A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Subjects with Treatment Refractory Stiff Person Syndrome

Stiff person syndrome (SPS) is a rare progressive immune-mediated disorder of the central nervous system (CNS) that is characterized by progressive rigidity and painful spasms of predominantly axial and proximal limb muscles. The condition gradually worsens over time and left untreated, it can lead to permanent disability and in some cases, mortality.

B cells contribute to systemic autoimmunity and development of disease in several ways, most notably via cytokine production, antigen presentation and complement activation (via autoantibody production). In SPS, B cell involvement is supported by the presence of antibodies against glutamic acid decarboxylase (GAD), which is widely expressed within the CNS, catalyzing the conversion of the excitatory neurotransmitter l-glutamate to the inhibitory GABA.

CAR-T therapy such as KYV-101 may be an effective treatment for SPS, by targeting these autoreactive B cells. Using chimeric antigen receptor (CAR) T-cell technology, engineered T cells with receptors are designed to recognize and eliminate B cells, including those that produce GAD autoantibodies. This approach aims to intervene at the root of the autoimmune response, offering a precise and potentially transformative treatment for SPS. CAR-T cell therapy holds promise as a targeted and effective intervention, addressing the autoimmune component directly and potentially halting disease progression.

Key Inclusion Criteria:

• Subject must have been diagnosed SPS per the following criteria:

  • Rigidity of limb and axial (trunk) muscles prominent in the abdominal and thoracolumbar paraspinal areas and making bending difficult
  • Clinical or electrophysiological evidence of continuous contraction of agonist and antagonist muscles
  • Episodic spasms precipitated by unexpected noises, tactile stimuli, or emotional upset
  • Absence of any other neurologic disease that could explain the stiffness and rigidity
  • High titer serum anti-GAD65 antibodies shown at screening -OR- seropositive for anti-glycine antibodies. If anti-GAD65 antibodies are lower than the high titer threshold peripherally but positive in the cerebrospinal fluid (CSF), the subject can be included. A prior documented high titer anti-GAD65 antibody level may be acceptable subject to sponsor review.

• Active symptoms with inadequate response to at least one immunomodulatory therapy.

• Stiffness index ≥2.

• At least 20 of the 25 enrolled subjects should be ambulatory.

Key Exclusion Criteria:

• Bedridden subjects for more than 3 months.
• History of CNS or spinal cord tumor, metabolic or infectious cause of myelopathy, genetically inherited progressive CNS disorder, sarcoidosis, non-SPS progressive neurologic condition or progressive multifocal leukoencephalopathy (PML).
• History of stroke, seizure, dementia, Parkinson's disease, cerebellar diseases, psychosis, aphasia, and any other neurologic disorder that is of a nature and severity that the investigator considers would increase the risk for the subject.
• Cardiac ejection fraction ≤ 40%.