The death of two patients has halted a clinical trial that explores a new approach to treating cancer. They died following severe brain swelling, according to Juno Therapeutics. It is the second time the company's experimental therapy has been tied to fatal side effects.

The incident is believed to derail the program entirely. Previously, the FDA stopped the same study that tests the therapy on adults with acute lymphoblastic leukaemia (ALL), as three patients died of cerebral edema. The comapny claimed that it was not due to the product - an infusion of genetically engineered cells - but rather due to the cocktail of chemotherapies used to treat patients before they underwent experimental therapy.

The company removed the drug fludarabine from the cocktail and the FDA quickly approved the continuation of the study. However, with recent events, the safety of the therapy called JCAR015 is being questioned.

One of the patients who died was younger than 30 and the other was older, but no specifics were provided by the company. Brad Loncar, founder of a cancer immunotherapy fund, said Juno was "going way too fast on this."

"It's just terrible," Loncar said. "They've killed a couple of people, and it seems like, in part, it's because of the rush to judgement."

CAR-T: A promising treatment gone awry

The company has been working on treatments made by harvesting a patient's own immune cells and rewiring them to home in on tumours in the body. These therapies known as CAR-Ts, had promising early results in certain cancers, but scientists have acknowledged that they have just began to understand the field.

It appears that the rapid proliferation of CAR-T cells, once injected back into the body, seems to be directly correlated with patients developing cerebral edema, said Dr. Mark Frohlich, Juno’s executive vice president of portfolio strategy. The "big focus" of the company now is to understand what went awry with the JCAR015 trial.

“It is our view that the removal of fludarabine has reduced the incidence of severe neurotoxicity,” Juno CEO Hans Bishop said. “It just hasn’t gotten us as far as we hoped that it would.”

However, CAR-T therapy is known for its laundry list of highly toxic symptoms. Apart from cerebral edema, patients can also develop "cytokine release syndrome" - in which T cells expel chemicals that lead to severe fevers, nausea, difficulty in breathing, low blood pressure, and organ swelling. The more serious the cancer, the worse the cytokine storm.

“Patients have virtually no other options”

Apart from developing CAR-T therapies for ALL, Juno is also developing it for other blood cancers but ALL was prioritised as they "appear to be the most challenging to balance toxicity and efficacy," Frolich said.

The alternative for patients with ALL is salvage chemotherapy, which is "infrequently efficacious" with 11% to 23% of patients dying from treatment-related symptoms, according to Juno's CFO, Steve Harr.

"We all are grasping with how we control this better," Harr added. "But we need to expect that if we have efficacy in this setting, there will be some toxicity."

Bishop also emphasised that the patients involved were already quite ill before joining the trial.

"These patients have virtually no other options, and have a highly lethal disease," he said.

The company's other clinical trials are still not affected and Juno is on track to launch its first drug as early as 2018. However, Loncar argued that the Juno management still have no idea why the patients involved have been dying in the JCAR015 trial.

Added pressure on FDA's transparency and approval policies

The FDA will also undergo scrutiny for allowing Juno to continue trials just days after the first time it was halted. Some experts have argued that the FDA made the right decision as the patients are running out of time, but others question about how the FDA weigh the benefits and risks accordingly.

“What did the FDA review during that period from when the hold was announced to when it was lifted? What exactly was the decision-making process? What was the logic behind going so quickly towards lifting the hold?” asked Maxim Jacobs, a health care analyst who researches oncology drugs.

No comment was provided by the FDA but while it is possible that the FDA has a systematised process to review clinical holds, it is impossible to tell as companies consider that information to be trade secrets, said Dr. Aaron Kesselheim, who studies the intersection of law, regulation, and drug development.

He added that apart from disclosures for panel hearings - that are sometimes held to debate the risks and benefits of a drug in line for approval - any insight into FDA's deliberations before approval is up to the company's discretion to make public. MIMS

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