CABA-201 for myasthenia gravis

Last updated Oct. 10, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What is CABA-201 for myasthenia gravis?

CABA-201 is an experimental CAR T-cell therapy designed to ease disease severity in people with myasthenia gravis (MG) by lowering the number of a patient’s immune B-cells.

Developed by Cabaletta Bio, the therapy is being tested in a Phase 1/2 clinical trial as a potential treatment for generalized myasthenia gravis (gMG), in which muscle weakness affects different parts of the body. It is being explored as a single intravenous, or into-the-vein, infusion following a course of chemotherapy.

CABA-201 is also being investigated as a potential treatment for several other autoimmune conditions.

Therapy snapshot

How does CABA-201 work in myasthenia gravis?

In people with MG, the body mistakenly produces self-reactive antibodies that attack proteins involved in nerve-muscle communication. These autoantibodies, which are produced by a type of immune cells called B-cells, cause damage that ultimately results in the disease’s hallmark symptoms of muscle weakness and fatigue.

An investigational chimeric antigen receptor (CAR) T-cell therapy, CABA-201 is designed to temporarily deplete B-cells from the body. This may help reset the immune system and promote the regrowth of healthy B-cells, while eliminating those that produce the harmful autoantibodies that drive MG. In the long term, this approach is expected to help patients be symptom-free and remain in a state of remission without the need for additional treatments.

CABA-201 is an autologous therapy that uses a patient’s own immune T-cells, which have the ability to kill other cells. After being collected, the T-cells are engineered in the lab with a gene that provides the instructions for them to produce a specialized receptor called a chimeric antigen receptor or CAR.

The receptor in CABA-201 is designed to bind to CD19, a protein found on the surface of B-cells. Essentially, it works by teaching the T-cells to target and destroy the disease-causing B-cells once they are infused back into the patient’s body. Importantly, while approved CD19 CAR T-cell therapies contain antibodies derived from mice, the receptor in CABA-201  recognizes its target through a fully human antibody fragment, which is expected to make it safer than previous approaches.

This CAR also contains a 4-1BB costimulatory domain and a CD3 zeta signaling domain. The 4-1BB domain helps promote T-cell activation, survival, and persistence, while preventing exhaustion — a state in which T-cells become dysfunctional and unable to keep fighting off potential threats. For its part, the CD3 zeta domain plays a key role in the initiation of events following T-cell activation that ultimately lead to the destruction of other cells.

How will CABA-201 be administered in myasthenia gravis?

CABA-201 is designed to be administered via a one-time intravenous infusion following a preconditioning chemotherapy regimen. The preconditioning regimen is given to wipe out the patient’s immune cells before the modified T-cells are reinfused back into the body.

In a Phase 1/2 clinical trial, people with gMG are receiving a CABA-201 injection at an initial dose of 1 million CAR T-cells per kilogram of body weight. The preconditioning regimen consists of fludarabine and cyclophosphamide. Still, it is too early to know if this will be the selected dose and chemotherapy regimen to be used if the therapy ultimately receives regulatory approval.

CABA-201 in myasthenia gravis clinical trials

Because the B-cells produced are involved in many autoimmune conditions, Cabaletta is running a series of Phase 1/2 clinical trials, collectively called the RESET studies, to investigate the safety, tolerability, and early signs of efficacy of CABA-201 in several autoimmune populations.

One of those trials, dubbed RESET-MG (NCT06359041), is an open-label study expected to enroll 12 people with gMG, ages 18 to 70, who have active and treatment-resistant disease. Participants are being divided into two groups of six patients each: One group has antibodies targeting the acetylcholine receptor (AChR), the most common type of MG-causing antibodies, while the other is negative for these antibodies.

After undergoing a procedure used to collect T-cells from the bloodstream, patients will complete a preconditioning chemotherapy regimen with fludarabine and cyclophosphamide. They will then receive a single intravenous infusion of CABA-201 containing 1 million CAR T-cells per kilogram.

The trial’s main goal is to evaluate the incidence and severity of any side effects occurring in the first 28 days following treatment with CABA-201. Secondary goals, which will be evaluated for up to 156 weeks, or about three years, include assessing the therapy’s long-term safety and pharmacological properties, and evaluating its effects on the levels of self-reactive antibodies. Assessing changes in different measures of MG severity is also a secondary goal.

Data from RESET-MG, which was cleared to be launched in the U.S. in late 2023, is expected before the end of this year. The trial is slated to be completed in 2029.

Common side effects of CABA-201

Clinical testing of CABA-201 in people with gMG is still in the early stages and no results have been reported to date, so the therapy’s side effect profile in this patient population is still unknown.

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