CAR T-cell therapy offers year-long relief for gMG patients in trial
Single course of Descartes-08 significantly eases disease activity, final data show
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- Descartes-08, a CAR T-cell therapy, offers year-long relief for gMG patients.
- It significantly improves daily functioning, muscle strength, and quality of life.
- The therapy targets disease-driving antibodies; a Phase 3 trial is underway.
A single course of six once-weekly infusions of Descartes-08, an investigational CAR T-cell therapy, was well tolerated and resulted in sustained clinically meaningful responses in people with generalized myasthenia gravis (gMG).
That’s according to final data from the Phase 2b MG-001 clinical trial (NCT04146051), which also showed that the therapy developed by Cartesian Therapeutics improved patients’ daily functioning, muscle strength, and quality of life.
“The results of this trial indicate that a valuable new treatment opportunity in gMG — a brief course of treatment leading to at least a year-long benefit — may be achievable,” James Howard Jr., MD, neurology professor at the University of North Carolina School of Medicine and the study’s senior author, said in a university press release.
Complete trial findings were described in the study, “BCMA-directed mRNA CAR T cell therapy for myasthenia gravis: a randomized, double-blind, placebo-controlled phase 2b trial,” published in Nature Medicine.
A Phase 3 clinical trial called AURORA (NCT06799247) is confirming Descartes-08’s safety and efficacy in about 100 adults with gMG. The first patient was enrolled last June, with recruitment ongoing at sites across the U.S. and Europe.
Outpatient treatment
Myasthenia gravis (MG) is driven by self-reactive antibodies that disrupt communication between nerves and muscles, leading to muscle weakness and fatigue. gMG is a severe form of the disease characterized by the involvement of multiple muscle groups.
The self-reactive antibodies are secreted by immune B-cells, particularly those that carry a receptor protein called the B-cell maturation antigen (BCMA).
Descartes-08 is designed to leverage the body’s immune system to kill BCMA-positive B-cells, lowering levels of MG-driving antibodies. The treatment involves collecting a patient’s immune T-cells and engineering them in a lab to carry a chimeric antigen receptor (CAR) protein targeting BCMA. The modified T-cells are then infused back into the patient.
Unlike traditional CAR T-cell therapies, Descartes-08 does not require hospitalization or chemotherapy preconditioning to destroy existing immune cells, allowing treatment to be delivered in an outpatient setting.
The Phase 2b study enrolled 36 people with gMG, most of whom tested positive for antibodies against acetylcholine receptors (AChRs), the most common type of MG-driving antibodies. Participants were randomly assigned to receive either Descartes-08 or a placebo via once-weekly infusions into the bloodstream for six weeks.
The study’s primary goal was to determine the proportion of patients who achieved a 5-point improvement in the MG Composite (MGC) score, a measure of disease severity, after three months.
Secondary goals included changes in two other standardized scales of MG severity — Quantitative MG and the MG Activities of Daily Living — and Quality of Life 15-revised, a measure of quality of life.
Previously announced data showed that Descartes-08 treatment led to sustained reductions in disease severity compared with the placebo, which were maintained as long as one year.
New data show promise
The new data show that at three months, 66.7% of Descartes-08-treated participants achieved a meaningful MGC response compared with 27.3% of those on the placebo. A significant group difference was also observed among patients positive for anti-AChR antibodies (63.6% vs. 12.5%).
Those receiving Descartes-08 showed significantly greater improvements in daily activities, muscle strength, and quality of life at three months, with 83% of patients “achieving a sustained and clinically meaningful response at month 12,” the researchers wrote.
One-third of treated patients (33.3%) reached a near symptom-free state by six months, and all maintained that level of improvement through one year. From month six to month 12, the median daily dose of oral prednisone, a corticosteroid, in the Descartes-08 group dropped by 55%, from 20 mg to 9 mg.
Among participants with early-onset MG (before age 50), four times as many people on the therapy were MGC responders at three months relative to those on the placebo (80% vs. 20%). Still, treatment-related reductions in disease severity were consistent across participants with early-onset MG and those with late-onset MG.
Patients who had not received prior biologic therapy (derived from living organisms) responded better to Descartes-08. By six months, more than half (55.6%) of these patients had almost no symptoms, a trend that persisted through 12 months. Better responses in the biologic-naive group were also noted for all three disease severity measures.
Adverse event rates were similar between the groups, and most events were mild or moderate in severity. Even so, more infusion-related reactions were reported in the Descartes-08 group than in the placebo group (80% vs. 56.3%).
Researchers conducted a parallel biomarker analysis of MG-001 data, published in the same journal as a separate study, “BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial.”
They found that Descartes-08 caused a targeted immune reprogramming rather than broad immune system suppression. It lowered the activity of BCMA-positive B-cells and plasmacytoid dendritic cells — key drivers of autoimmunity — reduced levels of pro-inflammatory signaling proteins, and reshaped the subsets of self-reactive antibodies and T-cells.
The immune reset occurred without immunosuppression, as there was no reduction in protective antibodies generated in response to vaccines and no evidence of hypogammaglobulinemia, or lower-than-normal antibody levels.
Cartesian recently began a Phase 2 basket trial, called HELIOS-001 (NCT07089121), testing Descartes-08 in people with juvenile MG and other autoimmune conditions. Participants are being recruited at a single U.S. site. A basket trial investigates a drug in different populations that share similar characteristics.
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