CAR T-cell therapy continues to show promise for myasthenia gravis

Descartes-08, Cartesian Therapeutics’ experimental CAR T-cell therapy, appears to be generally safe and symptom severity is markedly improved in the first five generalized myasthenia gravis (gMG) patients enrolled in a Phase 1b/2a clinical trial.

“I am very encouraged by the results of the interim analysis” as the therapy “appears to be safe and well tolerated, and the extent of clinical improvement seen in our early participants is remarkable,” said Volkan Granit, MD, principal investigator of the trial at the University of Miami, said in a press release.

“If future data from a controlled study support these findings, Descartes-08 would become a welcome addition to our arsenal for the treatment of MG,” Granit added.

“The Descartes-08 therapy is intended to cleanse the 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.

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“In accordance with this new, broadly applicable mechanism of action, we plan to study Descartes-08 for other autoimmune diseases,” Miljković added.

Interim trial results were shared in an oral and poster presentation at the Myasthenia Gravis Foundation of America’s (MGFA) 14th International Conference on Myasthenia Gravis 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 Chimeric Anti-mRNA-Modified Antigen Receptor Chimeric T Cells for the Treatment of Severe Generalized Myasthenia Gravis.”

MG is an autoimmune disease in which the immune system produces self-reactive antibodies that mistakenly recognize proteins essential for nerve-muscle communication as foreign immune attacks against them.

These abnormal immune attacks are mainly caused by two types of immune cells: activated B cells or plasma cells, which produce antibodies – including those that drive MG – and T cells, which can regulate the activity of other cells. immune.

A CAR T-cell therapy, Descartes-08, involves collecting T cells from a patient and genetically modifying them in the laboratory to produce a man-made chimeric antigen receptor, or CAR, which helps them recognize the BCMA protein present on the surface of plasma cells. The modified T cells are then expanded and returned to the patient.

By recognizing and binding to BCMA, Descartes-08 is expected to kill plasma cells, thereby reducing levels of self-reactive antibodies driving MG and ultimately alleviating the severity of symptoms.

A Phase 1b/2a trial (NCT04146051) is evaluating the safety and preliminary efficacy of Descartes-08 in up to 18 adults with gMG who are recruited from multiple US sites. More information can be found here.

Its phase 1b completed, the dose escalation part evaluated the manufacturability of the therapy, as well as the safety of three increasing weekly doses (3.5, 17.5 and 52.5 million cells per kg) in three patients with severe gMG who have not responded to standard therapy.

The ongoing Phase 2a, dose expansion portion is testing three treatment regimens 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 life-threatening immune reaction that has been reported with other CAR T-cell therapies.

A mild, temporary headache was the only recurring adverse event.

All three patients showed at least full class improvement on the MGFA clinical classification and reductions in the MG severity scales – both highlighting the therapy’s potential to significantly alleviate symptom severity.

The Myasthenia Gravis Composite (MGC) scale – comprising objective and subjective measures of disease severity – showed an average score improvement of more than 50% three months after treatment.

The recently presented interim Phase 2a data included the first two patients with severe gMG who received a six-week weekly regimen of high-dose Descartes-08 and completed their 10-week follow-up visit.

The results showed that both patients tolerated the treatment well and experienced pronounced and sustained reductions on all scales of disease severity. In particular, from the start of the study to one month after the end of treatment, the MGG score had fallen 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,” said Miljković.

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