A study of an experimental treatment for leukemia was abruptly halted this week following two patient deaths, raising questions about a closely-watched approach to cancer that involves reprogramming cells to seek and destroy the disease.
The development-stage biotechnology company is testing genetically engineered immune cells known as CAR-T cells to treat acute lymphoblastic leukemia in adults. It is the company's most advanced drug candidate and therefore the most visible indicator of progress for investors.
The Food and Drug Administration suspended the Juno Therapeutics trial Wednesday, after the company reported that two patients on its most advanced treatment died from swelling of the brain. A similar death was reported in May though both the FDA and Juno concluded there were "compounding factors," company executives said in a Thursday conference call.
Seattle-based Juno blamed the two recent deaths on the addition of a second chemotherapy drug to its pre-treatment regimen, rather than on the company's new therapy. The FDA is expected to let the study of the drug continue without the additional chemotherapy drug.
Juno's initial studies used only one chemotherapy drug to prime the immune system to work with the experimental therapy. But after adding a second drug, fludarabine, doctors saw an increase in "severe neurotoxicity," said CEO Hans Bishop.
"The last week has been difficult and humbling for everyone involved, in particular, of course, the physicians and the patients' families," said Bishop.
Experts said the researchers are taking the right approach by stopping the study and proceeding with caution. But they added that such setbacks are part of the research process.
"This sort of thing is incredibly common in new drug development. It's unfortunate, but I don't know how you avoid it," said Dr. Otis Brawley, chief medical officer for the American Cancer Society.
Juno's approach is part of a promising, but still unproven, approach that reengineers patients' immune systems to attack cancer. The company filters patients' blood to remove white blood cells called T-cells and genetically alters them in the lab so they can target cancer cells. They then return the modified cells to the patient.
One of study's researchers says that more than 300 patients have been treated with similar therapies in the U.S., without reports of brain swelling.
"These are relatively rare events, so I don't think it changes the fundamental promise or the long-term plan here," said Dr. Jae Park of Memorial Sloan Kettering Cancer Center in New York, who is one of several physicians conducting the trial.
Dr. Stephan Grupp, Novotny Professor of Pediatrics at the University of Pennsylvania Perelman School of Medicine, is running a similar trial funded by Novartis CAR T cells to treat pediatric leukemia patients.
He notes that none of the patients in his trial -- most of whom received the same chemotherapy drug added to the patients in Juno's trial -- have experienced significant brain swelling. Side effects related to the central nervous system seen in a small number of his patients include confusion, aphasia and seizures, "but these effects have all resolved," he said.
"Obviously, it is always hard to attribute toxicity to the chemo as opposed to the CAR-T cells when both are given around the same time, but we believe the self-limited CNS side effects we have reported from our study are more likely to be due to the T cells," Grupp said. "Right now, I don't see this affecting other CAR-T trials or the field as a whole, since this issue appears not be seen more broadly. There may be some discussion about the appropriate role of the drug fludarabine, but this wouldn't be a central issue."
Juno's therapy, known only as JCAR015, is in mid-stage testing, a make-or-break phase of development that usually focuses on effectiveness. Twenty patients are now enrolled in the trial and the company aims to eventually enroll 90 patients.
The company said it will seek FDA permission this week to continue the study without fludarabine. For now, the trial is on hold until the FDA signs off on new testing protocols, patient disclosure forms and other elements of the trial. Juno said that the FDA has agreed to review those materials on an accelerated timetable.
Juno is studying several similar gene-altering immunotherapies for various forms of leukemia and expects its first approval in early 2018. Other companies in the field include Novartis and Kite Pharma.
Juno shares plunged more than 30 percent in trading Friday to close at $27.81.