After Trial Deaths, Juno Pivots and Scraps Lead CAR-T Therapy

Xconomy Seattle — 

Juno Therapeutics said today it would discontinue its experimental CAR-T cell product known as JCAR015. It was once Juno’s top candidate as the company raced rivals to be the first to win approval of a new kind of cancer treatment called CAR-T. The decision was not unexpected.

Juno (NASDAQ: JUNO) hoped that a 110-person clinical study called Rocket would be the stepping stone to an approval, perhaps this year, to treat adults with desperate cases of acute lymphocytic leukemia (ALL). Instead, five people died from JCAR015 in extremely unusual circumstances, ultimately dooming the experimental medicine and knocking Juno back at least a year or two behind competitors.

“We have decided not to move forward with the ROCKET trial or JCAR015 at this time, even though it generated important learnings for us and the immunotherapy field,” Juno president CEO Hans Bishop said in a statement.

Bishop added that the company plans to begin a trial with a different experimental product in adult ALL next year.

In this type of CAR-T treatment, a cancer patient’s own T cells, usually immune system killers that attack would-be cancer, are given a boost with genetic surgery outside the patient’s body, then put back inside to hunt down the patient’s cancer.

The death rate due to the treatment in the ROCKET trial was 13 percent (5 of 38 patients receiving JCAR015), which Bishop has said is roughly on par with other CAR-T trials in the same patient group—adults with late-stage ALL. Those rates are also lower than the death rate due to bone-marrow transplant in the same patient group. The red flag, however, is that all five deaths were from cerebral edema, or severe brain swelling, a side effect that has not cropped up with other experimental CAR-T programs—at least not publicly or with deadly effect.

Juno first reported three deaths in July 2016. Executives blamed the chemotherapy combination patients were given in advance of the T cells, even though other CAR-T companies were using the same drug combination for their patients without any sign of edema.

A few days later, the FDA allowed Juno to continue the trial if one of the chemotherapies, fludarabine, was removed. It didn’t help. Juno reported two more deaths in November, and the trial was shelved. Juno vowed to investigate thoroughly. In January, Bishop told Xconomy that its inquiry was looking “at every manufacturing and product attribute you could think about, and at a whole series of clinical attributes related to patients and their pretreatments.”

“Until the picture is complete, it’s wrong to isolate any variable,” Bishop said at the time.

The picture still remains unclear. In a statement this afternoon, Juno said it identified “multiple factors” that could have contributed to the problem, from the chemotherapy to the product itself. But while certain “modifications and process improvements” could help Juno proceed with a new trial of JCAR015, it would effectively need to hit the reset button and start in Phase 1 again. The delay, combined with the other options Juno has in its pipeline, led the company to put its resources elsewhere.

When asked in January if Juno should have waited longer to restart the trial, Bishop said fludarabine was “the most appropriate and modifiable factor” of several factors in the deaths, so the firm decided to move forward without it. Bishop said Juno had in mind the well-being of patients in the trial. “There were patients who benefited from continuing the trial,” he said. “These decisions are always difficult.”

Scott Solomon is an oncologist whose Atlanta-based clinic, the Blood and Marrow Transplant Group of Georgia, was preparing to enroll patients in Rocket before the hold last summer. He agreed that the patient population—those who have failed traditional therapies such as bone marrow transplants—would otherwise have survival “measured in weeks to months, not years.” In aggregate, he said that CAR-T programs have shown a “reasonable degree of safety, especially compared to bone-marrow transplant,” where the treatment-related deaths are in the 15 to 20 percent range, he said. When transplants work, however, they often cure patients. CAR-T therapies haven’t been around long enough to determine how long patients successfully treated will stay in remission.

None of Juno’s other experimental products have been affected by the Rocket study deaths. In December, Bishop and other Juno officials touted data from a different experimental treatment, JCAR017, that it hopes to move into a pivotal study in non-Hodgkin lymphoma (NHL)—one designed to present regulators with data for commercial approval. Juno also has experimental CAR-T products such as JCAR016, JCAR018, and JCAR014, which are being developed for other blood cancers such as acute myeloid leukemia and chronic lymphocytic leukemia.

Still, the entire episode has left Juno behind its rivals. Kite Pharma (NASDAQ: KITE) will soon ask the FDA for approval to use its CAR-T therapy, known as axicabtagene ciloleucel, to treat patients with desperate cases of NHL. An FDA decision could come this year. Novartis has also said it plans to seek FDA approval this year of a CAR-T therapy for kids with acute lymphocytic leukemia.

Ben Fidler contributed to this report