C-CAR168, an Autologous Anti-CD20/BCMA Chimeric Antigen Receptor T-Cell Therapy, in Participants With Systemic Sclerosis (SSc) Refractory to Standard Therapy

• C-CAR168 (Biological): Autologous anti-CD20/BCMA chimeric antigen receptor T-cell therapy administered as a single intravenous infusion

Primary outcomes

• Incidence and severity of treatment-emergent adverse events [Through Month 24]: Incidence and severity of treatment-emergent adverse events, serious adverse events, dose-limiting toxicities, CRS, ICANS, adverse events of special interest, and treatment- or procedure-related adverse events.

Secondary outcomes

• Proportion of Participants Achieving Response [Through Month 24]: Proportion of participants achieving a response per the revised Composite Response Index for Systemic Sclerosis (r-CRISS)
• Pharmacokinetics of C-CAR168 Utilizing Flow Cytometry [Through Month 24]: Characterize T-cell expansion and persistence utilizing flow cytometry
• Pharmacokinetics of C-CAR168 measured by quantitative polymerase chain reaction (qPCR) [Through Month 24]: Characterize CAR T-cell expansion and persistence using qPCR
• Proportion of Participants Progressed [Through Month 24]: Proportion of participants that progress meeting any of the protocol defined progression criteria
• Time to First Response [Through Month 24]: Time to participant meeting first response as defined in the protocol
• Duration of Response (DOR) [Through 24 months]: Time of response from first response until progression as defined in the protocol

Sex: All, ages: 18 Years to 70 Years

Key Inclusion Criteria:

1. Able to sign and date the Informed Consent Form (ICF).
2. Female or male, aged 18-70 years (inclusive) with body weight ≥40 kg.
3. Have a clinical diagnosis of diffuse cutaneous SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification.
4. Disease duration between the onset of the first non-Raynaud's sign/symptom and ICF signing shall be ≤ 6 years.
5. SSc Disease Activity meet all following criteria:

   1. Modified Rodnan Skin Score (mRSS) ≥15.
   2. Chest High Resolution Computed Tomography (HRCT) shows SSc related ground-glass opacities.
   3. Percent predicted forced vital capacity (ppFVC)<70% or precent predicted (diffusing capacity of the lungs for carbon monoxide) ppDLco<70%.
6. Positivity for at least one SSc-specific autoantibodies:

   1. anti-Scl70 antibody.
   2. anti-RNA polymerase III antibody.
   3. anti-centromere antibody.
   4. anti-Th/To antibody.
   5. and anti-U3RNP antibody.
7. Refractory to at least two prior standard-of-care regimens, including immunosuppressives and/or a biologic note: "Refractory" is defined as receiving each listed drug for ≥6 months with either no response, disease progression after transient remission, or persistent disease progression on treatment.
8. Ability to taper steroids to protocol allowed doses

Exclusion Criteria:

1. ppFVC<45% or ppDLco <40%.
2. Severe pulmonary arterial hypertension (PAH) as measured by screening echocardiogram (ECHO), or had documented mean positive airway pressure PAP (mPAP) > 45mmHg on recent right heart catheterization (RHC).

   Note: RHC is not mandatory at screening, however participant with high-risk ECHO findings warrant close clinical vigilance, and participant with mPAP> 45mmHg at baseline shall not proceed with lymphodepletion.
3. Presence of clinically significant abnormalities on chest high-resolution computed tomography (HRCT) that are UNRELATED to SSc.
4. Cutaneous sclerosis that impedes venous access required for leukapheresis, lymphodepletion, C-CAR168 infusion, other study procedures and emergency rescue interventions.

• Yihong Yao, PhD, Study director, AbelZeta Inc.