KYV-101 found safe, effective for woman with severe gMG

CAR T-cell therapy KYV-101 being developed for multiple autoimmune diseases

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by Steve Bryson, PhD |

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Kyverna Therapeutics’ investigational cell therapy KYV-101 safely and effectively improved muscle strength and reduced fatigue in a woman with severe, hard-to-treat generalized myasthenia gravis (gMG), according to a case report.

The patient was treated based on an individual case evaluation and outside of a clinical trial.

“This groundbreaking case report rewards and reinforces our commitment to provide potentially paradigm-shifting therapeutic options to patients suffering from autoimmune diseases,” Peter Maag, PhD, Kyverna’s CEO, said in a company press release. “We want to commend patients and their medical care teams that are helping advance the field of treatment options for B cell-driven autoimmune diseases.”

After receiving the green light from the U.S. Food and Drug Administration last week, the company will launch a multicenter Phase 2 clinical trial called KYSA-6 to test the therapy in MG patients.

The case study, “Anti-CD19 CAR T cells for refractory myasthenia gravis,” was published in the journal The Lancet Neurology.

In MG, self-reactive antibodies disrupt the communication between nerves and muscles, leading to muscle weakness and other MG symptoms. Antibodies are proteins produced by immune B-cells to help fight infections, but they can also mistakenly target healthy tissues and drive autoimmune disorders like MG.

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KYV-101 designed to destroy disease-causing B-cells by targeting CD19 protein

KYV-101 is a CAR T-cell therapy designed to destroy such disease-causing B-cells by targeting CD19, a cell surface protein found at high levels in plasma cells, the matured form of B-cells that produce high amounts of antibodies.

It involves collecting a patient’s immune T-cells and modifying them in the lab to produce a chimeric antigen receptor, or CAR, that selectively binds to CD19. Modified T-cells are then infused back into the patient, where they are expected to eliminate CD19-positive B-cells.

In this report, researchers in Germany and at Kyverna described the first successful use of anti-CD19 CAR T-cell therapy in a person with severe and refractory, or treatment-resistant, gMG — the most common type of MG which is characterized by widespread muscle weakness and fatigue.

“We believe this case report provides compelling evidence for the potential of anti-CD19 CAR T-cell-mediated deep B cell depletion in inducing remission and improving symptoms in severe, treatment-refractory MG,” said Aiden Haghikia, MD, the study’s first author and director of the department of neurology at Otto-von-Guericke University Magdeburg, in Germany.

A 33-year-old woman was diagnosed with gMG in 2012 and tested positive for self-reactive antibodies against the acetylcholine receptor (AChR) protein, the most common target of MG-driving antibodies.

From 2021 to 2023, she experienced difficulties in breathing, swallowing, and walking without mobility aids. She also had several myasthenic crises, or sudden worsening of symptoms, requiring invasive breathing support during five hospitalizations at the researchers’ institution.

She tried several approved MG treatments, including the B-cell-depleting therapy rituximab, but none stabilized her disease, which was classified as severe. Between March and May 2023, her disease progressed despite treatment with standard immunosuppressive drugs and corticosteroids.

“Given the refractory nature of the disorder, and following successful use of anti-CD19 CAR T cells in autoimmune rheumatic diseases, we decided to treat her with a rationally designed CAR T approach,” the researchers wrote.

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Patient given single infusion of KYV-101 using own T-cells

She was given a single infusion of KYV-101 using her own T-cells. Consistent with previous results in treated people with other conditions, CAR T-cells in her bloodstream reached their peak growth 16 days after infusion, and were still detectable after about two months.

CD19-positive B-cells, which were already reduced due to prior treatments, were eliminated from her bloodstream after eight days and remained undetectable after about two months. At the same time, the levels of anti-AChR antibodies fell by 70%, while those of protective antibodies associated with vaccinations remained unchanged.

These findings indicate most disease-causing antibodies were produced by short-lived plasma cells positive for CD19, which are targeted by KYV-101, the researchers noted.

By contrast, protective antibodies produced by long-lived plasma cells in the bone marrow that do not have CD19 “are shielded from the effects of CD19 CAR T cells,” the team wrote.

In addition, the patient’s muscle strength and fatigue improved during the first two months after treatment. She was able to hold out her arm horizontally for longer, walk without supportive devices, and had lower scores for disease activity and severity, as assessed by validated measures.

Notably, rituximab targets CD20, a protein found at high levels on the surface of B-cells across their several stages of maturation, but at lower levels on plasma cells. This may explain why KYV-101 was successful in this patient when rituximab was not.

Additionally, the observed clinical improvements occurred despite very reduced exposure to corticosteroids and the MG therapy Mestinon (pyridostigmine bromide), both of which were to be stopped in the coming months.

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No adverse events reported with KYV-101 CAR T-cell therapy

The woman experienced no adverse events associated with CAR T-cell therapies, such as excessive immune responses, immune cell-related neurological damage, or deficient levels of overall antibodies.

However, she had a mild increase in liver enzymes, suggesting liver injury, that resolved without treatment.

“We are extremely happy with the outcome so far, which suggests that a different CAR T-cell approach targeting CD19 with a stably expressed CAR … has the potential to be safe and effective in severe and refractory MG,” said Dimitrios Mougiakakos, MD, the study’s senior author and director of the clinic of hematology, oncology, and stem cell transplantation at the university.

Kyverna is developing KYV-101 as a potential treatment for various other autoimmune diseases driven by B-cells, including lupus, scleroderma, and multiple sclerosis.