1. Juno Therapeutics

Juno earns a rotten tomato because at least two of its CAR-T trial deaths might have been avoided.

In Roman mythology, Juno was the wife of Jupiter and queen of the heavens. In today's world, it's a celestial name for a biotech that fell far from the stars in 2016. Juno Therapeutics is, of course, part of a collective of new biotechs, including rivals Kite Pharma and Bluebird Bio, as well as Big Pharmas, such as Novartis, in trying to become the first to market a new class of cancer medicine using CAR-T (chimeric antigen receptor T cells).

Juno is now, however, far behind Novartis and Kite Pharma, which are set for possible FDA approvals in 2017 or early 2018 for their blood cancer candidates CTL019 and KTE-C19 (a.k.a. axicabtagene ciloleucel), respectively.

Juno had too been in this leading pack, but a string of deaths in its key phase 2 test of JCAR015 changed all that. The so-called Rocket trial, studying the Juno med in relapsed or refractory B cell acute lymphoblastic leukemia in adults, was brought back to the ground with a clinical hold.

Three young adult patients died, and all of the deaths were attributed to cerebral edema. Juno was quick to announce that its drug candidate did not cause the deaths, blaming instead a pre-conditioning regimen it (and other companies) use before administering experimental CAR-T treatment.

Juno said it would remove the perceived culprit, fludarabine, from the trial and move on. The FDA promptly agreed, allowing the biotech to re-start its test under the new study protocol just a few days later. Juno's shares jumped about 25% on the news.

After the first trial deaths and halt, legal firm Block & Leviton sued Juno and its CEO Hans Bishop for alleged securities fraud, saying that Juno “made misleading omissions regarding a patient death in the Phase 2 “ROCKET” trial of its lead product candidate, JCAR015 […] Juno knew the patient death was important and consulted with the FDA about an appropriate response. Yet it failed to tell investors.”

It said that instead, in early June, Juno issued “a glowing press release that boasted of “[l]ower side effects” and made partial, misleading disclosures—revealing that “Grade 3 or higher neurotoxicity was observed in 15/51 (29%) patients” in a phase 1 trial but failing to disclose the patient death in May.”

It also alleged that Bishop and other Juno insiders “sold heavily in the weeks prior to these revelations.” A Juno spokesman said those sales were prescheduled "well before the events of the Rocket trial," under Securities and Exchange Commission rules designed to allow insiders to sell their shares without worrying about running afoul of insider trading rules.

Then in November, the decision to carry on proved fatal: Two more deaths were reported from the modified Rocket trial, again from cerebral edema. Juno put a hold on its own study toward the end of November to investigate.

In an email, a Juno spokesman said the company had believed fludrabarine was "an appropriately modifiable factor" that could improve the treatment regimen's safety, but that the improvement wasn't enough. "The data show that removing fludarabine did indeed reduce the incidence of severe neurotoxicity," the spokesman said. "Unfortunately, it did not completely eliminate the toxicity, and we saw additional treatment-related deaths in November."

In an update on the study, offered during January’s J.P. Morgan presentation, Juno said it was still mulling its options. The company might further modify the Rocket trial to continue testing JCAR015, start another trial of the med that “explores opportunities to modify benefit/risk ratio,” or abandon the candidate altogether to focus on its other CAR-T candidates, namely JCAR017, which has not been affected by these safety concerns.

Analysts at Leerink said in a note to clients issued in November that there was a “question of whether the company moved into a pivotal trial too fast.”

Then, in March, the inevitable happened: Juno dropped JCAR015 completely to focus on its other CAR-T candidates. In a statement, Juno said, "Through the investigation Juno identified multiple factors that may have contributed to this increased risk, including patient specific factors, the conditioning chemotherapy patients received, and factors related to the product.

"Although Juno believes there are protocol modifications and process improvements that could enable Juno to proceed with JCAR015 in clinical testing ... Juno would first need to establish preliminary safety and dose in a phase 1 trial. As a result of the timing delay that would entail and Juno’s belief that it has other product candidates in its pipeline that are likely to provide improved efficacy and tolerability," the company decided to set JCAR015 aside.

In the middle of summer last year, Juno was nearing $50 a share on the promise of its CAR-Ts; just over six months down the line and it’s now trading at more than half that, at $23, after the study halts and deaths.

Trials are by their nature experimental, and the danger of death remains a possibility when pushing at the edges of medical science, as CAR-T tests are doing, and especially in patients with an aggressive form of cancer.

Meanwhile, the current standard of care has a treatment-related mortality rate of "roughly 25%," the Juno spokesman said via email, and that's "higher than what we have seen on CAR-T trials, including Rocket."

"We have treated over 200 adult ALL patients, so we have extensive experience with this patient population, and it is clearly a very difficult disease to treat, and patients have few, if any, clinical options," the spokesman said.

But Juno earns a rotten tomato award (and the FDA does not come out ripe here either) because at least two of these deaths might well have been avoided, had Rocket been placed on hold for longer, and a more extensive investigation into the fatalities been sought.

The lightening quick turnaround and Juno’s absolute insistence that fludarabine was to blame smacks of a concern with share prices and future market leadership. Juno's decision to drop the drug came too late for several patients, and questions will long remain over why it was allowed to continue its trial after the summer of 2016 when it was still unclear as to what had caused the deaths. 

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1. Juno Therapeutics

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