Cartesian Therapeutics Submits IPO Filing Highlighting Descartes-08: First mRNA-Based CAR-T Therapy to Show Clinical Success in Autoimmune Disease

Jun 24, 2023 14:51 CST Updated Jun 27, 17:38

Cartesian Therapeutics

Pharmaceutical R&D Developer

University of California, Irvine

The University of California, Irvine (abbreviated as UC Irvine or UCI), also translated as the University of California, Irvine, was founded in 1965. It is one of the most comprehensive and powerful campuses within the University of California system, a world-renowned institution of higher learning and a top-tier research university globally. It is a member of the Association of American Universities (AAU), the Association of Pacific Rim Universities, and the “Public Ivy” league.

University of North Carolina at Chapel Hill

The University of North Carolina at Chapel Hill (UNC), founded in 1789, is a public research university in the United States, renowned as a “Public Ivy” and a “New Ivy.” Its faculty and alumni include 9 Nobel laureates, 23 Pulitzer Prize winners, and 51 Rhodes Scholars. Other distinguished alumni include one U.S. President, one U.S. Vice President, 38 U.S. state governors, 98 U.S. members of Congress, 9 cabinet secretaries, 39 Henry Luce Scholars, 3 astronauts, as well as numerous founders and CEOs of Fortune 500 companies.

UM

The University of Miami (UM or UMiami), located in Miami, Florida, is a premier private research university founded in 1925. It is particularly renowned for its business and law schools, having produced numerous leaders in business and government, including the Prime Minister of Belize, the Minister of Commerce of Peru, U.S. Senators and Representatives, multiple mayors, and several Supreme Court Justices. Marco Rubio, a 2016 U.S. presidential candidate, is also an alumnus of the University of Miami School of Law.

CAR-TCell therapy is an innovative class of cancerImmunityTherapy, inLeukemia、Lymphomaand has achieved remarkable and powerful efficacy in blood-related cancers such as multiple myeloma. Currently,FDASix CAR0T cell therapies have been approved for marketing.

In addition to cancer treatment, Professor Georg Schett from the University of Erlangen-Nuremberg in Germany has successfully treated two autoimmune diseases, systemic lupus erythematosus and anti-synthetase antibody syndrome, using CAR-T cell therapy.

Myasthenia Gravis (MG) is an autoimmune disease of the nervous system, most commonly caused by the body's immune system attacking proteins at the neuromuscular junction, leading to muscle weakness.

CAR-T cell therapy may cause severe side effects, which can be acceptable for patients with advanced cancer but seems too risky for chronic autoimmune diseases like myasthenia gravis. Typically, CAR-T cells are constructed by delivering and integrating DNA into T cells, resulting in the persistent presence of the delivered DNA within T cells, which replicates along with cell division. This may lead to an amplification effect and severe side effects.

To avoid this side effect of CAR-T cell therapy, Cartesian Therapeutics has developed a new platform called RNA Armory®, which uses mRNA instead of DNA to reprogram T cells. The delivered mRNA does not integrate into the T-cell genome and therefore does not replicate with cell division. This mRNA-based CAR-T cell therapy is a short-term treatment that requires multiple repeated injections.

Cartesian Therapeutics, Inc. has developed a therapy called DESCARTES-08, the first RNA-based CAR-T cell (rCAR-T) treatment for autoimmune diseases, which has advanced to clinical trials for the first time. This clinical trial aims to determine the optimal dose to effectively alleviate muscle weakness symptoms in patients with myasthenia gravis while minimizing side effects.

Recently, researchers from the University of California, Irvine, the University of North Carolina at Chapel Hill, the University of Miami, and Cartesian Therapeutics collaborated to publish a paper titled:Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study's research paper [1].

In this prospective, multi-center, open-label, Phase 1b/2a clinical study, the mRNA-based CAR-T cell therapy demonstrated the potential for more durable relief of myasthenia gravis symptoms and was well-tolerated, with no significant adverse reactions observed in patients.

CAR-T cell therapy is highly effective in treating hematologic malignancies, but treatment-related toxicity and the need for lymphodepletion (myeloablation) prior to treatment have limited their application in patients with autoimmune diseases. To explore the use of CAR-T for treating autoimmune disease patients and enhance its safety, the research team utilized mRNA instead of traditional DNA to engineer CAR-T cells (rCAR-T) targeting B-cell maturation antigen (BCMA) expressed on plasma cells.

To test the applicability of this method, the research team used rCAR-T to treat patients with myasthenia gravis, a neurological autoimmune disease partially mediated by pathogenic plasma cells expressing autoantibodies.

In this clinical trial, a total of 14 patients with generalized myasthenia gravis received rCAR-T cell therapy (Descartes-08) at different doses, targeting cells that produce myasthenia gravis antibodies, without lymphodepletion (non-myeloablative conditioning) prior to treatment. In the Phase 1b trial (3 patients), patients received three escalating doses to determine the maximum tolerated dose. In the Phase 2a trial (11 patients), patients received six treatments at the maximum tolerated dose (once weekly). The primary endpoint was the safety and tolerability of the therapy, while secondary endpoints included assessment of disease severity and biomarkers in treated patients.

Results showed that three patients experienced complete or near-complete symptom resolution, an effect that persisted for six months post-treatment. Additionally, two other patients no longer required chronic intravenous immunoglobulin therapy (a treatment approach for severe myasthenia gravis).

No dose-limiting toxicity, cytokine release syndrome, or neurotoxicity occurred during treatment. Common adverse events included headache (6/14), nausea (5/14), vomiting (3/14), and fever (4/14), all of which resolved within 24 hours after infusion.

Overall, in this first clinical trial of rCAR-T cell therapy for autoimmune diseases, Descartes-08 was generally safe and well-tolerated. During the follow-up period of up to 9 months after infusion, the Myasthenia Gravis Severity Scale showed a clinically meaningful decrease. This suggests that rCAR-T cell therapy could be a potential new treatment for myasthenia gravis and other autoimmune diseases, warranting further research.

Dr. Murat Kalayoglu, President and CEO of Cartesian Therapeutics, Inc., stated that we have observed profound and durable responses to the Decartes-08 treatment in clinical trials, which lasted for at least six months post-treatment. The company has now initiated a larger-scale randomized, placebo-controlled clinical trial, marking the first time such research has been conducted on engineered adoptive cell therapy.