Study to Assess Safety, Efficacy, and Cellular Kinetics of YTB323 in Generalized Myasthenia Gravis

Official title

An Open-label, Multi-center, Phase I/II Study to Assess Safety, Efficacy, and Cellular Kinetics of YTB323 in Participants With Treatment-resistant Generalized Myasthenia Gravis

Overview

This is a phase I/II study to assess safety, efficacy, and cellular kinetics of YTB323 in participants with treatment-resistant generalized myasthenia gravis. YTB323 is a Biological CAR-T cell therapy.

Detailed description

This is an open-label, multi-center, non-confirmatory study intended to assess safety, efficacy, and cellular kinetics of YTB323 treatment in participants with treatment-resistant generalized myasthenia gravis in order to enable a benefit to risk assessment for further development in generalized myasthenia gravis (gMG). The study plans to enroll approximately 15 participants with treatment-resistant gMG. The study utilizes a single dose design across 2 cohorts, consisting of a sentinel cohort of 3 patients followed by an expansion cohort of an additional 12 patients.

All participants dosed with YTB323 will be followed until 15 years after YTB323 administration in the Long-Term Follow-up (LTFU).

Interventions

• Genetic YTB323
  CAR-T cell suspension for intravenous infusion

Primary outcome measures

• Occurrence, severity, and frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: Baseline up to 2 years]

Secondary outcome measures (12)

• Plasma Pharmacokinetics (PK) of YTB323 - CMAX [Time frame: Pre-dose Day 1 up to 2 years]
• Plasma Pharmacokinetics (PK) of YTB323 - AUC [Time frame: Pre-dose Day 1 up to 2 years]
• Plasma Pharmacokinetics (PK) of YTB323 - Tmax [Time frame: Pre-dose Day 1 up to 2 years]
• Plasma Pharmacokinetics (PK) of YTB323 - Clast [Time frame: Pre-dose Day 1 up to 2 years]
• Plasma Pharmacokinetics (PK) of YTB323 - Tlast [Time frame: Pre-dose Day 1 up to 2 years]
• Cellular immunogenicity of YTB323 [Time frame: Pre-dose lymphodepletion up to 2 years]
• Humoral immunogenicity of YTB323 [Time frame: Pre-dose lymphodepletion up to 2 years]
• Neutralizing immunogenicity of YTB323 [Time frame: Pre-dose lymphodepletion up to 2 years]
• Change from Baseline of MG-ADL score [Time frame: Baseline up to 2 years]
• Change from Baseline of QMG total score [Time frame: Baseline up to 2 years]
• Proportion of patients with a ≥3-point reduction of QMG total score sustained for 6 months post Baseline [Time frame: Baseline up to 2 years]
• Proportion of patients with a ≥2-point reduction of MG-ADL score sustained for 6 months post Baseline [Time frame: Baseline up to 2 years]

Eligibility criteria

Inclusion criteria

• Confirmed gMG diagnosis supported by the following:

• Documented report of positive serology testing for either AChR antibodies or MuSK antibodies at screening AND at least one of the following:
• History of abnormal neuromuscular transmission test demonstrated by repetitive nerve stimulation or single-fiber electromyography
• History of positive acetylcholinesterase inhibitor test
• Improvement in MG signs on an oral acetylcholinesterase inhibitor as assessed by the treating physician
• MGFA Class III-IVa (gMG) at screening
• Treatment-resistant gMG as defined by: MG-ADL score ≥ 6 (≥50% non-ocular) at screening despite adequate treatment trials with at least two different non-steroidal immunosuppressive drugs given at adequate doses and duration of therapy.
• If on chronic corticosteroids, must be on a stable dose of corticosteroids for ≥1 month prior to screening and have the ability and willingness to taper to a maximum dose of 10 mg prednisolone daily or equivalent at least one week before leukapheresis
• If treated with cholinesterase inhibitors, patients must be on a stable dose for at least two weeks prior to screening

Exclusion criteria

• Exclusively ocular myasthenia gravis (MGFA I), mild symptoms (MGFA II), or severe bulbar disease or MG crisis, MGFA Class IVb or V at screening
• History of bone marrow/hematopoietic stem cell or solid organ transplantation.
• Clinically significant active, opportunistic, chronic or recurrent infection (including positive for hepatitis B or hepatitis C) confirmed by clinical evidence, imaging, or positive laboratory tests one month prior to leukapheresis
• Other uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids, at screening
• Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody, at screening
• Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy).

Other protocol-defined inclusion/exclusion criteria may apply

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• Univ Cali Irvine ALS Neuromuscular — Orange
• Wake Forest Univ School of Medicine — Winston-Salem
• Thomas Jefferson University — Philadelphia
• Houston Methodist Hospital — Houston

France · 3 centers

• Novartis Investigative Site — Bordeaux
• Novartis Investigative Site — Brest
• Novartis Investigative Site — Lille

Japan · 2 centers

• Novartis Investigative Site — Chiba
• Novartis Investigative Site — Kyoto

United Kingdom · 2 centers

• Novartis Investigative Site — Sheffield
• Novartis Investigative Site — London

Identifiers

NCT: NCT06704269 · CYTB323O12101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗