OP0079 Clinical, Cellular Kinetics, Pharmacodynamics and Biomarker Data Up to 12 Months After YTB323 (Rapcabtagene Autoleucel), a Rapidly Manufactured CD19 CAR-T Therapy, From an Open-Label, Phase 1/2 Study in Severe Refractory SLE

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Background: Patients with severe refractory systemic lupus erythematosus (srSLE) are those who do not respond to standard of care treatments, resulting in progressive organ damage, morbidity and mortality. Current evidence suggests that B cell depletion through CD19-directed chimeric antigen receptor T cell (CAR-T) therapies can induce marked clinical improvements in patients with srSLE [1]. However, data from formal clinical trials assessing efficacy and safety of CAR-T therapies in multicentre settings and long-term outcomes are needed. YTB323 (rapcabtagene autoleucel) is a rapidly manufactured, autologous CD19 CAR-T therapy that has so far demonstrated favourable risk/benefit in haematological malignancies [2]. Here we report results from this phase 1/2 open-label study investigating YTB323 in patients with srSLE which has recently completed enrolment [3]. Objectives: To describe clinical, cellular kinetics, pharmacodynamics and biomarker outcomes up to 12 months after YTB323 treatment of patients with srSLE. Methods: This open-label, single-arm, multicentre phase 1/2 study (NCT05798117) to assess the safety, efficacy and cellular kinetics of YTB323 in patients with srSLE (defined as SLE disease activity index 2000 [SLEDAI-2K] ≥8 with organ involvement, having failed to respond to ≥2 standard immunosuppressive therapies and ≥1 biological agent) is fully enrolled (n = 21) and currently ongoing [3]. YTB323 treatment was administered in a single dose of 12.5 × 10 6 CAR-positive viable T cells, following lymphodepletion with cyclophosphamide/fludarabine. Efficacy assessments included the SLEDAI-2K. Cellular kinetics were monitored by quantitative polymerase chain reaction and flow cytometry; pharmacodynamics and biomarker assessments included levels of anti-dsDNA, complement C3 and C4, IgG, IgA, and IgM. Results: To date, data from 13 patients in the study have been analysed and detailed below. Data from all enrolled patients (n = 21) and longer follow-up data will be available at the time of presentation. At baseline, the median age was 36 (range: 24–54) years, and 12 of 13 patients were female. The median duration of follow-up was less than 4 months, with 1 patient with follow-up data at 12 months and 3 patients with follow-up data at 9 months (Table 1). In the 3 patients with a follow-up of at least 9 months, marked improvement from baseline in disease activity was observed with a mean SLEDAI-2K decrease of 14.7 points, decrease in anti-dsDNA antibodies (geometric mean ratio to baseline of 8.4%), and increase in complement C3 (geometric mean ratio of 130%) at 9 months. Cellular kinetics and pharmacodynamics data from 13 patients revealed peak expansion of CAR-T cells 2-3 weeks post-infusion and B cell depletion, with subsequent B cell recovery occurring 60 to 90 days after CAR-T administration in most patients. Analysis of early reconstituted B cells showed a dominant naive phenotype, with a drastic reduction in memory B cell subsets and plasmablasts. Safety data from 13 patients indicated that YTB323 was generally well tolerated. Transient lymphodepletion-related cytopenia (grade 3/4) was observed in all patients. No patient had grade 4 neutropenia or lymphopenia lasting >28 days. Grade 1/2 cytokine release syndrome (CRS) was observed in 8 of 13 patients; all events resolved with (n = 7) or without (n = 1) tocilizumab treatment. A single grade 2 event of immune cell-associated neurotoxicity syndrome (ICANS) presenting with ataxia, with immune effector cell-associated encephalopathy (ICE) score of 10 out of 10 (where 10 is least severe and 0 is most severe), was reported; the patient recovered 4 days after corticosteroid treatment was initiated. Three serious adverse events (treatment-related: n=2 [CRS and pneumonia]; non-related: n=1 [urinary tract infection]) were reported; all patients fully recovered. Conclusion: YTB323 treatment resulted in improved disease activity, effective B cell depletion and recovery of naive B cell phenotype. Early clinical data suggest remarkable efficacy in the srSLE population [4], and a safety profile that is in line with that reported for CD19 CAR-T therapy in autoimmune disease [1]. These data support the continued evaluation of YTB323 in srSLE. REFERENCES: [1] Müller et al. N Eng J Med . 2024;390;8:687-700. [2] Barba P et al. Blood . 2022;140;Suppl1:1056–59. [3] ClinicalTrials.gov. NCT05798117. Accessed January 7, 2025. https://clinicaltrials.gov/study/NCT05798117. [4] Kandane-Rathnayake R et al. Ann Rheum Dis . 2024;83,Suppl.1:399-400. Table 1. Patient baseline characteristics (n=13). Acknowledgements: The authors thank Rangariroyashe Chipika and Seonadh O'Leary (Novartis Ireland Limited, Dublin, Ireland) for editorial and medical writing support, which was funded by Novartis Pharma AG, Basel, Switzerland in accordance with the Good Publication Practice (GPP 2022) guidelines (http://www.ismpp.org/gpp-2022). This study was sponsored by Novartis Pharma AG, Basel, Switzerland. Disclosure of Interests: Eric Morand has received consulting fees and/or speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, DragonFly, Eli Lilly, EMD Serono, GlaxoSmithKline, Novartis, Remegen, Quell, UCB, and Zenas, has received consulting fees and/or speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, DragonFly, Eli Lilly, EMD Serono, GlaxoSmithKline, Novartis, Remegen, Quell, UCB, and Zenas, has received research funding from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech-Hoffman La Roche, GSK, Janssen, Novartis, Takeda, and Union Chimique Belge, Rangi Kandane-Rathnayake has received research grants from BMS, GSK, and Novartis, Josefina Cortés-Hernández has received speaker fees from GSK, Zahir Amoura has received speaker fees and honoraria for advisory boards from AstraZeneca, BMS, GSK, Novartis, Merck, and Roche, has received speaker fees and honoraria for advisory boards from AstraZeneca, BMS, GSK, Novartis, Merck, and Roche, Julia Weinmann-Menke has received speaker fees and honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Otsuka, Takeda, and Vifor, has received consulting fees from Novartis, Boerhinger-Ingelheim, AstraZeneca, Otsuka and GSK, has received grant/research support from Toray, Miltenyi, Diamed, Britta Maurer has received lecturing fees from Boehringer Ingelheim, GaxoSmithKline, Novartis, Otsuka, and Merck Sharpe & Dohme, declares an mir-29 patent for the treatment of systemic sclerosis (US8247389, EP2331143), has received consulting fees from Novartis, Boehringer Ingelheim, Janssen-Cilag, financial support for congresses (ie, for registration fees and travel) from Medtalk, Pfizer, Roche, Actelion, Mepha, and Merck Sharpe & Dohme,and GaxoSmithKline, and has been on an advisory board for Janssen and Boehringer Ingelheim, has received research grants from AbbVie, Protagen, and Novartis Biomedical Research, Christophe Richez has received speaker fees and honoraria for advisory boards from Abbvie, AstraZeneca, Amgen, BMS, Boehringer Ingelheim, GSK, Lilly, and Novartis, has received speaker fees and honoraria for advisory boards from Abbvie, AstraZeneca, Amgen, BMS, Boehringer Ingelheim, GSK, Lilly, and Novartis, Edouard Forcade has received speaker fees and honoraria for advisory boards from Novartis, Gilead, Alexion, GSK, MSD, Astellas, Jazz, and Sobi, has received speaker fees and honoraria for advisory boards from Novartis, Gilead, Alexion, GSK, MSD, Astellas, Jazz, and Sobi, Stephanie Finzel has received speaker honorarium from AbbVie, Alfasigma/Galapagos, Biotest, Celltrion, Chugai, Johnson&Johnson, Novartis, and UCB, has received consulting fees from Johnson & Johnson, Novartis, NovoNordisk, and UCB, has received meeting or travel grants from Biotest, Eli Lilly, Johnson&Johnson, Novartis, UCB, Galapagos, and Sobi, Jose-Maria Alvaro-Gracia has received speaker and consulting fees for AbbVie, AstraZeneca, BMS, Gala

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