Juno ROCKETs On Fast Clinical Hold Resolution
Executive Summary
The FDA lifted a clinical hold on the Phase II ROCKET clinical trial for Juno's lead CAR-T therapy candidate JCAR015 less than a week after it was instituted, allowing the company to proceed without using fludarabine in a pre-conditioning chemotherapy regimen.
Juno Therapeutics Inc. soared in after-hours trading on July 12 following the company's late-day announcement that a clinical hold on its Phase II ROCKET clinical trial for the chimeric antigen receptor T-cell (CAR-T) therapy JCAR015 has been lifted just a few business days after the US FDA instituted the hold in response to three deaths in the study.
Seattle, Washington-based Juno fell more than 27% after the stock market closed on July 7 when the company first revealed the clinical hold, despite assurances that the FDA was likely to expedite its review of the ROCKET enrollees' deaths. The trial, which is testing JCAR015 in the treatment of certain acute lymphoblastic lymphoma (ALL) patients, will continue without the use of fludarabine in a pre-conditioning chemotherapy regimen.
Juno speculated that the three cases of lethal cerebral edema observed in ROCKET were caused by fludarabine, which was added to cyclophosphamide to prime the immune systems' of adults with relapsed or refractory B-cell ALL.
The FDA responded quickly to the company's request to resume enrolling patients in ROCKET as long as the trial's protocol required pre-conditioning with a cyclophosphamide-only chemotherapy regimen. Juno rose 25% to $34.75 after the stock market closed on July 12 in response to the news.
The announcement carries a mix of good and bad news for the company, however, since pre-treating patients with fludarabine plus cyclophosphamide improved response rates, progression-free survival and overall survival in earlier studies for JCAR015, other Juno CAR-T therapies and competing product candidates. Removing fludarabine from the ROCKET trial could impact the reengineered T-cells' efficacy in advanced ALL patients.
Datamonitor Healthcare analyst Hardik Patel told Scrip before Juno revealed that the ROCKET clinical hold was lifted that "JCAR015 may not reach its maximum potential efficacy without" fludarabine.
However, Juno is not the only CAR-T developer to benefit from the use of fludarabine in pre-conditioning chemotherapy regimens, and Patel said he doesn't expect the company's experience in ROCKET to upend its other CAR-T clinical trials or studies sponsored by its competitors.
A CAR-T Class Effect? Maybe Not
"In terms of the broader CAR-T cell field, I don't think this is drastically bad news. If it is the fludarabine, it may just be a matter of finding the optimal dose to be used. [Kite Pharma Inc.] announced that their ZUMA trial would continue to use a low dose of fludarabine. I believe some of Juno's other trials with CAR-T cell therapies will also continue to use fludarabine, such as JCAR018," Patel said.
Juno noted when the ROCKET clinical hold was instituted that none of its other clinical trials were affected. Even so, its competitors' stocks also slumped on July 7.
Likewise, Kite surged 7.6% in after-hours trading to $50.55 on July 12 and Novartis AG rose 0.3% to $81.95 after the ROCKET clinical hold was lifted. Earlier-stage CAR-T developers Bellicum Pharmaceuticals Inc. rose 2.6% to $14.91, bluebird bio Inc. gained 1.2% to reach $50.59 and Cellectis SA jumped 1.9% to $25.90.
With the ROCKET clinical hold so quickly resolved, it looks like Juno remains on track to seek accelerated FDA approval in early 2017 for JCAR015 in relapsed or refractory ALL – if the Phase II trial's final result in patients pre-treated with a cyclophosphamide-only chemotherapy regimen is positive.
The company's other CAR-T therapy candidates may have the potential for even greater efficacy, since ongoing studies for those programs use low-dose fludarabine-containing pre-conditioning regimens.
Biomedtracker analysts highlighted the differences between Juno's product candidates and trials in a July 7 report. "The JCAR015 construct is the only one of Juno's constructs to use the CD-28 co-stimulatory moiety. The JCAR014 and JCAR017 constructs use the 41BB moiety. Nevertheless, company officials pointed out that it is too early to reach any conclusions about the role of the co-stimulatory moiety. They have proposed that fludarabine might be acting as a dose magnifier by allowing for a rapid expansion of the CAR-T cells," the report states.
The analysts noted that "77 patients have been treated to date with either JCAR014 or JCAR017 using the combination conditioning protocol with an acceptable safety record. For JCAR017, both the pediatric ALL and the [non-Hodgkin lymphoma (NHL)] trials are using a low-intensity regimen of fludarabine and cyclophosphamide, which may lower the rate of neurotoxicity compared to the high-intensity regimen used for JCAR015."