BASEL. Novartis has halted eight clinical trials of its experimental cell therapy rapcabtagene autoleucel after three patients died from a severe immune reaction, the Basel based drugmaker confirmed on Tuesday. The pause took effect on 24 August and was disclosed after a report in the Wall Street Journal.
The therapy, known as rap-cel or YTB323, belongs to the CAR-T class, in which a patient’s own white blood cells are extracted, genetically modified to attack a target, in this case the CD19 protein, and infused back. In cancer the approach has produced remissions once thought impossible. The paused studies were testing whether the same trick could reset an immune system that has turned on the body itself.
The deaths were caused by complications of immune effector cell associated haemophagocytic syndrome, or IEC-HS, a runaway inflammatory reaction in which the newly armed immune cells trigger the body’s defences to attack its own organs. It is a known and feared risk of CAR-T treatment, rarer than the cytokine storms doctors have learned to manage, and harder to reverse.
The eight studies span the breadth of autoimmune medicine: two trials in systemic lupus and lupus nephritis, others in systemic sclerosis, ANCA associated vasculitis and inflammatory muscle disease, and early phase studies in rheumatoid arthritis, Sjögren’s disease, myasthenia gravis and both relapsing and progressive multiple sclerosis. Screening, enrolment and dosing are all suspended; patients already treated remain under monitoring.
The company was at pains to draw a cordon around the programme that matters most to its near term revenue. The rap-cel studies in oncology are not affected, it said, and its approved cancer cell therapies continue as before. The pause applies only to the autoimmune and neurology pipeline, the newer and, until now, most promising expansion of the technology.
Novartis is not alone in the caution. Bristol Myers Squibb has voluntarily paused enrolment in studies of a rival autoimmune CAR-T therapy as a precaution, a sign that regulators and companies alike are recalculating the risk calculus of using cancer grade immunotherapy in patients whose diseases are serious but rarely fatal.
That calculus is the heart of the matter. In late stage cancer, a small risk of death from treatment is weighed against a near certainty of death without it. In lupus or multiple sclerosis, where standard drugs keep most patients alive for decades, the tolerance for a fatal side effect is far lower, and regulators will now ask whether the threshold for deploying cell therapy was set too low.
The company has not said when the three deaths occurred, and the exact relationship between the three fatal cases and the three serious IEC-HS events described to trade publications has not been spelled out. A comprehensive safety review is under way with the independent data monitoring committees overseeing each study, and findings are being shared with regulators, including Swissmedic.
The setback lands on what many clinicians consider the most exciting idea in immunology: that a one time cell treatment could induce lasting, drug free remission in diseases patients currently manage for life. Early results in lupus, published by academic teams in Germany, were striking enough to trigger a gold rush among drugmakers. Tuesday’s news is the gold rush’s first serious reckoning.
For Basel, the pause is a reminder that the city’s biggest industry trades in probabilities measured in single lives. Novartis says it will use the review to build tighter monitoring and earlier detection of the reaction into any resumed studies. Whether the trials restart, and on what terms, now depends on what the safety committees find in the data of three patients who volunteered to be first.