Gregory Sahagian

Abstract We report the 12-month follow-up results of a phase 2 clinical of Descartes-08 ( NCT04146051 ), BCMA-directed RNA chimeric antigen receptor T-cell (rCAR-T) therapy for myasthenia gravis (MG) given as an outpatient treatment without lymphodepletion. In the Phase 2a part of the study, all 7 participants who received six weekly infusions of Descartes-08 exhibited clinically meaningful improvement in common MG severity scales (MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15-revised) at Month 3. At Month 9 follow-up, all participants continued to experience marked clinical improvements. Five out of seven participants maintained clinical improvement at Month 12. Of the two participants who experienced loss of clinical effect at Month 12 and were eligible for retreatment, one was retreated and had rapid improvement in clinical scores with minimal symptom expression which was ongoing at Month 6 of follow-up. All three participants with detectable anti-acetylcholine receptor (AChR) antibody levels at baseline experienced autoantibody reductions by Month 6, which deepened further by Month 9, and were maintained at Month 12. These data support continued development of Descartes-08 in myasthenia gravis and other autoantibody-associated autoimmune disorders.

OBJECTIVE: We report the 12-month follow-up outcomes from a Phase 2 clinical trial (NCT04146051) evaluating Descartes-08, a BCMA-directed RNA chimeric antigen receptor T-cell (rCAR-T) therapy for refractory generalized myasthenia gravis (MG). These findings provide insight into the potential applicability of BCMA-targeted rCAR-T therapy for antibody-mediated autoimmune diseases. METHODS: CAR+ cells/kg per infusion with varying dosing frequencies as an outpatient treatment and without lymphodepletion chemotherapy. A subset of participants received Descartes-08 as six weekly infusions and were followed long term with assessments conducted at 2, 3, 6, 9, and 12 months. RESULTS: All seven participants who received six weekly infusions of Descartes-08 exhibited clinically meaningful improvement in common MG severity scales (MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15-revised) at Month 3 without significant toxicity. At Month 9 follow-up, all participants continued to experience marked clinically meaningful improvements. Five out of seven participants maintained the response at Month 12. A third participant experienced a relapse approximately 6 months after completing on-study follow-up. All three participants who experienced loss of clinical effects were retreated. Two had rapid improvement in clinical scores with minimal symptom expression at Week 8, which was maintained through 12 months of retreatment follow-up. The third participant experienced similar improvement in MG severity scores to their initial treatment. INTERPRETATION: These data support continued development of Descartes-08 in myasthenia gravis and other autoantibody-associated autoimmune disorders.

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 .

Chimeric antigen receptor (CAR)-T cell therapies have the potential to transform treatment of autoimmune disease by resetting the immune system. However, adoption of cell therapies in the autoimmune space is limited by hurdles such as inpatient administration, lymphodepletion and safety concerns around cytokine release syndrome and non-specific immunosuppression. RNA-based cell therapy has potential to address these limitations. Here we report prespecified exploratory analyses from a successful placebo-controlled, double-blind, randomized phase 2b trial in patients with generalized myasthenia gravis who received Descartes-08, an autologous, RNA-encoded anti-B cell maturation antigen (BCMA) CAR-T cell therapy. In 66.7% of patients (n = 10/15), transient targeting of BCMA with Descartes-08 administered in an outpatient setting without lymphodepletion resulted in durable clinical efficacy. Comparison of Descartes-08-treated (n ≤ 19) and placebo (n ≤ 15) cohorts by flow cytometry, serum profiling, multiplexing cytokine analysis and bulk/single-cell transcriptional analysis reveals a precision retuning of self-reactivity demonstrated by increased pro-immune function, decreased activity of BCMA+ plasma cells and plasmacytoid dendritic cells and reductions in disease-associated cytokines, such as IL-6. Furthermore, antibody and T cell receptor analysis revealed altered circulating repertoires of self-reactive antibodies and T cell clones among Descartes-08 participants. These effects occurred without immune suppression, indicated by the lack of decline in vaccine-specific antibodies or hypogammaglobulinemia. Our findings unveil a new type of immune reset and support the development of BCMA-targeted RNA cell therapies as a more accessible therapy for autoimmune diseases. ClinicalTrials.gov identifier: NCT04146051 . Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Abstract Diagnostic assessments of mild cognitive impairment (MCI) are lengthy and burdensome, highlighting the need for new tools to detect MCI. Time-domain functional near-infrared spectroscopy (TD-fNIRS) can measure brain function in clinical settings and may address this need. In this study (NCT05996575), MCI patients ( n = 50) and age-matched healthy controls (HC; n = 51) underwent TD-fNIRS recordings during cognitive tasks (Verbal Fluency, N-Back). Machine learning models were trained to distinguish MCI from HC using neural activity, cognitive task behavior, and self-reported impairment as input features. Significant group-level differences (MCI vs HC) were demonstrated in self-report, N-Back and Verbal Fluency behavior, and task-related brain activation. Classifier performance was similar when using self-report (AUC = 0.76) and self-report plus behavior (AUC = 0.79) as input features, but was strongest when neural metrics were included (AUC = 0.92). This study demonstrates the potential of TD-fNIRS to assess MCI with short brain scans in clinical settings. Clinical trial registration: NCT05996575.