The disclosure—which came ahead of a presentation of data from the Phase 1 Breakfree-2 study at the ACTRIMS-ECTRIMS meeting—follows Bristol Myers Squibb’s late summer revelation that it had paused certain trials of zolacabtagene autoleucel.
In late August, Bristol Myers Squibb disclosed it had voluntarily paused some autoimmune trials of its CAR T cell therapy zolacabtagene autoleucel after identifying safety signals. Now, BMS has revealed that a death occurred in a Phase 1 study of the candidate in autoimmune disease.
After the data cutoff, one patient with highly active relapsing MS (haRMS) experienced septic pneumonia, which proved fatal, according to BMS’ press release. After infusion of the cell therapy, the patient experienced late onset, non-immune effector cell-associated neurotoxicity syndrome (ICANS) motor symptoms, BMS said. This was not able to be resolved by treatment with intermittent corticosteroids and intravenous immunoglobulin (IVIG) and the patient died the day after developing the pneumonia and 44 days after the infusion of zola-cel.
No additional deaths have been reported “across all zola-cel programs in autoimmune diseases,” BMS added, which include 190 patients treated in Phase 1 studies.
In the Breakfree-2 trial, which included patients with various forms of multiple sclerosis or refractory myasthenia gravis, 42.4% of participants—28 of 66 total—experienced cytokine release syndrome (CRS) events, a common safety issue with cell therapies. Of these cases, 36.4% were deemed Grade 1 and 6.1% were Grade 2 (mild), while all resolved in a median of two days, according to the press release. Beyond the one patient death, one other patient suffered a life-threatening ICANS event that was managed with corticosteroids and anakinra—a biologic drug that helps with the pain and swelling of arthritis—and resolved within four days.
The Breakfree-2 study’s primary endpoint was safety, with efficacy as a secondary measure.
The trial showed “early and promising efficacy” across patients with haRMS and progressive forms of MS (PMS), with all patients treated at dose level 2. At last follow up, all patients treated at this dose level remained off of disease-modifying therapies, including nine patients who had been followed for more than 12 months.
Safety issues have become a significant concern in clinical trials of CAR T therapies for autoimmune diseases, with some experts questioning the benefit-risk ratio of using this treatment mechanism in conditions that are not normally fatal.
BMS did not disclose in August the nature of the safety events that prompted the autoimmune trial pauses, or whether they covered all autoimmune trials of zolacabtagene autoleucel (zola-cel). The company did not report any deaths linked to zola-cel, though William Blair pointed out in an investor note at the time that at least one case of serious immune effector cell-associated hemophagocytic syndrome (IEC-HS) had previously been reported for the candidate.
After disclosing the patient death in the MS trial, BMS clarified that the safety event happened after the company made the decision to pause the zola-cel program. That pause stemmed from an increase in ICANS events in the pivotal Breakfree-SLE study of systemic lupus, a BMS spokesperson told BioSpace in an email, adding that the company “did not see the same break in trend in the Phase 1 MS study.”
Also in August, news broke that Novartis paused several immunology and neurology studies of its CAR T candidate rapcabtagene autoleucel (rap-cel) after the deaths of three patients who had received the therapy. Novartis’ decision to pause the studies stemmed from three cases of serious IEC-HS, a spokesperson told BioSpace at the time.
Editor’s note (Oct. 26): This story has updated to include a clarification from BMS that the safety event in the Breakfree-2 trial occurred after the company paused some trials of zola-cel this summer.
