gilbert said.

All three patients who died received Actemra and steroids in case of CRS, but Juno does not believe those individuals had CRS or infections that would have contributed to their demise. Autopsy information from at least one patient will be made available to the company, which could shed more light on the connection between CAR-T treatment after fludarabine pre-conditioning and the patients' deaths.

Meanwhile, it remains to be seen when Juno can get ROCKET back on track and whether the clinical hold delay will keep JCAR015 from being approved in the US in 2017. Trials for the company's other CAR-T therapies are unaffected by the clinical hold, but JCAR015 is the most advanced asset in Juno's pipeline.

This is the second clinical hold for JCAR015. Juno had a trial put on hold in early 2014 following two deaths that may have been related to CRS. The study resumed after certain protocol amendments.