Zola-cel Off-DMT Signal Intrigues but Phase 1 Data Cannot Prove Immune Reset

Bristol Myers Squibb Presents Positive Phase 1 Zola-cel Data in MS

Bristol Myers Squibb announced interim safety and efficacy results from the Phase 1 Breakfree-2 study of zolacabtagene autoleucel (zola-cel), an investigational CD19-directed CAR T cell therapy, in 66 patients with highly active relapsing multiple sclerosis (haRMS) and progressive forms of MS (PMS). Presented at MSToronto 2026, the data showed a safety profile consistent with previous zola-cel trials, with 42.4% experiencing cytokine release syndrome (mostly Grade 1) and 7.6% immune effector cell-associated neurotoxicity syndrome (mostly Grade 1/2). Promising efficacy was observed, as all 60 patients treated at dose level 2 (DL2) remained off disease-modifying therapies (DMTs) at last follow-up, including nine with over 12 months of follow-up, suggesting potential for immune reset and treatment-free remission.

• The Breakfree-2 study demonstrated a safety profile for zolacabtagene autoleucel consistent with prior Phase 1 data. Key adverse events included cytokine release syndrome (CRS) in 42.4% of patients (majority Grade 1) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 7.6% (mostly Grade 1/2), with most resolving quickly. One Grade 4 ICANS event occurred, and one fatal septic pneumonia event was reported post-data cutoff, though no additional Grade 5 events have been seen across 190 patients in autoimmune disease studies.
• A significant efficacy finding was that all 60 patients treated at dose level 2 (DL2) remained off disease-modifying therapies (DMTs) at their last follow-up. This included nine patients who had been followed for more than 12 months, highlighting the potential for durable treatment-free remission and a sustained immune reset through complete B-cell depletion, which could transform care for MS patients.
• Beyond DMT cessation, zolacabtagene autoleucel showed encouraging results in disability and MRI outcomes. Six of seven evaluable haRMS patients met criteria for no evidence of disease activity (NEDA) at ≥ Week 26. All eight evaluable haRMS patients demonstrated stability or improvement in Expanded Disability Status Scale (EDSS). Furthermore, 22 of 24 (92%) PMS patients showed stability or improvement in disability progression, and all 24 PMS patients had no new MRI activity, indicating disease control.

The Unmet Need for Transformative Therapies in MS

High-efficacy Disease-Modifying Therapies (DMTs) have transformed relapse control in multiple sclerosis, yet Progression Independent of Relapse Activity (PIRA) persists. Contemporary care reliably controls inflammatory activity, but mitigating PIRA remains the key unmet need.

• Smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI.

• Early disability increase signals higher risk of secondary progressive multiple sclerosis (SPMS), with a higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001); a higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk.

• Treatment continuity is constrained by switching and safety risks, with the need for close monitoring in patients who plan to switch from fingolimod to other treatments because of the risk of severe rebound with tumefactive demyelinating lesions (TDLs), high rate of natalizumab treatment switch mainly due to the risk of PML with rebound in the wake of discontinuation (7.5%), and dimethyl fumarate did not eliminate the possibility of disease reactivation after natalizumab discontinuation.

• Response assessment and pipeline remain incomplete, as across therapies, sNfL generally decreases, whereas GFAP and smouldering-lesion MRI biomarkers often change more slowly, and CNS-penetrant Bruton's Tyrosine Kinase (BTK) inhibitors target compartmentalized inflammation, with mixed late-phase results, while anti-CD40L, EBV-directed and CD19 CAR-T, and remyelination approaches are promising but require definitive trials, and CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy remains investigational.

Breakfree-2: Zola-cel Shows Promising Safety and Efficacy in MS

Recent studies in relapsing multiple sclerosis have evaluated anti-CD20 therapy, treatment discontinuation in older patients, and long-term oral therapy. The studies below summarize study identity, intervention, and key efficacy and safety outcomes.

• BCD-132-2 — divozilimab (DIV) 125 mg or 500 mg versus teriflunomide (TRF) and placebo (PBO) in relapsing remitting multiple sclerosis: 263 patients completed 24 weeks of treatment; 94.44% on 125 mg and 93.06% on 500 mg had no lesions on T1-weighted MRI after 24 weeks, compared with 68.06% in TRF and 56.36% in PBO (both p<0.05); proportions of relapse-free patients were 93.06% and 97.22% (125 mg and 500 mg, respectively); DIV reduced the CD19+ B-cells with more pronounced repopulation in the 125 mg group mainly due to the recovering pool of CD27-naive B-cells; DIV showed a favorable safety profile at both doses, and a dose of 500 mg is recommended for further efficacy and safety evaluation during phase 3 CT.

• DISCOMS (NCT03073603) — continue versus discontinue disease-modifying therapy in patients 55 years or older with no relapse within past 5 years or new MRI lesion in past 3 years: 259 participants enrolled (128 continue, 131 discontinue); six (4·7%) of 128 in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years, difference 7·5 percentage points (95% CI 0·6-15·0); similar numbers had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), with more adverse events (422 vs 347) and serious adverse events (40 vs 30) in the discontinue group.

• ENDORSE extension of DEFINE and CONFIRM — dimethyl fumarate (DMF) 240 mg twice daily up to 13 years in relapsing-remitting multiple sclerosis: 1736 patients enrolled/dosed with median follow-up 8.76 years and 52% treated for ⩾6 years; for DMF/DMF (n = 501), overall annualized relapse rate (ARR) was 0.143 (95% confidence interval (CI), 0.120-0.169), while for PBO/DMF (n = 249), ARR 0-2 years was 0.330 (95% CI, 0.266-0.408) and overall ARR was 0.151 (95% CI, 0.118-0.194); over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening; 551 (32%) experienced serious adverse events and 243 (14%) discontinued due to adverse events (4% gastrointestinal (GI) disorders).

Zola-cel's Expanding Potential in Autoimmune Diseases

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CAR T: A New Frontier for Multiple Sclerosis Treatment

The landscape of multiple sclerosis (MS) treatment has long been characterized by chronic disease-modifying therapies (DMTs) that aim to reduce relapse rates and slow disease progression. While these therapies have significantly improved outcomes for many, particularly those with relapsing-remitting MS, they are often only partially effective and come with the burden of lifelong administration, leading to challenges with patient adherence and potential long-term side effects. A significant unmet need persists, especially for patients with highly active relapsing MS and, critically, for those with progressive forms of the disease, where effective treatment options are severely limited.

The emergence of zolacabtagene autoleucel (zola-cel), an investigational CD19-directed CAR T cell therapy, represents a bold new approach. Early Phase 1 data suggest a potential paradigm shift: an 'immune reset' that could lead to sustained, treatment-free remission. This is a stark contrast to the continuous nature of current DMTs, which, despite their benefits, do not offer a definitive cure. The observation that all patients treated at the optimal dose level remained off DMTs at last follow-up, including some with over a year of follow-up, is a compelling early signal of profound efficacy.

However, this innovative therapy also introduces a unique set of considerations. As with other advanced cell therapies, zola-cel carries a distinct safety profile, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While these events were predominantly low-grade in the reported study, they necessitate specialized clinical management and infrastructure, which differs significantly from the administration of conventional MS drugs. Furthermore, the long-term durability of this immune reset and the potential for sustained remission beyond the current follow-up period are crucial questions that require further investigation in larger, later-phase trials. The heterogeneity of MS and the complexity of its underlying pathophysiology mean that early-phase results, while promising, must be rigorously validated across broader patient populations. This development, nonetheless, underscores the potential for advanced cell therapies to redefine treatment expectations in severe autoimmune diseases, moving beyond symptom management to targeting the root causes of immune dysregulation.