he fallout from the clinical hold that regulators placed late Thursday on a key clinical trial being run by Juno Therapeutics may not be known for weeks, if not longer. Of course, the ramifications are already being dissected, especially on Wall Street, where investors are trying to determine the extent to which the approach that Juno is taking to combating cancer will affect its fortunes and possibly other companies, as well.
To quickly recap, Juno is exploring CAR-T immunotherapy — genetically modifying patient T cells, which help fight cancer, and then injecting them back into the bloodstream. But its most advanced project, which involves a compound called JCAR015, led to three patient deaths. The mid-stage trial, known as Rocket, is testing the compound in adults with B-cell acute lymphoblastic leukemia.
Juno believes the culprit is fludarabine, a chemotherapy that was added to the mix of drugs used to treat patients before administering JCAR015. The FDA has asked the drug maker to submit various materials, but for now, it remains uncertain what happens. Meanwhile, Wall Street analysts are ballparking the odds. Here is what some of the wags are telling investors Friday morning …
Joshua Schimmer of Piper Jaffray:
“While the evolving data do not suggest that fatal neurotoxicity is a problem across all CAR programs, severe neurotoxicity (cerebral edema) and severe cytokine release syndrome … are consistently seen. As such, it’s not surprising to us to see fatalities emerge with the Juno program. Exactly what the recipe is that leads to a patient death is unclear, but it does highlight the need to consider the entirety of these regimens and not pretend that it’s all ‘just the cells’ that are responsible for the safety and efficacy profiles.
“We had spoken with Juno management earlier in the year and found it difficult to pin them down on any nuances of their (CAR) programs, which seemed like a moving and evolving target to us, further confounding the ability to ascribe blame to any particular aspect of their program. That said, it may be naive to believe that other potent CAR-based regimens won’t be associated with fatal events.”
Barclays analysts Jonathan Eckard, Geoff Meacham, and Bryan Czyzewski:
“We view the treatment-related patient deaths and clinical hold … add risk to this program, which could broaden if FDA concerns carry over to other Juno CAR-T programs. Our initial view is that the data suggest these events being specific to the Rocket trial, and therefore, the ultimate impact on Juno could be contained. However, if broader FDA concerns materialize, we expect this to occur quickly — days to weeks. … We believe most important will be to watch for any updates on other Juno trials. If there are no negative headlines over the next 1-2 weeks, we believe the risk could be contained to the Rocket program.”
Chris Shibutani and Santhosh Palani of Cowen:
They describe the clinical hold as a “bump in the road” and a “setback that appears manageable. The scope of the safety issue appears contained (to the Juno compound and the combination of both cyclophosphamide and fludarabine) and we see Juno’s response plans as reasonable. We see a delay in timelines, not a failure of the adult acute lymphoblastic leukemia program.
“Determining causality of the patient deaths is clearly a challenge given the multiple potentially contributing variables and the relatively small number of patients involved. That said, we are heartened by the data — which has shown thus far, the combination of solid efficacy, as well as reasonable safety (no patient deaths) seen in patients.” They note these patients have already been managed using the cyclophosphamide-only regimen, which Juno plans to use going forward.”
SunTrust Robinson Humphrey analysts Edward Nash, Yun Zhong, and Mike Guo:
In assessing the impact on Bluebird Bio, which is currently running a Phase 1 study in patients with refractory multiple myeloma, they do not think it will be affected by Juno safety issues. They note that neurotoxicity is common in all patients receiving chemotherapy, but is not frequently observed in multiple myeloma patients. And while the same regimen of fludarabine and cyclophosphamide is being used in the study (CRB-401), “the cyclophosphamide dose is only one-third to half of what was used in Juno‘s JCAR015 study so the dose is much lower and should be associated with a lower rate of side effects.”
For those of you wondering about the next steps at Juno, the FDA requested Juno submit four items to address the clinical hold: a revised protocol that will remove fludarabine; a revised informed consent form; a revised investigator brochure; and the presentation made to the agency on Wednesday. Juno plans to submit the materials this week and anticipates an expedited response.
But timelines can vary. The FDA has 30 days to respond or at least provide feedback. Of course, the process could extend beyond that timeline if the agency decides to conduct a safety analysis or asks Juno to modify the protocol.