Juno Soars After the FDA OKs Restart of Clinical Trial

July 13, 2016
By Mark Terry, BioSpace.com Breaking News Staff

On Friday, June 8, Juno Therapeutics , headquartered in Seattle, announced that the U.S. Food and Drug Administration (FDA) had placed a clinical hold on its Phase II clinical trial of JCAR015 for relapsed or refractory B cell acute lymphoblastic leukemia after three patient deaths.

Late yesterday, the company announced that after a modification of the trial protocols, the FDA has approved continuation of the trial.

The first patient died in May, but there were confounding factors and neither the company nor the FDA felt a change was necessary. But last week, two additional patients died. The deaths correlated with a change in the trial protocols, when, in addition to receiving JCAR015, patients received a chemotherapy drug, fludarabine. All three patients died from cerebral edema, or swelling in the brain caused by excess fluid.

In the trial, patients first receive a cocktail of chemotherapy drugs that kills their existing T-cells. They are then given new T-cells that have been genetically engineered to specifically attack the patient’s cancer. Adding fludarabine to the cocktail appeared to help the new T-cells take hold, which is why partway through the trial Juno began adding fludarabine to the regimen.

After the connection was made and the hold put in place, Juno asked the FDA to allow them to continue the trial without fludarabine, and only with cytoxan and JCAR015, which was what was being done earlier in the trial.

Juno plunged to $27.91 on July 8 from $40.82 on July 7. Share prices have jumped to $34.26 currently at news of the continuation of the trial.

George Budwell, writing for Madison.com says, “Juno’s stated goal is to be among the first to bring a CAR-T therapy to market—perhaps following closely behind Kite 's KTE-C19 as a possible treatment for aggressive non-Hodgkin lymphoma. Now that this clinical hold has been lifted, Juno may indeed be able to achieve this lofty goal. But the company’s rather aggressive commercialization strategy is going to depend on JCAR015’s ability to continue to produce unprecedented response rates in ALL without the use of fludarabine.”

And that response rate has indeed been impressive. Part of the trial was conducted at Memorial Sloan-Kettering Cancer Center, and patients had a complete response rate of approximately 80 percent.

That said, CAR-T is complicated. Chimeric Antigen Receptor (CAR) T-cell therapy involves removing T-cells from the patient, genetically engineering them to express a CAR specific to the patient’s tumor, and infuse them back into the patient. It’s very personalized and labor-intensive. Juno, Kite Pharma, Bluebird Bio and Ziopharm Oncology have all shown positive patient responses.

But fairly dangerous side effects have also been noted, particularly in leukemia patients. One is cytokine release syndrome (CRS), which is a fast and huge release of proinflammatory cytokines into the bloodstream. The other is tumor lysis syndrome (TLS), which is when the contents of dying cells explode into the bloodstream. Together they pose serious health risks, which is part of why chemotherapy is used as a pre-treatment to cut toxicity.

If there’s a race to the market, primarily between Juno and Kite, Juno is not the only company to benefit from this news. John Newman, an analyst with Canaccord, wrote in a note to investors that the trial continuation is “encouraging for all CAR-T companies. Importantly, we believe that FDA views each clinical trial and construct differently, but that the agency was able to rapidly gain comfort with Juno’s new clinical plan using only cyclophosphamide in the conditioning regimen.”

Newman added, “We remind investors that Kite’s revenue opportunity in their lead relapsed/refractory DLBCL indication is nearly four times larger than Juno’s lead relapsed/refractory ALL indication, giving a distinct advantage to Kite, in our view. Importantly, we do not expect CAR-T therapies to be used off-label, suggesting that Kite’s first-move position for relapsed/refractory DLBCL is unlikely to be challenged by Juno unless robust clinical data and FDA approval are secured first.”