Investors brush off Car-T scare

Yesterday’s announcement by the FDA that it was investigating reports of Car-positive lymphoma in patients receiving Car-T therapy might have caused consternation among doctors, but investors largely shrugged off the news.The agency homed in on CD19 or BCMA-directed autologous products, citing a list of approved therapies in the hands of big pharma. This probably helped limit stock market carnage, as Car-T is only a small part of these companies’ businesses.Car-T’s cause was probably also aided by the agency noting that the benefits of these products continued to outweigh their potential risks, at least in their approved uses of late-line blood cancers.However, the development could be worse news for Car-T’s prospects in earlier blood cancer therapy lines, and in autoimmune disease, where the risk/benefit considerations would be different.The FDA said T-cell malignancies had occurred with several products in the class. Currently approved Car-T therapies comprise Bristol Myers Squibb’s Abecma and Breyanzi, Novartis’s Kymriah, Gilead’s Tecartus and Yescarta, and Johnson & Johnson and Legend Biotech’s Carvykti.All of those companies’ stocks remained unmoved yesterday, with the exception of Legend, which fell 5% – the smaller group is more exposed to any Car-T fallout than its partner J&J.There are also various companies with CD19 or BCMA-targeted Car-Ts earlier in development, but many of these are private. Of those with a market listing, Carsgen dropped 23%, while Arcellx dipped 4%. Autologous BCMA-targeting Car-T therapies in western trialsProduct/projectCompanyStatusAbecmaBristol Myers Squibb/2seventyApproved for ≥5L MMCarvyktiJ&J/LegendApproved for ≥5L MMCART-ddBCMAGilead/ArcellxImmagine-1 pivotal ph2 trial in 4L MM, data due H2 2024Zevorcabtagene autoleucelCarsgen TherapeuticsPh2 LUMMICAR-2 (NCT03915184) in ≥4L MM completes Dec 2024, BLA filing due H1 2025PHE885NovartisPh2 (NCT05172596) in ≥4L MM completes Dec 2025GC012F*GracellPh1/2 (NCT05850234) in ≥4L MM completes Mar 2026AUTO-8*AutolusPh1 Mcarty** in ≥4L MM, data due at ASH 2023Equecabtagene autoleucelIASO BiotherapeuticsPh1 (NCT05698303) in ≥4L MM completes May 2024ACLX-001Gilead/ArcellxPh1 (NCT04155749) in ≥4L MM completes Aug 2024NXC-201NexcellaPh1 NEXICART-2 in light chain amyloidosis completes Dec 2025*BCMA & CD19-targeting CAR-T; **investigator-sponsored trial. Source: OncologyPipeline. While, as a whole, Car-T cancer players were not too hard hit, groups developing Car-T for autoimmune disorders were not so lucky. Cabaletta and Cartesian, both fully focused on this burgeoning space, fell 27% and 9% respectively.Gracell and Autolus are exposed on both the cancer and autoimmune side: the former’s BCMA/CD19-directed project GC012F is already in early trials in lupus, while the latter recently said it would start a study next year of its CD19-targeting asset obe-cel in the same disease. Gracell’s stock slumped 17% yesterday, while Autolus closed off 5% after being down as much as 30% earlier in the day. That group recently filed obe-cel for a more conventional Car-T use, relapsed/refractory adult B-cell acute lymphoblastic leukaemia.Allogeneic Car-T players escaped damage, presumably because the FDA release only mentioned autologous therapy. However, the allogeneic field has already been hit by worries over chromosomal abnormalities, and companies active here are trading well off previous highs.It is worth noting that approved autologous Car-T therapies already carry a class warning about secondary malignancies, because of the risk posed by the viral vectors used to engineer the cells. It might take a while before it becomes clear whether the FDA will impose more restrictions. But, in the meantime, the impact on the sector has not been too disastrous. Autologous CD19-targeting Car-T therapies in western trialsProduct/projectCompanyStatusKymriahNovartisApproved for ≥2L ALL (pts ≤25yrs), ≥3L DLBCL, ≥3L FLYescartaGileadApproved for ≥2L DLBCLTecartusGileadApproved for r/r MCL & ALLBreyanziBristol Myers SquibbApproved for ≥2L DLBCLObecabtagene autoleucelAutolusFiled in US Nov 2023 for r/r ALLZamtocabtagene autoleucel*Miltenyi BiotecPh2 (NCT04792489) in ≥3L DLBCL completes Dec 2024Rapcabtagene autoleucel**NovartisPh1/2 (NCT03960840) in CLL, 3L+ DLBCL, ALL and 1L HR LBCL, data already availableIMPT-314*ImmPACT BioPh1/2 (NCT05826535) in ≥3L BCL (CAR-T-naive & experienced), data due H1 2024GC012F^GracellPh1/2 (NCT05850234) in ≥4L MM completes Mar 2026AUTO-8^AutolusPh1 Mcarty^^ (NCT04795882) in ≥4L MM, data due at ASH 2023KITE-363*GileadPh1 (NCT04989803) in ≥3L BCL completes Apr 2024SYNCAR-001 + STK-009SynthekinePh1 (NCT05665062) + IL-2 in ≥2L CD19+ haematologic malignancies completes Apr 2024Prizloncabtagene autoleucel*J&J/Cellular BiomedicinePh1 (NCT05421663) in ≥3L BCL completes May 2026*CD19 & CD20-targeting Car-T; **uses Novartis’s T-Charge fast production tech, also being developed in autoimmune diseases; ^BCMA & CD19-targeting Car-T; ^^investigator-sponsored trial. Source: OncologyPipeline.