Fatal Late Infection After CAR-T Tempers Early MS Signal With No Clean Precedent

BMS Reveals Patient Death in Phase 1 CAR T Trial for MS

Bristol Myers Squibb (BMS) disclosed a patient death in its Phase 1 Breakfree-2 study of zolacabtagene autoleucel (zola-cel) for autoimmune diseases. The patient, suffering from highly active relapsing multiple sclerosis (haRMS), died from septic pneumonia 44 days post-infusion, following late-onset non-immune effector cell-associated neurotoxicity syndrome (ICANS) motor symptoms. This revelation follows BMS's earlier voluntary pause of some zola-cel autoimmune trials due to identified safety signals. The study, which included 66 participants, also reported cytokine release syndrome (CRS) in 42.4% of patients, mostly Grade 1, and showed early promising efficacy in MS patients.

• Bristol Myers Squibb reported a fatal case of septic pneumonia in a patient with highly active relapsing multiple sclerosis (haRMS) participating in the Phase 1 Breakfree-2 study of zolacabtagene autoleucel. This death occurred 44 days after infusion and was preceded by late-onset non-immune effector cell-associated neurotoxicity syndrome (ICANS) motor symptoms, which were refractory to treatment. This disclosure underscores the significant safety challenges associated with CAR T therapies in autoimmune conditions.
• The Breakfree-2 trial, involving 66 participants, also documented cytokine release syndrome (CRS) in 42.4% of patients, with 36.4% being Grade 1 and 6.1% Grade 2, all resolving within a median of two days. Beyond the fatal event, one other life-threatening ICANS case was managed successfully. This safety profile contributes to an ongoing industry-wide debate regarding the risk-benefit ratio of CAR T therapies for non-fatal autoimmune diseases, especially given similar pauses by other companies like Novartis.
• Despite the safety concerns, the Phase 1 Breakfree-2 study demonstrated "early and promising efficacy" in patients with both highly active relapsing MS and progressive forms of MS. All patients treated at dose level 2 remained off disease-modifying therapies at last follow-up, including nine patients observed for over 12 months. This suggests potential therapeutic benefits for zolacabtagene autoleucel in these challenging neurological conditions, balancing the safety risks.

Zolacabtagene Autoleucel: A Look at Its Safety Profile

The knowledge base does not have sufficient information to answer this question.

Breakfree-2: Promising Efficacy Amidst Safety Concerns

Recent long-term data come from the ULTIMATE I and II Open-Label Extension Study evaluating ublituximab in relapsing multiple sclerosis. Participants continuing ublituximab (UBL-UBL) had further annualized relapse rate reductions after the double-blind period (0.053, 0.032, and 0.020 for years 3, 4, and 5, respectively), while participants switching from teriflunomide to ublituximab (TER-UBL) experienced a 58.4% ARR reduction at 1 year after the switch (0.182 vs 0.076; rate ratio, 0.42; 95% CI, 0.29-0.60; P < .001), decreasing further to 0.048 (year 4) and 0.045 (year 5). At year 5, 24-week confirmed disability progression was 8.0% in UBL-UBL participants vs 14.3% in TER-UBL participants (P = .01), and 24-week confirmed disability improvement was 17.0% vs 12.2% (P = .02). Adverse events were consistent with the established safety profile, with exposure-adjusted incidence rates per 100 participant-years of serious infections (excluding COVID events) of 2.10 (UBL-UBL) and 2.58 (TER-UBL). On average, immunoglobulin levels remained above the lower limit of normal, and no significant differences in serious infection rates were observed regardless of immunoglobulin level.

The active-comparator Phase 3 OPTIMUM Study compared ponesimod 20 mg once daily with teriflunomide 14 mg once daily in relapsing multiple sclerosis. The relative rate reduction for ponesimod vs teriflunomide in annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001), with relative risk reduction in combined unique active lesions per year of 56% (1.405 vs 3.164; P < .001) and odds ratio for NEDA-3 achievement of 1.70 (25.0% vs 16.4%; P < .001). Reductions in time to 12-week and 24-week confirmed disability accumulation risk estimates were 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively, and brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups, while treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

Comparative effectiveness in routine practice was assessed in a target trial emulation using MSBase and Observatoire Français de la Sclérose en Plaques registries comparing ofatumumab and ocrelizumab in relapsing-remitting multiple sclerosis. Annualised relapse rate was 0.07 (95% CI 0.05 to 0.08) with ofatumumab and 0.04 (0.03 to 0.05) with ocrelizumab, corresponding to an ARR ratio of 1.75 (1.43 to 2.13). Ofatumumab was associated with a lower risk of confirmed disability progression (HR 0.66; 0.49 to 0.87) and progression independent of relapse activity (0.53; 0.39 to 0.73), but a lower probability of confirmed disability improvement (0.76; 0.60 to 0.96). No significant differences were observed in MRI activity or treatment discontinuation.

The Unmet Need for New MS Treatment Approaches

Current disease-modifying therapies have significantly reduced relapse-associated worsening, yet disability accumulation driven by chronic neurodegeneration continues across treatment classes. Treatment of progression independent of relapse activity is described as a relevant unmet need, only modestly affected by disease-modifying treatments which target predominantly adaptive immunity in the periphery.

• Persistence of progression independent of relapse activity despite high-efficacy therapy: High-efficacy early therapy vs low-efficacy early therapy had a similar risk of PIRA (adjusted hazard ratio = 0.99, P -adjusted = 0.95) but a significantly lower risk of RAW (adjusted hazard ratio = 0.48, P -adjusted = 0.015), with similar risk of sustaining an EDSS score ≥ 5.0. Progression independent of relapsing biology rates remained consistent across disease-modifying therapies (3.75% dimethyl fumarate, 3.67% fingolimod, 3.72% ocrelizumab, 3.52% minocycline) despite varied rates of disability progression, and vertical switching achieved higher NEDA-3 rates than horizontal switching (45.8% vs 33.7%) while differences in EDSS progression and PIRA were not significant.

• Suboptimal immune depletion and long-term disease control: Insufficient B-cell depletion was the strongest PIRA predictor (OR 3.73, 95% CI: 2.50-5.43, p < 0.001) and increased EDSS progression risk (HR 0.50, 95% CI: 0.26-0.97, p = 0.039) in RMS patients receiving ocrelizumab treatment, with suboptimal depletion defined as ⩾10 CD19+ B-cells/µL. Cumulative proportion of patients with PIRA was 10% vs 21% at year 5, and 10% versus 49% at year 10 for autologous haematopoietic stem cell transplantation-treated compared with natalizumab-other DMTs treated patients, supporting the hypothesis that bioavailability within the central nervous system may affect long-term PIRA.

• Remyelination failure and lack of neuroprotective options for progressive biology: Remyelination failure becomes an increasingly pronounced feature of the pathology of chronic multiple sclerosis lesions, with chronic demyelination predisposing axons to atrophy, and fibronectin aggregates persisting in chronic multiple sclerosis thus inhibiting remyelination. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events, but there is minimal therapy to treat progressive disease and there is no cure.

• Measurement limitations distinguishing neurodegeneration from inflammation in trials: PIRA and RAW in their current definitions do not reliably distinguish between disability worsening due to inflammatory disease activity and neurodegeneration in RRMS. Among 2,113 participants, 42.2% of participants with PIRA had MRI activity in the first year of follow-up and 30.9% in the second, improvement events exceeded PIRA events throughout follow-up, and there was no difference in time-to-PIRA between participants with and without radiologic disease activity.

• Sequencing complexity and cumulative safety burden: Discontinuation or de-escalation of therapy is associated with a significant risk of disease reactivation, particularly after lymphocyte-trafficking inhibitors, while anti-CD20 therapies are associated with long-term risks including hypogammaglobulinemia and infections. The main safety signal for oral cladribine relates primarily to herpes zoster infection, which was more common in patients with higher grades of lymphopenia, in particular grade 3 and 4 lymphopenia, and introduction of monoclonal antibodies (e.g. natalizumab, rituximab, efalizumab) has led to an increased incidence of progressive multifocal leukoencephalopathy.

CAR T in Autoimmune Disease: A Crowded and Evolving Field

The knowledge base does not have sufficient information to answer this question.

CAR T in Autoimmune MS: Balancing Promise and Peril

The emergence of CAR T-cell therapy for autoimmune diseases, particularly multiple sclerosis, has been heralded as a potential paradigm shift, moving beyond chronic immunosuppression towards durable immune tolerance. Research indicates that autoreactive B cells are central to conditions like relapsing-remitting MS, making targeted B-cell depletion a compelling therapeutic strategy. Early data from studies exploring CAR T-cells in neuroimmune disorders have shown promising efficacy, including reduced relapse rates and stabilization of disability, often with an anticipated 'favorable safety profile' compared to their oncologic applications.

However, the recent disclosure of a patient death in Bristol Myers Squibb's Phase 1 zolacabtagene autoleucel (zola-cel) study for highly active relapsing multiple sclerosis presents a sobering reality check. The patient's death from septic pneumonia, following late-onset ICANS motor symptoms, underscores the profound and potentially life-threatening risks associated with deep immune modulation. This event, coupled with the reported 42.4% incidence of cytokine release syndrome, necessitates a critical re-evaluation of the risk-benefit calculus for these innovative therapies in autoimmune populations.

Several key considerations emerge:

• Infection Vulnerability: The fatal septic pneumonia highlights heightened susceptibility to severe infections following CAR T-cell induced immune depletion. This risk is not new; other B-cell depleting agents for MS, such as alemtuzumab and ublituximab, have also been associated with increased infection rates, including bacterial and viral pneumonias. Managing this vulnerability in a patient group already experiencing immune dysregulation is critical.

• Neurotoxicity Management: Late-onset ICANS motor symptoms suggest neurological adverse events, while potentially less frequent than in oncology, can still manifest with significant clinical impact. Robust monitoring and early intervention protocols will be paramount.

• Patient Selection and Stratification: The incident will likely drive a more conservative approach to patient selection, prioritizing individuals with highly refractory disease where potential benefit outweighs substantial risks. Developing biomarkers to predict both efficacy and toxicity will be crucial.

This development will undoubtedly influence the pace and direction of CAR T-cell development in autoimmune diseases. While the therapeutic promise remains, the path forward demands meticulous attention to safety, robust risk mitigation strategies, and a clear understanding of the unique vulnerabilities of autoimmune patient populations. The industry must now navigate the delicate balance between pioneering transformative treatments and ensuring patient safety in this rapidly evolving field.