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Cartesian Therapeutics Advancing RNA-Based CAR-T in Myasthenia Gravis After Promising Early Data

Stock photo of medical professional counseling a male patient

NEW YORK – Biotech firm Cartesian Therapeutics is ramping up enrollment of a randomized, Phase IIb trial of Descartes-08, an investigational cell therapy for generalized myasthenia gravis (gMG), after a smaller study has given it confidence about a novel approach that relies on modifying a patient's RNA.

In this trial, which is slated to read out in the first half of 2024, the Gaithersburg, Maryland-based firm is hoping to further establish that this type of RNA CAR T, called rCAR T for short, can improve tolerability and reduce toxicities seen with conventional DNA-based CAR T-cell approaches.

Descartes-08 is an autologous treatment engineered from a patient's own T cells. The T cells are extracted from a blood sample, engineered to target the BCMA cell-surface protein, and reinfused back into the patient. Inside the body, the engineered T cells home in on BCMA found on the surface of plasma cells that produce the autoantibodies at the root of gMG.

"The CAR T that we've developed … goes after and kills the pathogenic plasma cell that is making not just autoantibodies for myasthenia, but we think autoantibodies for a whole array of other diseases," said Cartesian CEO Murat Kalayoǧlu, highlighting that Descartes-08 is the first rCAR T-cell therapy to be tested in patients with an autoimmune disease.

gMG is a rare, chronic autoimmune disease in which self-reactive antibodies target proteins participating in nerve-muscle communication, activating the complement system and causing the immune system to attack the neuromuscular junction. This results in debilitating weakness and loss of function in patients' muscles. There's no cure for the disease, and standard care involves regularly taking drugs, such as immunosuppressants, which only address the symptoms of gMG.

Cartesian launched in 2016, focused initially on developing cell therapies for early-stage cancers. During this time, scientists at the company had the idea to modify cellular RNA rather than the DNA itself as a way to reduce the risk of serious side effects.

"The conventional way to engineer these cells was through DNA," Kalayoǧlu said. But unlike with conventional CAR T cells, where the cellular DNA is engineered to provide instructions for making the CAR, rCAR T cells are engineered to only provide the mRNA template for the CAR.

The use of rCAR T cells, Cartesian is betting, will provide two distinct advantages over their DNA-based counterparts. First, the fact that mRNA does not replicate with cell division may confer more precise pharmacokinetic control. Second, Descartes-08 bypasses the need for chemotherapy to deplete existing immune cells prior to rCAR T infusion.

Tobias Weiss, senior physician at University Hospital Zurich's neurology department, believes that rCAR Ts will also prove more cost-efficient than DNA-based CAR T-cell therapies and be "very effective because multiple RNAs can be brought into the cell to express various transgenes." Weiss noted, however, that the need to administer repeat doses of these drugs due to their transient expression could be a disadvantage in some cases.

While Cartesian has multiple cancer drugs in its pipeline, it has pivoted to testing the rCAR T approach first in autoimmune diseases with Descartes-08 as its lead asset. All of the company's products are developed using its RNA Armory platform, which introduces the mRNA into human cells.

Although Cartesian's Descartes-08 trial is the first time an rCAR T is being tested in an autoimmune setting, attempts are ongoing to explore this type of cell therapy against cancer. For example, Weiss is currently assessing an rCAR T within a glioma trial, and Marcela Maus, director of the cellular immunotherapy program at Mass General Hospital Cancer Center, has tested rCAR T in other solid tumors.

"The transient, temporary method of expressing the CAR by using RNA was not very effective in solid tumors," she acknowledged. Still, Maus expressed excitement at the prospect of a BCMA-targeted RNA-based CAR undergoing evaluation in patients with gMG.

She pointed out, however, that Cartesian is testing much higher doses of CAR T cells that will be given to patients multiple times rather than the one-time doses of conventional CAR T cells patients receive today. These high doses, she cautioned, could come with manufacturing challenges, while repeat doses can increase the risk that patients will develop allergies to the CARs.

In The Lancet Neurology last month, Cartesian published promising results from a smaller-scale non-randomized Phase Ib/IIa study, in which Descartes-08 safely eased gMG symptoms in 14 patients. Researchers, who followed patients who received six doses of the rCAR T for a median of six months, found no dose-limiting toxicities, instances of cytokine release syndrome, or neurotoxicity. Common adverse events included headache, nausea, vomiting, and fever, all of which resolved within 24 hours of infusion. On average, with up to nine months of follow-up, gMG patients' strength and ability to do daily activities improved on various measurement scales, and three patients saw near complete or complete eradication of their symptoms.

Taken together, findings from the study indicate that Descartes-08 is safe, potent, and durable for the treatment of gMG, Kalayoǧlu said. "Patients are not requiring continuous administration of the product," he said. "After six weeks, they're totally done with the therapy … which is very different compared to any other treatment of myasthenia [gravis]."

"This is exciting data," agreed Maus, who wasn't involved with the above study. However, she said that larger trials will be needed to assess the impact and durability of the rCAR T system.

Cartesian's recently launched randomized Phase IIb crossover study, in which the firm hopes to enroll around 30 gMG patients, could offer such insights. The smaller-scale study gave Cartesian the "conviction" to test its rCAR T for the first time in a gold-standard, placebo-controlled trial in an autoimmune disease setting, according to Kalayoǧlu. "The path to any approval for a cell therapy in autoimmune disease has to involve a placebo-controlled trial," he said, noting that depending on the results of this study, Cartesian will decide whether to move forward with a registrational trial in 2024.

The company also plans to start testing RNA-based CAR T-cells in other autoimmune diseases, such as lupus, in the coming months. "The mechanisms at play for myasthenia [gravis] were common with many other autoimmune diseases," Kalayoǧlu said, characterizing gMG as a textbook autoimmune disease. "If we … demonstrate safety as well as efficacy, then what we see from myasthenia [gravis] could likely be applied to a whole array of other autoimmune diseases."