Treatment with CAR T-cell therapy seen to reduce gMG severity in trial

Cartesian readies for Phase 3 study with positive Descartes-08 data

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with the investigational CAR T-cell therapy Descartes-08 led to deep and sustained reductions in disease severity among generalized myasthenia gravis (gMG) patients, according to top-line data from a Phase 2b clinical trial.

The therapy, designed somewhat differently than others in its class, also avoided some of the potentially serious side effects that are common to CAR T-cell treatments, per the researchers.

With the positive data in hand, developer Cartesian Therapeutics is planning to hold an end-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) by year’s end, with the launch of a Phase 3 trial sometime thereafter.

To accomplish this, the company can leverage its recently granted regenerative medicine advanced therapy (RMAT) designation, which offers early and intensive interactions with the regulatory body.

“We believe [these] positive data … demonstrate clinical proof-of-concept of our novel … platform and highlight the potential of Descartes-08 to provide deep and durable improvements for patients with MG,” Carsten Brunn, PhD, president and CEO of Cartesian, said in a company press release.

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Descartes-08 CAR T-cell therapy uses RNA instead of DNA

In gMG, self-reactive antibodies attack healthy proteins involved in nerve-muscle communication, leading to muscle weakness and fatigue.

Descartes-08 is a CAR T-cell therapy that’s designed to deplete the levels of the immune B-cells that produce those self-reactive antibodies, thereby easing disease severity. Essentially, a person’s immune T-cells are isolated and engineered to be equipped with a chimeric antigen receptor, or CAR, that will help them specifically recognize and destroy B-cells when infused back into the body. The CAR is designed to bind to BCMA, a protein found on the surface of B-cells.

Most CAR T-cell therapies use DNA to introduce the CAR into T-cells. With such an approach, patients must undergo chemotherapy to deplete existing immune cells before the engineered ones can be infused.

Descartes-08 is unique in that it instead uses RNA, an intermediate molecule that’s produced when cells convert the information stored in DNA to make a functional protein.

Using RNA enables the treatment to be given without the need for chemotherapy, and is also believed to avoid some of the standard side effects of DNA-based CAR T-cells.

On the other hand, while usual CAR T-cell therapies are designed to be administered just once, Descartes-08 does need to be given repeatedly to continue having a therapeutic effect.

The ongoing MG-001 clinical trial (NCT04146051) contained Phase 1b, Phase 2a, and Phase 2b parts, all of which involved heavily pretreated adults with gMG. Cartesian recently presented findings from the Phase 2b study, which enrolled 36 participants with a mean age of 58.2 years.

Participants were randomly assigned to receive Descartes-08 or a placebo, administered as six weekly infusions into the bloodstream. They then were followed up to month three. Patients initially on the placebo could then crossover to Descartes-08 in an open-label follow-up period lasting up to week 52, or the one-year mark.

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Over 70% of Descartes-08-treated patients saw 5-point gain in MGC score

The study’s main goal was to evaluate the proportion of patients who experienced at least a five-point improvement on the MG Composite (MGC) score — a composite measure of disease severity that takes into account aspects of several validated clinical scales — after the first three months.

Cartesian now reported that the study met its main goal. Specifically, 71% of Descartes-08-treated patients achieved at least a five-point improvement in their MGC score after three months compared with a quarter of those on the placebo.

Treatment responders also saw deep improvements across other validated scales of MG severity after three months, the data showed. Clinical responses were sustained for up to month six, consistent with efficacy analyses from the Phase 2a part of the trial, according to Cartesian.

“The durable improvements observed across all disease severity scales, the average of which was approximately three times greater than what is considered clinically meaningful, firmly support the potential for Descartes-08 to serve as an important new therapy for patients with MG that can be administered safely in the outpatient setting,” said Tahseen Mozaffar, MD, a professor at the University of California Irvine and director of its ALS and Neuromuscular Center.

As with earlier analyses from the Phase 1b and Phase 2a parts, Descartes-08 was generally well tolerated, with no evidence of cytokine release syndrome or neurotoxicity. Both are serious types of immune responses that are common with DNA-based CAR T-cell therapies.

The durable improvements observed across all disease severity scales, the average of which was approximately three times greater than what is considered clinically meaningful, firmly support the potential for Descartes-08 to serve as an important new therapy for patients with MG that can be administered safely in the outpatient setting.

In the earlier Phase 2a portion of the trial, which involved seven gMG patients, a six-week course of Descartes-08 was found to lead to durable reductions in disease-driving antibodies and MG severity scores.

In the new update, Cartesian also reported that for two patients who have since received a second six-week treatment cycle, rapid reductions in disease severity were observed and again maintained for up to a year.

Cartesian plans to leverage these proof-of-concept data in gMG to move forward with developing Descartes-08 as a CAR T-cell therapy for additional indications, including systemic lupus erythematosus and other autoimmune conditions.