Clinical trial NCT06704269: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Generalized Myasthenia Gravis
Keywords: myasthenia gravis
generalized myasthenia gravis
YTB323
CAR-T
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2024-11-26
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 (gMS). 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).

Eligibility criteria: Inclusion Criteria:

1. 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
2. MGFA Class III-IVa (gMG) at screening
3. Treatment-resistant gMG as defined by: MG-ADL score ≥ 6 at screening despite adequate treatment trials with at least two different non-steroidal immunosuppressive drugs given at adequate doses and duration of therapy.
4. If on chronic corticosteroids, the ability and willingness to taper to a maximum dose of 10 mg prednisolone daily or equivalent at least one week before leukapheresis
5. If treated with cholinesterase inhibitors, patients must be on a stable dose for at least two weeks prior to screening

Exclusion Criteria:

1. Exclusively ocular myasthenia gravis (MGFA I), mild symptoms (MGFA II), or severe bulbar disease or MG crisis, MGFA Class IVb or V at screening
2. History of bone marrow/hematopoietic stem cell or solid organ transplantation.
3. 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
4. Other uncontrolled disease states, such as asthma, or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids, at screening
5. Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody, at screening
6. 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

Primary outcomes:
measure: Occurrence, severity, and frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to 2 years
Secondary outcomes:
measure: Plasma Pharmacokinetics (PK) of YTB323 - CMAX
timeFrame: Pre-dose Day 1 up to 2 years
measure: Plasma Pharmacokinetics (PK) of YTB323 - AUC
timeFrame: Pre-dose Day 1 up to 2 years
measure: Plasma Pharmacokinetics (PK) of YTB323 - Tmax
timeFrame: Pre-dose Day 1 up to 2 years
measure: Plasma Pharmacokinetics (PK) of YTB323 - Clast
timeFrame: Pre-dose Day 1 up to 2 years
measure: Plasma Pharmacokinetics (PK) of YTB323 - Tlast
timeFrame: Pre-dose Day 1 up to 2 years
measure: Cellular immunogenicity of YTB323
timeFrame: Pre-dose lymphodepletion up to 2 years
measure: Humoral immunogenicity of YTB323
timeFrame: Pre-dose lymphodepletion up to 2 years
measure: Neutralizing immunogenicity of YTB323
timeFrame: Pre-dose lymphodepletion up to 2 years
measure: Change from Baseline of MG-ADL score
timeFrame: Baseline up to 2 years
measure: Change from Baseline of QMG total score
timeFrame: Baseline up to 2 years
measure: Proportion of patients with a ≥3-point reduction of QMG total score sustained for 6 months post Baseline
timeFrame: Baseline up to 2 years
measure: Proportion of patients with a ≥2-point reduction of MG-ADL score sustained for 6 months post Baseline
timeFrame: Baseline up to 2 years
measure: Proportion of patients with a MGFA-PIS of minimal manifestations (MM) or better and sustained for 6 months post Baseline
timeFrame: Baseline up to 2 years
measure: Manufacture success (defined as meeting release specifications and target dose)
timeFrame: Day -9 to Day -2
Other outcomes:
Locations:
city: Orange
country: United States
facility: Univ Cali Irvine ALS Neuromuscular
state: California
city: Winston-Salem
country: United States
facility: Wake Forest Univ School of Medicine
state: North Carolina
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Brest
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Kyoto
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: