Safety concerns spark FDA probe into CAR-Ts
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The FDA on Tuesday said it has launched an investigation into reports about serious risk of T-cell malignancies with CAR-T therapies, including CAR-positive lymphoma, and is considering whether it needs to step in. The agency suggested that this risk applies to all currently approved BCMA- and CD19-directed autologous CAR-T immunotherapies, noting that T-cell malignancies have occurred in patients treated with "several products."
Therapies in the class currently authorised in the US include Bristol Myers Squibb' Breyanzi (lisocabtagene maraleucel) and Abecma (idecabtagene vicleucel), the latter partnered with bluebird bio spinout 2seventybio; Johnson & Johnson and Legend Biotech's Carvykti (ciltacabtagene autoleucel); Novartis' Kymriah (tisagenlecleucel); and Gilead Sciences' Tecartus (brexucabtagene autoleucel) and Yescarta (axicabtagene ciloleucel). All of these have been approved for various blood cancers.
"Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalisation and death, and is evaluating the need for regulatory action," it said.
Tougher hurdle in autoimmune disease
The news sent several developers of autologous CAR-T therapies spiralling downward, while those working on similar allogeneic treatments saw gains.
Cabaletta Bio, whose shares tumbled as much as 46%, is working on CABA-201, an autologous CD19-directed CAR-T being advanced in Phase I/II trials for various non-cancer indications including systemic lupus erythematosus, myositis, systemic sclerosis and generalised myasthenia gravis. The company plans to share initial results of the lupus trial in the first half of 2024, and while some analysts do not think Tuesday's announcement by the FDA will impact this upcoming readout, which will only include early data, they see it as more of a longer-term debate surrounding the safety profile of CABA-201.
Gracell Biotechnologies declined around 25% on the news, a day after the FDA gave its blessing for the company to begin Phase I/II testing of the lupus treatment GC012F. The autologous CAR-T therapeutic targets both BCMA and CD19, and uses Gracell's proprietary FasTCAR next-day manufacturing platform. Autolus Therapeutics, which is developing the autologous CD19 CAR-T therapy obe-cel for blood cancers and lupus, slid 28%.
Meanwhile, Allogene and Cellectis, which are both developing allogeneic CAR-T products, saw stock gains of about 2% and 9%, respectively. The pair are already partnered, with Cellectis having granted Allogene an exclusive, worldwide license to develop and commercialise CAR T-cell products directed against a total of 15 selected targets, including BCMA, FLT3, DLL3 and CD70.
Life-long monitoring
As with all gene therapy products with integrating lentiviral or retroviral vectors, the FDA noted that the risk of developing secondary malignancies is labeled as a class warning in the prescribing information for approved BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies. Initial approvals of these products included post-marketing requirements to conduct 15-year follow-up safety studies to assess long-term safety and the risk of secondary malignancies occurring after treatment.
On Tuesday, the agency recommended that patients and clinical trial participants receiving treatment with BCMA- and CD19-directed autologous CAR-T immunotherapies should be monitored life-long for new malignancies.
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