Bristol Myers Squibb (BMS) has shared more details with Fierce about the death of a patient who received the pharma's investigational CAR-T in a multiple sclerosis (MS) trial.
The company already paused enrollment in autoimmune trials of the autologous CD19-directed CAR T-cell therapy, zolacabtagene autoleucel (zola-cel) in August due to “transient and reversible inflammatory events.” In an interim readout on Friday for a phase 1 trial of zola-cel in patients with highly active relapsing and progressive forms of MS, BMS disclosed that one patient had died of septic pneumonia.
Specifically, the patient experienced “late-onset, non-ICANS motor symptoms that were not resolved by treatment with intermittent corticosteroids and intravenous immunoglobulin.” The patient died 44 days after infusion and a day after high-dose cyclophosphamide was administered, according to BMS, which noted that no other deaths had been reported across the 190 patients treated with the CAR-T in autoimmune trials.
In an interview with Fierce on Friday, Lynelle Hoch, president of cell therapy organization at BMS, explained that the patient had received the CAR-T before the company had paused enrollment in the study, with the death occurring “well after the pause.”
“This was not related to our pause in any way, because this patient's toxicities was not even a signal and related to the ICANs and why we paused the trial,” Hoch added. Immune effector cell-associated neurotoxicity syndrome (ICANS) is a known, potentially severe neurological side effect linked to CAR-T cell therapy across both oncology and emerging autoimmune disease trials.
BMS made the call to pause enrollment earlier this summer “out of [an] abundance of caution,” according to Hoch.
The Breakfree-2 study at the center of Friday's update included 66 patients with ongoing MS disease activity or worsening disability despite treatment. The 60 patients who received the second dose level of zola-cel had remained off disease-modifying therapies as of the data cut-off, according to BMS' readout.
When it came to other secondary efficacy endpoints, BMS noted that 92% of patients with progressive forms of MS treated with the second dose level had demonstrated stability or improvement in disability progression.
“This is something that just a few years ago no one dreamt was possible, and so it is very important we think about the severity of these diseases and the debilitating effects it has on these patients,” Hoch told Fierce. “Of course, the Grade 5 event that happened weighs heavily on our hearts.”
When it came to the study's primary endpoint of safety, BMS reported that 42.4% of patients experienced cytokine release syndrome (CRS), a common but potentially serious side effect of CAR-T therapy. For 36.4% of patients in the trial, their CRS was Grade 1, while 6.1% experienced a Grade 2 event. All cases resolved in a median of two days, the pharma reported.
When it came to ICANS, one case reached Grade 4. This case occurred in a patient with a progressive form of MS, but was managed with corticosteroids and the inflammation drug anakinra and resolved within four days, BMS noted.
“Now that we have seen and found the root cause for the trend break that we saw, we're eager to return zola-cel to clinical trials with our previous process,” Hoch told Fierce. “We're working with health authorities to get restarted.”
BMS isn't the only pharma whose CAR-T plans have been derailed by adverse events. The summer also saw Novartis temporarily halt development of its autologous CD19 CAR-T therapy, rapcabtagene autoleucel (rap-cel), for several autoimmune diseases in immunology and neuroscience following three deaths from complications caused by serious immune effector cell-associated hemophagocytic syndrome.