Bluebird’s Zynteglo safety snag could spell trouble for other gene therapies: analysts

Cancer cases that cropped up in a clinical trial definitely set back Bluebird Bio’s one-time blood disorder gene therapy Zynteglo. But the incident could ripple beyond the company's specific products, analysts argued.

Bluebird has already hit pause on selling Zynteglo as a beta-thalassemia therapy in Europe, even though the two cases—acute myeloid leukemia and myelodysplastic syndrome—happened in the drug’s sickle cell disease trial. It’s not approved in the U.S. for either use.

The company launched an investigation into the cancer cases to determine whether there’s a causal link, and the European Medicines Agency said Wednesday that it would examine the evidence and decide on future regulatory moves for Zynteglo “or any similar medicines under evaluation.”

The question focuses on whether Zynteglo’s lentivirus vector inserted itself into the human genome to cause cancer. Even though no other approved medicines use the same viral vector—as the EMA noted—analysts at Jefferies and J.P. Morgan figure the problem could reach beyond Bluebird.

“[I]t is hard to see how this news doesn’t have some clinical, regulatory, and eventually commercial implications...regardless of what further investigation uncovers,” JPM’s Cory Kasimov wrote in a Wednesday note.

RELATED: Bluebird Bio hits pause on rollout for ill-fated gene therapy Zynteglo as trial flags 2 cancer cases

Jefferies analysts listed three ways the Bluebird problem could affect the company itself and other gene therapies.

First, the team figures it would be difficult for Bluebird to completely rule out a causal relationship between Zynteglo and the blood cancers, given the small number of patients involved and the large number of potential generic culprits.

So far, 47 patients with sickle cell disease have been treated with the drug in clinical trials, and none of the 63 beta-thalassemia patients who've received it has developed cancer so far, Bluebird chief Nick Leschly said on a call Tuesday.

Bluebird’s approach is to investigate whether the vector is inserted into regions of the genome close to cancer-driving genes and whether the vector triggers any change in gene expression, Bluebird’s chief scientific officer, Phil Gregory, told investors on the call.

Even if evidence later proves that Zynteglo isn’t to blame for the two cancer cases among sickle cell disease patients, the drag on the drug’s commercial rollout could last for a while, the Jefferies team said, adding that physicians and the FDA may want to see longer-term follow-up data—possibly up to five years.

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Besides the vector and each patient’s own underlying risk factors, Bluebird also fingered the chemotherapy busulfan as a possible culprit. Zynteglo patients first take a busulfan preconditioning regimen to prepare their bodies for the gene therapy.

If that’s the case, the Jefferies team expects safety scrutiny across all gene therapy programs that use busulfan as a conditioning regimen. One example would be CRISPR Therapeutics and Vertex’s investigational CRISPR gene-edited therapy CTX001, a potential treatment for sickle cell disease and beta-thalassemia.

“The bigger issue is how to administer ex vivo cells with a non-chemo regimen that can successfully engraft cells and ensure patient safety, and we believe this is the long-term challenge for the field,” the Jefferies team said.