The Food and Drug Administration has cleared Allogene Therapeutics to resume testing its cancer cell therapies after determining the company's technology wasn't to blame for a "chromosomal abnormality" observed in a patient who received one of the treatments.
According to Allogene, the agency agreed with the conclusion of its investigation, which found the abnormality wasn't related to the gene editing involved in its treatment and didn't lead to any health problems. As a result, Allogene will work to restart as quickly as possible the studies that had been halted — all tests of experimental drugs for several blood cancers.
The green light is critical for Allogene, shares of which had sunk to all-time lows after the FDA halted its clinical trials in October. It's also a boost for the field of allogeneic, or "off the shelf," cellular treatments for cancer, which are meant to be more convenient alternatives to the personalized CAR-T therapies now used to treat several blood cancers. Allogene is furthest along, giving the investigation and its outcome far-reaching implications for other developers of off-the-shelf treatments, many of which involve gene editing.
In an email, Allogene said it intends to publish the details of its investigation in a scientific forum. "We now know all aspects of this abnormality," Allogene said. But "for the benefit of patients, we believe the field needs to better understand" what happened.
Allogene is developing its treatments for lymphoma, leukemia, multiple myeloma and some solid tumors. They consist of donor cells engineered to find and destroy cancerous cells expressing a certain protein. A gene editing technology, called TALEN, is also used to alter the cells so they don't trigger a potentially dangerous immune response.
These types of treatments could expand the reach of the CAR-T therapies, which are made from patient cells and, though powerfully effective, have been hampered by the logistical challenges of producing and delivering them.
But while experimental drugs from Allogene, CRISPR Therapeutics and others have produced response rates in line with their CAR-T counterparts, they haven't appeared as durable. Allogene and CRISPR Therapeutics have started evaluating second doses to boost their effects.
In early study results, off-the-shelf CAR-T treatments appeared safe, with no signs of graft-versus-host disease, a top worry with drugs that use genetically engineered donor cells. But concerns emerged in October, when Allogene said some of the biopsied cells in a study participant who received its most advanced therapy, a lymphoma treatment called ALLO-501a, had a "chromosomal abnormality" that was detected after the patient experienced a series of side effects.
The finding alarmed the FDA, which immediately halted studies not just of ALLO-501a, but of all Allogene's therapies, pending an investigation. Analysts questioned whether the gene editing or manufacturing of the treatment played a role, a potential link that would have damaged the potential of allogeneic therapies, if established.
In the three months since, Allogene conducted an "extensive investigation," which included mapping the abnormality, developing lab tests to analyze various samples and scrutinizing multiple manufacturing lots, the company said in an email. It concluded the abnormality was an "isolated event" that occurred after the product was administered and didn't cause any problems. The abnormality involved regions of genes that "naturally undergo rearrangement" as part of the process by which immune cells mature, Allogene said.
Allogene now intends to start what's meant to be a pivotal study of ALLO-501a in the middle of the year, months later than its previous target of by the end of 2021. It's too early to say how the timelines for its other programs will change, the company said.
The entire episode has taken Allogene executives by surprise. In October, for example, CEO David Chang stressed that the finding was from one patient out of more than 100 who have been treated with its therapies in clinical trials, and appeared on a fraction of the cells that were examined. What's happened since shows "there is now a greater burden of proof" for off-the-shelf cell therapy developers, Allogene said in its email.
"There are so many new companies and the pace and required sophistication at which we are all learning cannot be compared to three to five years ago, both within industry and the FDA," the company added. "The bar is very high."