Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Loss of Lives in Clinical Trials Has Companies, and Investors, Proceeding with Caution

The seven patient deaths disclosed recently by Juno Therapeutics and Ziopharm aren’t likely to derail cancer-fighting cell and gene therapies for years as happened with gene therapy after 18-year-old Jesse Gelsinger died in a 1999 clinical trial.

But the recent deaths are sobering reminders of the risks associated with both therapies—risks that have cooled what last year had been red-hot investor enthusiasm for developers of both types of treatments.

“A year ago, there was total euphoria. There was euphoria for gene therapy, and euphoria for these cell-based cancer therapies,” Brad Loncar, CEO of Loncar Investments, told GEN. The firm last year launched the first exchange-traded fund to hold shares exclusively of public companies focused on cancer immunotherapies. “Definitely a lot of excitement has left the arena.”

That has been especially true in recent days. On July 13, Juno Therapeutics acknowledged in a regulatory filing that four patients have died in trials related to its chimeric antigen receptor (CAR) T-cell candidates.

One death occurred during a trial of JCAR014, designed to treat patients with acute lymphoblastic leukemia (ALL) as well as relapsed or refractory (r/r) chronic lymphocytic leukemia and non-Hodgkin lymphoma (NHL). The other three took place during the Phase II ROCKET trial of its ALL candidate JCAR015. The JCAR015 deaths—all instances of cerebral edema in patients under age 25—led the FDA to briefly impose a partial clinical hold on the ROCKET trial, a hold that was lifted less than a week later after Juno agreed to modify the protocol to cyclophosphamide alone.

Juno blamed the deaths on a change to its protocol that entailed preconditioning patients with a combination of cyclophosphamide and fludarabine, adding that the JCAR014 death may also reflect a higher dose of the treatment than is now used.

From July 7 to 11, Juno shares fell 33%, from $40.82 to $27.33, before inching back up to $28.65 on July 20.

A day after Juno’s disclosure, Ziopharm submitted its own regulatory filing confirming the deaths of three patients in a Phase I study of its viral gene therapy candidate Ad-RTS-hIL-12 plus oral veledimex in patients with recurrent or progressive glioblastoma (GBM) or grade III malignant glioma.

On July 19, Ziopharm said the third death, involving a patient who developed an intracranial hemorrhage, was unrelated to Ad-RTS-hIL-12, on the basis of a data analysis by the company and the trial’s safety review committee. The company’s shares fell 17% between July 14 and 20, from $5.67 to $4.68.

The Juno and Ziopharm tragedies add to setbacks that began, Loncar said, with data that failed to match investor expectations presented at last December’s 57th American Society of Hematology (ASH) Annual Meeting. A case in point is bluebirdbio, whose shares fell nearly 38% on December 7, a day after this gene therapy developer released mixed data on its LentiGlobin® BB305 treatment for patients with beta-thalassemia major and severe sickle cell disease.

Also at the ASH meeting, Novartis presented mixed Phase IIa data revealing an overall response rate (ORR) of just 47% (7 of 15 patients) in adult patients with r/r diffuse large B-cell lymphoma (DLBCL) after 3 months of treatment with its CAR T-cell therapy CTL019. The therapy fared better in adult patients with follicular lymphoma, where the ORR reached 73% (8 of 11 patients).

Novartis, like Juno, is among CAR T-cell therapy developers, as are Celgene and Kite Pharma. On the day Juno disclosed its clinical hold, Kite announced it had completed its enrollment of 72 patients with diffuse large B-cell lymphoma in the Phase II portion of their ZUMA-1 trial, designed to assess its lead candidate KTE-C19. The protocol of ZUMA-1, Kite emphasized, has patients receiving fludarabine plus cyclophosphamide at lower doses than what Juno used.

“These companies will proceed with a little bit more caution in how they mix these chemotherapies with their CAR T-cell therapy. And I think that they will have to be as cautious as possible,” Jane Andrews, Ph.D., senior consultant, healthcare & lifesciences, North America with Frost & Sullivan, told GEN. “You’re going to see a blip and people are going to say, ‘I want to make sure that there’s nothing that’s going to be really bad happening here.’”

Another lesson for companies, she said, is that optimal efficacy isn’t always the best efficacy if it’s dangerous. Juno changed its preconditioning protocol, CEO Hans Bishop told analysts, after the fludarabine and cyclophosphamide combination showed greater efficacy in other trials without added problems.

“Unless there are more of these deaths, and it becomes something like, every time you try something, there’s a death, I don’t think it’s going to have a long-term effect on investment,” Dr. Andrews added.

Global biopharmas, she said, remain eager for collaborations focused on cell, gene, and stem cell therapies. Just how eager was most recently seen July 19, when Celgene launched an up-to-$2.6 billion-plus collaboration with Jounce Therapeutics. Celgene will receive options to develop and commercialize jointly Jounce’s lead candidate JTX-2011 and other cancer immunotherapies.

Loncar said CAR T-cell therapy developers are particularly vulnerable to aggressive investors willing to oversell good news or overplay bad news for their own gain.

“There’s a huge debate over whether CAR T-cell therapy is eventually going to be a commercially applicable approach. And so, you have a lot of people who are bullish, and who have long positions, and you have a lot who are bearish, that have short positions,” Loncar said. “This is something that Wall Street is imposing on these companies in a bad way. Sometimes investors, sadly, view these companies as stocks first and companies second. Of course, the reality and the priority should be the exact opposite.”

Loncar thinks investors will remain especially cool to CAR T-cell therapy until some company comes out with positive clinical data. Such an event, he said, may come as soon as the second half of this year, when Kite has said it will release interim results from the pivotal Phase II portion of the ZUMA-1 trial: “If that’s good, people might forget about the Juno case.”

Kite Pharma has not been immune to ups and downs with investors. Loncar recalled how last year, Kite was forced to calm uneasy investors following the death of a patient treated with KTE-C19 in the Phase I portion of a Phase I/II trial assessing the candidate in patients with refractory aggressive NHL.

Kite stock tumbled 24% from August 5 to 14 as news of the death circulated on Wall Street, before CEO Arie Belldegrun held an August 17 conference call where he emphasized that the death was unrelated to the treatment. The FDA did not order a clinical hold.

“With any new therapy, you’re going to have these kinds of things happen, especially when you’re dealing with critically ill people. And I would hate to see these kinds of therapies be stopped or put on hold because they have such curative potential,” Dr. Andrews said. “There is such promise in cell and gene therapy and CAR T cells, that the world realizes that to put these things on hold would be a disadvantage to humanity in general.”










































 

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