Descartes-08 for myasthenia gravis

Last updated Sept. 25, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What is Descartes-08 for myasthenia gravis?

Descartes-08 is an investigational CAR T-cell therapy that’s designed to lower the number of immune B-cells and potentially reduce disease severity in people with generalized myasthenia gravis (gMG). It is being developed by Cartesian Therapeutics to be administered via intravenous, or into-the-vein, infusions.

The therapy has been designated a regenerative medicine advanced therapy and an orphan drug by the U.S. Food and Drug Administration (FDA) for the treatment of myasthenia gravis (MG). Both are intended to support and accelerate its development and regulatory review.

Descartes-08 is in Phase 2 clinical testing for gMG, and the company is planning to hold an end-of-Phase 2 meeting with the FDA before the close of 2024. A Phase 3 clinical trial of Descartes-08 in MG patients is expected sometime thereafter.

In addition to gMG, Descartes-08 is being investigated as a potential treatment for systemic lupus erythematosus (SLE), the most common form of lupus. Cartesian also is planning to investigate Descartes-08 in a basket trial involving children with autoimmune diseases, such as  juvenile MG.

Therapy snapshot

How does Descartes-08 work in myasthenia gravis?

An autoimmune disease, MG is driven by the production of self-reactive antibodies that mistakenly attack proteins involved in nerve-muscle communication. These attacks result in disease symptoms, mostly muscle weakness that can affect different parts of the body.

It isn’t always clear why these self-reactive antibodies arise in MG, but they are produced by immune cells called B-cells, so targeting these cells may help to lower the levels of disease-driving antibodies and ease MG severity.

Descartes-08 is an investigational chimeric antigen receptor (CAR) T-cell therapy that’s designed to deplete, or lower, the number of B-cells that produce antibodies. Similar to other types of CAR T-cell therapies, it is an autologous therapy that uses T-cells — another type of immune cell, one capable of killing other cells — harvested from a patient’s own blood. After being collected, these T-cells are engineered to carry a special receptor, called a chimeric antigen receptor or CAR, that helps them to specifically recognize and destroy B-cells after being infused back to the patient.

In the case of Descartes-08, the CAR is designed to bind to a protein called B-cell maturation antigen, which is found on the surface of B-cells.

Unlike conventional CAR T-cell therapies, which use DNA to introduce the CAR into T-cells, Descartes-08 uses messenger RNA (mRNA) — an intermediate molecule produced from DNA that holds instructions for making a protein. This enables Descartes-08 to be given without chemotherapy, a pretreatment that’s required in standard CAR T-cell therapies to destroy immune cells before the engineered ones can be returned to the patient.

Other advantages of mRNA-based CAR T-cell therapies include not being integrated into the cells’ genome, which has been associated with the development of cancer, and their ability to be administered in an outpatient setting. They also tend to be less costly than standard DNA-based therapies.

In turn, while conventional CAR T-cell therapies are designed to be given only once, mRNA-based CAR T-cell therapies like Descartes-08 have to be administered multiple times to maintain their therapeutic effect.

How will Descartes-08 be administered in myasthenia gravis?

In clinical trials involving people with gMG, Descartes-08 has been administered via repeat intravenous injections, at different doses and dosing schedules, including twice a week, weekly, and monthly.

The therapy now is in a Phase 2b clinical trial, where it’s being given in cycles of six weekly intravenous infusions. However, it’s not known if this will be the selected regimen should the therapy ultimately be approved for this indication.

Descartes-08 in myasthenia gravis clinical trials

The safety and preliminary efficacy of Descartes-08 has been and still is being evaluated in a Phase 1/2 clinical trial called MG-001 (NCT04146051). The trial has three main parts (Phase 1b, Phase 2a, and Phase 2b), all involving heavily pretreated and highly symptomatic adults with gMG.

Phase 1b portion

The Phase 1b part focused on assessing the safety, tolerability, and manufacturability of Descartes-08, administered in three ascending doses. Investigators also aimed to determine the therapy’s maximum tolerated dose, that is, the highest dose that could safely be administered without significant side effects.

During this trial phase, three gMG patients received three weekly infusions of Descartes-08, with each infusion delivering an increasing dose of the therapy — 3.5, 17.5, and 52.5 million CAR T-cells per kilogram of body weight.

Results showed that Descartes-08 could be successfully manufactured for all patients, despite their continuous use of immunosuppressive therapy. The therapy also was generally well tolerated, with no reported cases of cytokine release syndrome (CRS), a potentially life-threatening immune reaction that has been associated with CAR T-cell therapies.

There were no dose-limiting toxicities (side effects preventing an increase in treatment dose), treatment-related serious adverse events, or cases of neurotoxicity, making the 52.5 million cells per kilogram the maximum tolerated dose for Descartes-08.

After receiving Descartes-08 in this initial trial phase, patients also showed reductions, or improvements, in several measures of MG severity, including the MG Composite and the Quantitative MG (QMG) scales, over the course of 24 weeks (about six months).

Phase 2a portion

The Phase 2a portion was designed to test three possible dosing schedules of the therapy’s maximum tolerated dose (52.5 million CAR T-cells per kg) in a larger group of gMG patients. Three patients received six doses of the therapy twice weekly, seven were given six weekly doses, and one patient received six monthly doses.

Data from 10 patients given six doses of Descartes-08 in a twice weekly or weekly dosing schedule showed improvements across several measures of MG severity by week five. These improvements further deepened or remained stable in most patients who reached 12 weeks of follow-up.

However, by week 16, all three patients in the twice-weekly dosing regimen had withdrawn from the study due to adverse events or worsening symptoms that required additional treatment, while the seven given weekly treatment continued to see improvements after a median of six months.

Pooled data from the three patients in the trial’s Phase 1b part and the 11 in its Phase 2a portion continued to show the therapy was generally well tolerated, and not associated with the side effects typically seen with conventional CAR T-cell therapies, such as CRS and neurotoxicity.

Updated data from the seven patients who received six weekly doses showed that all experienced marked improvements in four measures of MG severity and quality of life, the MG Activities of Daily Living, the Quality of Life 15-revised, the MG Composite, and the QMG scales, after nine months. Five patients maintained those clinically meaningful improvements after one year.

The other two participants experienced a loss of therapeutic benefits after one year and were eligible to be given another round of six weekly Descartes-08 infusions. In a more recent update, Cartesian noted that both retreated patients experienced rapid and sustained improvements in clinical scores that lasted up to one year following the second treatment cycle.

Phase 2b portion

The Phase 2b part of MG-001 involves a total of 36 gMG patients, who were randomly assigned to treatment with Descartes-08 or a to placebo, administered as six weekly intravenous infusions. After three months, patients assigned to placebo could move to Descartes-08 in an open-label extension lasting up to 52 weeks, or one year.

The main goal of this trial phase was to determine the proportion of patients who experienced at least a five-point improvement on their MG Composite scores after three months.

Top-line data showed that 71% of patients given Descartes-08 achieved this goal, compared with 25% of those on a placebo. Statistically significant improvements with Descartes-08 over a placebo also were observed in other measures of MG severity by the end of the third month, with scores either improving or being sustained out to six months. The therapy continued to be well tolerated, demonstrating a safety profile consistent with that observed in earlier phases of the trial.

The MG-001 clinical trial is slated to conclude in 2026.

Common side effects of Descartes-08

The most common side effects of Descartes-08 reported during clinical testing in gMG patients include:

• headache
• chills
• nausea
• fever
• fatigue.

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