Eyes are on CAR-T therapy clinical trials in autoimmune diseases for potentially more serious side effects, after Cabaletta Bio’s candidate was linked with a high-grade neurotoxicity event in one lupus patient.
Cabaletta said Thursday that a patient with lupus nephritis given CABA-201 experienced grade 4 immune effector cell-associated neurotoxicity syndrome, or ICANS. The event was resolved after “standard management,” and Cabaletta is amending its trial protocol to increase monitoring for fevers and neurologic symptoms and to include seizure prophylaxis, the company said.
Although high-grade ICANS is a known risk of CAR-T therapies, it hasn’t occurred in clinical trials of autoimmune patients until now, TD Cowen analysts said. Investors could therefore be concerned that Cabaletta’s contender carries a greater risk of the side effect, they added.
But concerns could extend beyond Cabaletta’s drug, Leerink analysts said, adding that they “do not rule out” more serious cases of ICANS or cytokine release syndrome occurring in autoimmune patients treated with CAR-T therapies in the future.
Other companies with CAR-T therapy focused on autoimmune disease include Kyverna Therapeutics and China’s Gracell Biotechnologies. Kyverna is developing KYV-101 for lupus nephritis and systemic sclerosis, while Gracell — which AstraZeneca bought in December for $1 billion — is advancing GC012F for systemic lupus erythematosus.
“These are early days for CAR T in [autoimmune disease], and we suspect part of the trailblazing process will be learning to identify and select the right patients,” Stifel analysts said.
Autoimmune studies of CAR-T therapies usually enroll patients with severe, life-threatening disease who have failed multiple lines of treatment. This is because the drug class comes with a risk of severe side effects, which wouldn’t be worth taking for autoimmune patients with more mild or moderate disease.
Cabaletta is running the open-label Phase 1/2 RESET-SLE trial of the CAR-T in systemic lupus erythematosus and lupus nephritis. The patient with grade 4 ICANS had refractory disease, was taking five to six medications for lupus and had experienced febrile events that led to hospitalization before CABA-201 administration, the Stifel analysts wrote.
The company’s share price $CABA plummeted 41% to close at $4.01 on Thursday.
The stock drop could have been driven by concerns about monitoring and managing autoimmune patients taking autologous CAR-T therapies and implications for the “scope of commercial use,” the Stifel analysts said. But use could broaden beyond “very severe patients” as drugmakers and physicians get more experience with managing side effects, the analysts added.