Dosing Begins in Study of Descartes-08 CAR T-Cell Therapy
First placebo-controlled trial of Descartes-08 for generalized myasthenia gravis
Patient dosing has begun in the first placebo-controlled clinical trial evaluating Cartesian Therapeutics’ Descartes-08, an investigational CAR T-cell therapy for people with generalized myasthenia gravis (gMG).
The Phase 2b randomized controlled trial (RCT), to include up to 30 adults with gMG, follows a crossover design, in which participants are assigned randomly to receive treatment or a placebo, and are then switched to the opposing regimen. A crossover RCT ensures all participants receive treatment.
This new trial expands on an ongoing Phase 1b/2a (NCT04146051) study. So far, early data has shown that Descartes-08 was generally safe and lessened symptom severity in five patients.
“As a physician who treats patients with myasthenia, I have been impressed by the magnitude and duration of responses seen in the Phase 2a trial of Descartes-08 in MG,” Tahseen Mozaffar, MD, professor of neurology at the University of California, Irvine, said in a press release. “A tantalizing observation is that, after a 6-week course of Descartes-08, clinical responses continue to persist for many months and counting.”
“RCTs are the gold standard for clinical trials, and I commend Cartesian for further studying Descartes-08 with this rigorous design,” Mozaffar said.
In MG, self-reactive antibodies wrongly target proteins that participate in nerve-muscle communication, leading to hallmark MG symptoms of increasing muscle weakness in various parts of the body.
Descartes-08 involves collecting immune T-cells from a patient and genetically modifying them in the lab to generate a human-made chimeric antigen receptor, or CAR. Such a receptor helps these cells recognize the BCMA protein found at the surface of plasma cells — a type of mature immune B-cell that produces antibodies, including those driving MG.
Engineered CAR T-cells are then grown and infused back into the patient to kill plasma cells, reduce self-reactive MG antibodies, and ease disease symptoms. The therapy also has the potential to treat other autoimmune conditions.
The now-completed Phase 1b portion of the trial assessed the safety of three increasing weekly doses of the therapy in three patients with severe gMG who failed to respond to standard treatment.
Data showed that Descartes-08 was generally well-tolerated, with no reports of serious treatment-related adverse events, including cytokine release syndrome (CRS) — a potentially life-threatening immune reaction seen with other CAR T-cell therapies. A mild, temporary headache was the only recurring side effect.
Efficacy assessments of all three patients showed that treatment lessened MG severity. Further, after three months, the treatment led to a 50% improvement in mean Myasthenia Gravis Composite (MGC) scores, a combined objective and subjective measure of disease severity.
The ongoing Phase 2a dose-expansion portion involves three treatment schedules of a high dose of Descartes-08. The first two participants received a six-week, high-dose regimen and completed their week 10 follow-up visit.
Treatment was well-tolerated in both patients, who reported a sustained reduction across all MG disease measures. From study’s start to one month after the end of treatment, one patient saw their MGC score drop from 27 to 2, and the second from 23 to 3.
Phase 2b RCT enrolling
The Phase 2b RCT, which just began enrolling, will evaluate the proportion of participants who achieve a six-point or greater improvement in the MG Activities of Daily Living (MG-ADL) score at 12 weeks (three months).
Secondary goals include evaluating treatment safety and other assessments of MG disease severity, as well as measures of disease processes, including levels of disease-causing antibodies.
“We are excited to begin this RCT in patients with MG,” said Miloš Miljković, MD, Cartesian’s chief medical officer. “A placebo-controlled design will provide a stringent evaluation of Descartes-08 efficacy while elucidating its mechanisms of action.”
“This will result in important insights on treating MG and other autoantibody-mediated autoimmune diseases with Descartes-08,” Miljković said.