Juno ditches lead CAR-T program following patient deaths

Juno Therapeutics has halted development of its lead CAR-T therapy months after patient deaths hindered the odds of success. The decision sees Juno switch its focus to JCAR017, a follow-up program that uses a defined CD4-CD8 composition company execs thinks will improve safety and efficacy.

JCAR015 has appeared destined for the chop since patients died of cerebral edemas either side of a FDA clinical hold last year. But Juno held off on publicly ditching development of the CAR-T in adults with acute lymphoblastic leukemia (ALL) until this week. That delay enabled Juno to dig into the causes of the safety failings—which it thinks stem from rapid early CAR-T cell expansion—and set JCAR015 back to the extent that further work on a flawed candidate was deemed pointless.

“The delay with JCAR015 means it no longer makes sense to continue its development as we can instead bring forward a defined cell product candidate in a similar timeframe,” Juno CEO Hans Bishop said on a conference call with investors. “We believe a defined cell product candidate will have higher complete remission rates, a better tolerability profile and importantly get a greater percentage of patients into durable remissions.”

JCAR017 is the defined cell product that will take the spotlight in the near term as a result of the pipeline rejig. As a defined cell composition candidate, JCAR017 goes through a manufacturing process that controls the number of CD4 and CD8 cells in the finished product. Juno thinks this approach will reduce the variability of the composition of JCAR017 in what Juno sees as vital areas, such as the number of viable CD8 cells and the capacity to release inflammatory cytokines.

Juno’s focus on these attributes stems from its analysis of what caused its safety problems. After the analysis, Juno continues to believe the use of fludarabine in the chemotherapy preconditioning regime contributes to the risk of safety problems, despite its CAR-T rivals using the drug without causing patients to die. The analysis also linked the age of patients and the number of lines of prior chemotherapy they have been through to the risk of toxicity.

If Juno is right, changes to conditioning regimes and inclusion-exclusion criteria will yield improved safety profiles. But, ultimately, Juno has more control over what it sees as the third factor affecting patient safety: The variability of the product. JCAR017 and Juno’s other defined cell composition candidates are designed to provide better safety and efficacy through exertion of greater control over factors such as cell health. Juno also thinks JCAR017’s co-stim domain may slow cell growth.

The CAR-T pioneer turned laggard has a lot resting on its bet on defined cell composition. Kite Pharma and Novartis have opened up commanding leads over Juno as a result of its safety issues. And, as such, Juno needs to ace the next steps in its R&D program, the centerpiece of which is a pivotal trial of JCAR017 in diffuse large B-cell lymphoma. Juno expects to start the study later this year. Juno is also working on a product similar to JCAR017 to replace JCAR015 as an ALL candidate.