Myasthenia Gravis mRNA CAR-T Demonstrates Clinically Meaningful Improvements in Phase 2a Trial

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In terms of safety, Descartes-08 was characterized as well-tolerated during the study and long-term follow-up period.

Cartesian Therapeutics’ Descartes-08, an investigational autologous mRNA-engineered chimeric antigen receptor T-cell therapy (CAR-T) therapy for the treatment of autoimmune diseases including myasthenia gravis (MG), has demonstrated clinically meaningful improvements in the phase 2a portion of a clinical trial (NCT04146051) for MG.1

Among 7 patients in the phase 2a portion of the study who were treated with a single infusion of Descartes-08 each week for 6 weeks, all 7 continued to show marked and long-lasting clinical improvements across the MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15-revised instruments at 9 months after beginning treatment. Cartesian noted that none of these patients had been treated with new or increased MG-directed drugs while on-study. The 7 patients underwent assessment on the 4 aforementioned instruments again at 12 months of follow-up and 5 maintained clinically meaningful improvement.The 2 patients who had experienced loss of clinical effect at this time point were eligible for retreatment and 1 of these patients went forward with retreatment. The patient who was retreated showed a rapid improvement in clinical scores. Six months after beginning retreatment, the patient had minimal symptom expression and showed an ongoing improvement in clinical scores.

Furthermore, prior to beginning treatment 3 of the 7 patients had detectable anti-acetylcholine receptor (AChR) antibody levels. It was noted that at 6 months of follow-up, marked decreases in antiAChR antibody levels were observed in these patients. The observed decreases deepened at 9 months of follow-up and remained stable at 12 months of follow-up.

In terms of safety, Descartes-08 was characterized as well-tolerated during the study and long-term follow-up period. There were no cases of dose-limiting toxicities, cytokine release syndrome, or neurotoxicity reported. Cartesian noted that the patients were treated in an outpatient setting and that lymphodepleting chemotherapy was not used prior to treatment.

Key Takeaways

  • Cartesian Therapeutics' Descartes-08, an autologous mRNA-engineered CAR-T therapy, demonstrated clinically meaningful improvements in a phase 2a trial for myasthenia gravis (MG).
  • Descartes-08 was well-tolerated with no dose-limiting toxicities, cytokine release syndrome, or neurotoxicity reported.
  • A phase 2b randomized clinical trial for MG is ongoing, with topline data expected in mid-2024.

“The 12-month data build on the positive data reported earlier this year in The Lancet Neurology, underscoring the potential of Descartes-08 to drive deep and durable responses in patients with MG,” Milos Miljkovic, MD, the chief medical officer of Cartesian Therapeutics, said in a statement.1 “Notably, most patients maintained robust, clinically meaningful improvements across all 4 standard MG severity scores approximately 10 months after the last infusion. In addition, the lasting reductions in autoantibody titers are consistent with the observed clinical responses and the proposed mechanism of action for Descartes-08, supporting the deep and long-lasting effects observed in the study. As the first clinical trial using mRNA CAR-T to treat autoimmunity, the study also highlights the potential of our approach to expand the capabilities of cell therapy to address a variety of autoimmune diseases.”

A phase 2b double-blind randomized placebo-controlled portion of the same trial evaluating Descartes-08 in MG is also ongoing, with the first patient having been dosed in January of last year.1,2 As of January 2024, enrollment in the 2b trial remains ongoing and the company anticipates announcing topline data in the middle of this year. Descartes-08 has also previously been granted orphan drug designation for MG by the FDA and an investigational new drug (IND) application clearance for a trial in systemic lupus erythematosus.

Descartes-08 is comprised of patients’ own T-cells that have been modified ex-vivo with RNA to target B-Cell Maturation Antigen (BCMA). The use of RNA engineering is intended to avoid risks of genomic integration associated with DNA-based CAR-T therapies and to allow for control of pharmacokinetics.

Cartesian Therapeutics is one of several companies currently developing CAR-T therapies for the treatment of MG. In November 2023, Kyverna Therapeutics’ CD19-directed CAR-T therapy KYV-101 received clearance of an IND application for a trial in MG, as did Cabaletta Bio’s CD19-directed CAR-T CABA-201.3,4 IASO Biotherapeutics’ BCMA-directed CAR-T therapy CT103A is being evaluated in a clinical trial in China for indications including MG.5

REFERENCES
1. Cartesian Therapeutics announces positive long-term follow-up data from phase 2a study of lead mRNA cell therapy candidate Descartes-08 in patients with myasthenia gravis. News release. Cartesian Therapeutics, Inc. January 8, 2024. Accessed January 9, 2024. https://www.cartesiantherapeutics.com/2024/01/08/cartesian-therapeutics-announces-positive-long-term-follow-up-data-from-phase-2a-study-of-lead-mrna-cell-therapy-candidate-descartes-08-in-patients-with-myasthenia-gravis/
2. Cartesian Therapeutics announces dosing of first participant in a phase 2b randomized clinical trial for generalized myasthenia gravis. News release. Cartesian Therapeutics. January 31, 2023. Accessed January 9, 2024. https://www.cartesiantherapeutics.com/2023/01/31/cartesian-therapeutics-announces-dosing-of-first-participant-in-a-phase-2b-randomized-clinical-trial/
3. Kyverna Therapeutics announces FDA Clearance of phase 2 IND for KYV-101, a fully human CD19 CAR T-cell therapy to treat Myasthenia Gravis. News release. Kyverna Therapeutics. November 13, 2023. Accessed January 9, 2024. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-fda-clearance-of-phase-2-ind-for-kyv-101-a-fully-human-cd19-car-t-cell-therapy-to-treat-myasthenia-gravis-301986135.html
4. Cabaletta Bio receives FDA clearance of CABA-201 IND application for treatment of generalized myasthenia gravis. News release. Cabaletta Bio, Inc. November 6, 2023. Accessed November 17, 2023. Accessed January 9, 2024. https://www.cabalettabio.com/news-media/press-releases/detail/99/cabaletta-bio-receives-fda-clearance-of-caba-201-ind
5. World's first CAR-T for NMOSD treatment, IASO Biotherapeutics' equecabtagene autoleucel, receives IND approval by NMPA. News release. IASO Biotherapeutics. August 19, 2022. Accessed January 9, 2024. http://www.iasobio.com/info.php?id=198

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