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

Bluebird Bio’s blood disease gene therapy Zynteglo simply can’t catch a break, even now that it’s cleared for the market.



Tuesday, the Massachusetts biotech said it has halted selling Zynteglo as a beta-thalassemia treatment in Europe after a phase 1/2 trial of the gene therapy in sickle cell disease turned up two blood cancer cases—one of acute myeloid leukemia (AML) and one of myelodysplastic syndrome (MDS). The drug’s not yet approved in the U.S.



The study and another phase 3 in sickle cell disease have been put under clinical hold as the company investigates whether there’s a causal relationship between the cancers and the use of the BB305 lentiviral vector used to deliver the gene therapy. Both the FDA and the European Medicines Agency have been alerted of the events, the company said.



During a conference call on Tuesday, Bluebird chief Nick Leschly cautioned that people “resist the temptation to draw premature conclusions, and let the rapidly emerging data lead the way.” He estimated that the company will have some preliminary answers in a timeframe measured by weeks as opposed to months.



Another viral vector, called gammaretrovirus, has been linked to cancer before. Orchard Therapeutics’ retrovirus-vectored Strimvelis, designed to treat the rare inherited condition ADA-SCID, was tied to one leukemia case.


RELATED: Orchard Therapeutics' gene therapy Strimvelis linked to a leukemia case


It’s believed that retrovirus may cause cancer by integrating its own gene into the human genome. But Zynteglo’s lentivirus vector was specifically designed to minimize that risk, Leschly pointed out.



The investigation is focused on two things, Bluebird’s chief scientific officer, Phil Gregory, explained on the call. First, researchers will try to understand the location at which the vector has landed. Part of gammaretrovirus’s problem is that its integration site is close to known genes involved in genome stability and cancer formation, Gregory said. Second, the company will aim to shed light on whether the vector exerts any change in gene expression in regions close to its insertion.



In the MDS case, Bluebird doesn’t yet know whether the tumor cell carries a lentiviral vector sequence, but the vector has been detected in the AML case’s cancer cell, Leschly said.



The CEO pointed to many other potential explanations for the cancers, including patients' existing underlying risk factors. In fact, the now-halted phase 1/2 trial had previously reported another MDS incident. In that case, the company was able to quickly exonerate the vector because there wasn’t any vector in the rogue blood cells and the patient was found to carry a classic driver mutation believed to be the cause of the cancer, Bluebird’s chief medical officer, Dave Davidson, told investors on the call.


RELATED: Bluebird tanks as FDA's LentiGlobin demands in sickle cell delay filing to late 2022


Zynteglo’s history is studded with all sorts of setbacks. The gene therapy was granted conditional approval to treat transfusion-dependent beta-thalassemia in Europe in mid-2019, but the company then delayed a launch into 2020 as it worked to improve its drug product specifications and manufacturing process.



Then COVID-19 hit. Despite a nominal launch in Germany last January, as of November, the company was still saying it expected to treat the first commercial patient by the end of 2020. But so far, there’s no word on that update. The company didn’t immediately reply to a request for comment on the drug’s commercial progress in Europe.



Meanwhile, the FDA recently hit back against the product in sickle cell disease the U.S. The agency is asking Bluebird to provide additional information on the manufacturing process it will use for the commercial product versus the clinical trial version, requesting the company to show drug product comparability. The extra demand pushed back the timing of a potential FDA application back to late 2022.



To add to Zynteglo’s misery, England’s drug cost watchdog, the National Institute for Health and Care Excellence, just declined to cover the gene therapy in draft guidance. It pointed to the drug’s small clinical trial size as well as its patient follow-up time as lacking evidence of long-term value.