Descartes-08, novel CAR T-cell therapy, shows promise in gMG
Phase 1/2 trial finds safety and meaningful gains, Phase 2b study enrolling
Descartes-08, an investigational RNA-based CAR T-cell therapy (rCAR-T), safely eased disease symptoms for up to nine months after treatment among 14 adults with generalized myasthenia gravis (gMG) taking part in a Phase 1b/2a clinical trial.
The open-label MG-001 trial (NCT04146051), now a recruiting Phase 2b study, is the first to test of this type of cell therapy in patients with an autoimmune disease, Cartesian Therapeutics, Descartes-08’s developer, reported in a company press release.
Findings were detailed in the study, “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,” published in The Lancet Neurology.
“This study showed the feasibility of preparing autologous rCAR-T for individuals on immunosuppressive therapy, of using the cells without lymphodepletion chemotherapy [typically given prior to cell therapy], and of administering rCAR-T in the outpatient setting with minimal monitoring … due to the notable safety profile of the product,” its researchers wrote.
Myasthenia gravis treatment designed to bypass need for chemotherapy
The Phase 2b study adds a placebo-controlled arm to the MG-001 trial, and it is enrolling up to 30 adults with gMG at sites across the U.S. and in Canada. It will follow a crossover design, with participants being randomly assigned to six, once-weekly doses of Descartes-08 or a placebo, and then switching to the opposite regimen.
An autoimmune disease, gMG arises when the immune system mistakenly attacks proteins essential for nerve-muscle communication. These attacks are driven by self-reactive antibodies that are produced by an activated form of immune B-cells, called plasma cells.
CAR T-cell therapies like Descartes-08 involve equipping the body’s immune T-cells with the means to kill these plasma cells. Briefly, a person’s own T-cells are isolated (an autologous approach) and engineered in the lab to be equipped with a chimeric antigen receptor, or CAR, that recognizes the BCMA protein found on the surface of plasma cells. When infused back to the patient, these modified T-cells are expected to specifically target and destroy those plasma cells.
Standard CAR T-cell therapies introduce DNA to T-cells, giving them the instructions needed to produce the CAR. That approach requires chemotherapy to deplete existing immune cells prior to the infusion of the CAR T-cells, and comes with toxicity-related safety concerns.
“Conventional, DNA-engineered CAR T-cells are highly effective in treating several blood cancers, but associated toxicities and the need for lymphodepletion chemotherapy limit their use beyond oncology,” said Miloš Miljković, MD, chief medical officer at Cartesian.
The RNA-based approach used by Descartes-08 bypasses the need for chemotherapy. Instead of giving DNA to T-cells, it skips a step and gives them RNA, an intermediate molecule that’s produced in the process of converting DNA to a protein.
Traditional CAR T-cells are a one-time therapy, while the RNA-based version requires repeat dosing. But is thought to have a much more favorable safety profile.
Descartes-08 was well tolerated, with gains seen across MG severity scales
The MG-001 Phase 1b/2a trial evaluated Descartes-08 in adults with gMG across eight U.S. sites.
After its initial dose-finding part in three patients, 11 gMG patients were enrolled and assigned to received six into-the-vein infusions of the therapy on various dosing schedules, along with their standard medications. They then were followed for up to nine months.
Eight of the 11 patients had antibodies targeting the acetylcholine receptor (AChR), and two had antibodies against muscle-specific tyrosine kinase (MuSK) proteins — the two most common MG-causing antibodies. The remaining patient was seronegative for disease-associated antibodies.
Across patients in both trial parts, Descartes-08 was well tolerated and not associated with side effects typical of DNA-based therapies. Such side effects include neurotoxicity, cytokine release syndrome — a serious type of immune response — and other blood-related abnormalities.
Common side effects reported with Descartes-08 included headache (43%), nausea (36%), fever (29%), and vomiting (21%), all of which resolved within a day of the infusion.
Most Phase 2a participants exhibited clinically meaningful improvements across four validated scales of MG severity, including the MG Activities of Daily Living (MG-ADL), the Quantitative MG (QMG), the MG Composite score (MGC), and the MG Quality of Life 15-revised (MG-QoL-15r), relative to the study’s start.
These benefits persisted for months after the six-week treatment regimen, with patients remaining in the trial — all of whom received a once weekly dose — still seeing improvements compared with baseline after a median six months of follow-up.
At six months post-treatment, average clinical improvements were about three times higher than thresholds considered to be clinically meaningful, according to the company.
Moreover, three people achieved complete or near-complete symptom remission, and two patients previously reliant on chronic intravenous immunoglobulin treatment did not need it after receiving Descartes-08.
“Descartes-08 might be useful as an infrequent, as-needed treatment, avoiding side-effects from continuous exposure to immunomodulators,” the researchers wrote.
While it is “too early” to definitively establish the benefits of Descartes-08 for gMG, trial findings “provided valuable information for the ongoing phase 2b study,” Andreas Meisel, MD, a professor of neurology at the NeuroCure Clinical Research Center in Berlin, wrote in an editorial that accompanied the study’s publication.
gMG, Meisel added, serves “as a model disease for exploring this innovative therapeutic approach, which is also of great interest for other autoantibody-mediated neurological diseases.”