Three patients died in Novartis trials of its CD19-directed CAR T treatment after a dangerous immune system response, and a similar therapy from Bristol Myers Squibb has also been put on hold to review safety issues, the companies separately told Endpoints News.
The treatment is known as rapcabtagene autoleucel, or rap-cel, and is being tested in immunology and neuroscience programmes. The three patients who died experienced what’s known as immune effector cell-associated haemophagocytic syndrome, a condition in which the immune system becomes overactive.
A Novartis spokesperson told Endpoints that “resulting complications led to fatal outcomes”, and that Novartis is conducting a “comprehensive review actively sharing information with health authorities”.
The Novartis trials being paused are in systemic lupus erythematosus/lupus nephritis; systemic sclerosis; antineutrophil cytoplasmic antibody-associated vasculitis; idiopathic inflammatory myopathies; rheumatoid arthritis and Sjogren’s disease; generalised myasthenia gravis; and relapsing multiple sclerosis and non-active progressive MS.
Bristol Myers has also voluntarily paused enrolment in autoimmune trials for zolacabtagene autoleucel, or zola-cel, another CD19-targeted CAR T, due to “transient and reversible inflammatory events during routine study surveillance”, a company spokesperson said. The company declined to comment on the number or nature of those events.
“To date, the overall safety profile of zola-cel remains consistent with the known profile of CAR T therapies,” the Bristol Myers spokesperson said.
The toxicities raise questions about cell therapies as drugmakers seek to expand their use beyond oncology. The treatment of certain blood cancers has been transformed by CAR T therapies, which re-engineer a patient’s T cells to find and destroy cancer.
Over the past several years, there’s been growing excitement about their potential to address autoimmune conditions by “resetting” the immune system. A handful of drug developers are in the clinic, including Autolus, Cabaletta and Kyverna.
Concerns for the category
“If Bristol Myers and Novartis aren’t able to resolve their safety questions, that would take out some of the bigger competitors,” William Blair analyst Matt Phipps told Endpoints.
“Bristol and Novartis are definitely two of the leaders. If these issues pop up in more trials, then that would really limit how competitive they could be in this space.”
Several trials of Kyverna’s therapy, known as miv-cel and a CD19-targeting CAR T treatment, also appear to have ended, according to ClinicalTrials.gov. But a Kyverna spokesperson said the update was due to the “conclusion of enrolment” for these Phase 1/2 trials (KYSA-1, KYSA-3 and KYSA-5).
“These updates are consistent with our strategy of prioritising the advancement of our late-stage neurologic autoimmune indications,” the spokesperson said, adding that Kyverna has “not observed any safety issues to date that would lead us to halt or pause any of our clinical programmes”.
Both Novartis’ rap-cel and Bristol Myers’ zola-cel are being developed using rapid manufacturing platforms. Analysts speculated on Monday that the toxicities could be linked to those manufacturing processes. But more information will be necessary to determine the actual cause and what it means for the field.
See more from MedicalBrief archives:
FDA adds compulsory boxed warning for CAR T therapy
FDA probes safety of CAR T therapies