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<p>Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (<i>n</i> = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (<i>n</i> = 15) or placebo (<i>n</i> = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (<i>n</i> = 10/15) versus 27.3% (<i>n</i> = 3/11), <i>P</i> = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (<i>n</i> = 7/11) versus 12.5% (<i>n</i> = 1/8), <i>P</i> = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were −7.1, −5.5 and −4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (<i>n</i> = 16/20); placebo, 56.3% (<i>n</i> = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/study/NCT04146051">NCT04146051</a>.</p>

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BCMA-directed mRNA CAR T cell therapy for myasthenia gravis: a randomized, double-blind, placebo-controlled phase 2b trial

  • 期刊论文

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  • 发表日期：

    2026年1月9日

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  • Tuan Vu,
  • Hacer Durmus,
  • Michael Rivner,
  • Sheetal Shroff,
  • Thomas Ragole,
  • Bennett Myers,
  • Mamatha Pasnoor,
  • George Small,
  • Chafic Karam,
  • Mithila Vullaganti,
  • Amanda Peltier,
  • Gregory Sahagian,
  • Marc H. Feinberg,
  • Adam Slanksy,
  • Carolina Barnett-Tapia,
  • Zaeem Siddiqi,
  • Kelly Gwathmey,
  • Michael A. Badruddoja,
  • Hafsa Kamboh,
  • Rachel N. Ruggerie,
  • Renee R. Fedak,
  • C. Andrew Stewart,
  • Metin Kurtoglu,
  • Murat Kalayoglu,
  • Michael Singer,
  • Christopher M. Jewell,
  • Milos D. Miljkovic,
  • Mazen Dimachkie,
  • Tahseen Mozaffar,
  • James F. Howard Jr

摘要

Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (n = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (n = 15) or placebo (n = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (n = 10/15) versus 27.3% (n = 3/11), P = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (n = 7/11) versus 12.5% (n = 1/8), P = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were −7.1, −5.5 and −4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (n = 16/20); placebo, 56.3% (n = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: NCT04146051.