CAR T-cell Therapy Descartes-08 Continues to Show Promise in Trial
Descartes-08, Cartesian Therapeutics’ investigational CAR T-cell therapy, appears generally safe and markedly lessened symptom severity in the first five patients with generalized myasthenia gravis (gMG) enrolled in a Phase 1b/2a clinical trial.
“I am very encouraged by the interim analysis findings,” as the therapy “appears safe and well tolerated, and the extent of clinical improvement seen in our early participants is remarkable,” Volkan Granit, MD, the trial’s principal investigator at the University of Miami, said in a press release.
“If future data in a controlled study corroborate these findings, Descartes-08 would become a welcome addition to our armamentarium for treating MG,” Granit added.
“Descartes-08 therapy is intended to clear reservoirs of [disease-causing] long-lived plasma cells, a central component of many autoimmune diseases including MG,” said Miloš Miljković, MD, Cartesian’s chief medical officer.
“Consistent with this novel and broadly applicable mechanism of action, we plan to study Descartes-08 for other autoimmune diseases,” Miljković added.
The trial’s interim results were shared in an oral presentation and through a poster at the 14th Myasthenia Gravis Foundation of America (MGFA) International Conference on Myasthenia and Related Disorders, held May 10–12 in Miami.
The oral presentation was titled “RNA CAR T-cell Therapy for Myasthenia Gravis,” and the poster was titled, “Phase 1b/2a Study of Autologous mRNA-Engineered Anti- B-cell Maturation Antigen Chimeric Antigen Receptor T-cells for Treatment of Severe Generalized Myasthenia Gravis.”
MG is an autoimmune disease in which the immune system produces self-reactive antibodies that wrongly recognize proteins essential for nerve-muscle communication as foreign, mounting immune attacks against them.
These abnormal immune attacks are mostly driven by two types of immune cells: activated B-cells or plasma cells, which produce antibodies — including those driving MG — and T-cells, which can regulate the activity of other immune cells.
A CAR T-cell therapy, Descartes-08 involves collecting T-cells from a patient and genetically modifying them in the lab to produce a human-made chimeric antigen receptor, or CAR, that helps them recognize the BCMA protein found at the surface of plasma cells. Engineered T-cells are then expanded and infused back into the patient.
By recognizing and binding to BCMA, Descartes-08 is expected to kill plasma cells, thereby reducing the levels of self-reactive antibodies driving MG and ultimately easing symptom severity.
A Phase 1b/2a trial (NCT04146051) is evaluating the safety and preliminary effectiveness of Descartes-08 in up to 18 adults with gMG who are being recruited at several U.S. sites. More information can be found here.
Its completed Phase 1b, dose-escalation portion assessed the therapy’s manufacturability, as well as the safety of three ascending weekly doses (3.5, 17.5, and 52.5 million cells per kg) in three patients with severe gMG who failed to respond to standard treatment.
The ongoing Phase 2a, dose-expansion portion is testing three treatment schedules of a high dose of the therapy in a larger number of patients.
As previously reported, Phase 1b data showed that Descartes-08 was generally well-tolerated, with no reports of cytokine release syndrome (CRS) or other serious treatment-related adverse events. CRS is a potentially life-threatening immune reaction that has been reported with other CAR T-cell therapies.
Mild, temporary headache was the only recurring adverse event.
All three patients showed at least a full-class improvement on the MGFA Clinical Classification and reductions in MG severity scales — both highlighting the therapy’s potential to substantially ease symptom severity.
The Myasthenia Gravis Composite (MGC) scale — including both objective and subjective measures of disease severity — showed a mean score improvement of more than 50% three months after treatment.
Newly presented, interim Phase 2a data concerned the first two patients with severe gMG who received a six-week weekly regimen of Descartes-08’s high dose and completed their week 10 follow-up visit.
Results showed that both patients tolerated the treatment well and experienced pronounced and sustained reductions on all disease severity scales. Particularly, from study’s start to one month after the end of treatment, the MGG score had dropped from 27 to 2 in the first patient and from 23 to 3 in the second patient.
“We look forward to sharing these exciting interim data with the myasthenia community,” Miljković said.