Descartes-08 CAR T-cell therapy continues to ease gMG severity
Phase 2b trial enrolled 36 patients who received six weekly infusions or placebo
Descartes-08, an investigational CAR T-cell therapy for generalized myasthenia gravis (gMG), markedly reduced disease activity among patients who completed the entire protocol of a three-month Phase 2b clinical trial.
The treatment was also associated with reduced levels of MG-driving self-reactive antibodies, but not in the broader antibody repertoire or antibodies generated by vaccines to protect against common infections.
“Descartes-08 has strong potential for deep and durable improvements in patients with MG treated in the convenient outpatient setting without preconditioning chemotherapy and with no observed-to-date increased risk of infection,” Carsten Brunn, PhD, president and CEO of Cartesian Therapeutics, the therapy’s developer, said in a company press release.
Brunn said the company looks forward to holding an end-of-Phase 2 meeting with the U.S. Food and Drug Administration by the end of the year and discuss plans to launch a Phase 3 trial.
In MG, self-reactive antibodies produced by immune cells called B-cells attack proteins involved in nerve-muscle communication, resulting in fatigue and muscle weakness that can affect different parts of the body. Descartes-08 is designed to lower the numbers of these B-cells, thereby reducing the production of disease-driving antibodies and easing symptoms.
Treatment with Descartes-08 involves harvesting a patient’s immune T-cells then modifying them with a chimeric antigen receptor, or CAR, that specifically binds to B-cell maturation antigen (BCMA), a protein on B-cells. When the engineered T-cells are infused back into the patient, they can selectively bind and destroy harmful B-cells.
How is Descartes-08 different from other CAR T-cell therapies?
In most CAR T-cell therapies, DNA is used to insert the CAR into T-cells, which has the advantage of being a one-time treatment. However, patients must undergo chemotherapy to kill off existing immune cells before they receive the modified ones, which has been linked with harmful side effects.
Descartes-08 instead uses messenger RNA (mRNA), the template molecule used by cells to make proteins. Although mRNA-based CAR T-cell therapies require repeated dosing to maintain their therapeutic effect, they can be administered without chemotherapy and in an outpatient setting.
The safety and efficacy of Descartes-08 are being evaluated in a Phase 1/2 clinical trial called MG-001 (NCT04146051) that’s made up of three parts — Phase 1b, Phase 2a, and Phase 2b — that all include heavily pretreated and highly symptomatic adults with gMG.
After a safe dose was identified in Phase 1b, 11 patients were enrolled in Phase 2a and received six infusions into the vein of Descartes-08 at various doses. Across both parts, the treatment was well tolerated, with no signs of neurotoxicity or cytokine release syndrome, which are serious immune responses associated with DNA-based CAR T-cell therapies.
Marked improvements in measures of MG severity were also seen among patients receiving treatment in the Phase 2a part and these were sustained for months after the six-week treatment ended in most cases. Participants also saw their levels of disease-driving antibodies drop.
Results of Phase 2b part of study
In Phase 2b, 36 gMG patients were randomly assigned to receive six weekly infusions of Descartes-08 or a placebo. This phase’s primary goal was to determine the proportion of patients who showed a 5-point minimum improvement on the MG Composite (MGC) score, a composite measure of disease severity, after three months.
Top-line data showed a significantly higher proportion of Descartes-08-treated patients achieved this goal compared with a placebo (71% vs. 25%). The responders who reached their four- and six-month assessments saw deep, durable, and clinically meaningful improvements in their MGC scores.
New Phase 2b data were recently presented at the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting in Savannah, Georgia.
Among the 31 patients who completed the entire Phase 2b protocol, the proportion of MGC responders continued to be significantly higher in the Descartes-08 group than the placebo group after three months (67% vs. 31%). Similar results were seen for the 24 patients who tested positive for self-reactive antibodies targeting the acetylcholine receptor (AChR), the most common type of MG-causing antibodies (64% vs. 20%).
Across the whole population and among anti-AChR-positive patients, there were also significant improvements in two standard scales of MG severity at three months — the MG Activities of Daily Living (MG-ADL) and the Quantitative MG (QMG).
Consistent with Phase 2a data, treatment with Descartes-08 in Phase 2b led to an approximate 15% reduction in anti-AChR antibody levels at three months compared with the placebo’s 38% increase. Moreover, the therapy didn’t deplete the broader antibody repertoire nor decrease antibodies generated in response to vaccines against common viruses.
Most adverse events were short-lived or mild, consistent with Phase 2a data, and there were no signs of neurotoxicity or cytokine release syndrome.
“We are steadfast in our commitment to advancing our pipeline of innovative mRNA cell therapy candidates to extend the reach of this powerful modality to patients with autoimmune conditions,” Brunn said.
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