A Clinical Study of TI-0032-III Injection in Patients With Relapsed and Refractory Autoimmune Diseases

A Clinical Study on the Safety and Efficacy of in Vivo CAR-T Cell Therapy (TI-0032-III Injection) for the Treatment of Relapsed and Refractory Autoimmune Diseases

This is an open-label, dose escalation study in patients with relapsed and refractory autoimmune diseases. Study drug, TI-0032-III injection, is composed of lipid nanoparticles (LNPs) targeting T cells that encapsulate circular RNA encoding the CD19 chimeric antigen receptor (CAR), which is a therapeutic biological product. It is clinically intended for the treatment of various relapsed and refractory B cell-related autoimmune diseases, such as systemic lupus erythematosus, sjögren's syndrome, systemic sclerosis, idiopathic inflammatory myositis, and antiphospholipid syndrome.

Inclusion Criteria:

• Understand trial procedures and methods, voluntarily sign the informed consent form .

• Age ranges from 18 to 65 years old (including threshold), regardless of gender.

• Positive expression of CD19 on peripheral blood B cells determined by flow cytometry.

• Bone marrow function: neutrophil count ≥ 1.5 × 10^9/L, lymphocyte count ≥ 0.8 × 10^9/L, hemoglobin ≥ 90 g/L, platelet ≥ 100 × 10^9/L. Blood transfusion and growth factors must not be used within 14 days prior to screening to meet the above requirements.

• Coagulation function: international normalized ratio or activated partial thromboplastin time ≤ 1.5× upper limit of normal range (ULN).

• Cardiopulmonary function: left ventricular ejection fraction ≥ 50% on echocardiography; for lung function, dyspnea ≤Grade 1 of the NCI-CTCAE version 5.0 standards when breathing room air, and pulse oximetry ≥ 92%.

• Liver function: alanine aminotransferase ≤ 1.5 × ULN, aspartate aminotransferase ≤ 1.5 × ULN, total bilirubin ≤ 1.5 × ULN (total bilirubin at least ≤ 3.0 mg/dL in patients with Gilbert syndrome).

• Renal function: creatinine clearance (by Cockcroft-Gault formula) ≥ 50 mL/min.

• Criteria for SLE：

  1. Meet the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria for SLE;
  2. SLEDAI-2000 score > 6 in the moderate to severe active phase of the disease;
  3. And have at least one British Isles Lupus Assessment Group (BILAG-2004) grade A (severe manifestation) or two grade B (moderate manifestation) organ scores, or both.
  4. Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (Above 1 mg/kg/d) and cyclophosphamide, and any of the following immunomodulatory drugs for more than 6 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as rituximab, belimumab, and telitacicept.

• Criteria for Sjögren's syndrome:

  1. Meet the 2002 AECG criteria for primary Sjögren's syndrome or the 2016 ACR/EULAR classification criteria;
  2. Disease activity ESSDAI ≥ 6;
  3. Anti-SSA/Ro antibody positive;
  4. Definition of relapse/refractory: disease activity that is ineffective to conventional treatment for more than 6 months or recurs after response. Definition of conventional treatment is use of glucocorticoids and cyclophosphamide, and any of the following immunomodulatory drugs: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, and telitacicept.

• Criteria for systemic sclerosis:

  1. Meet the 2013 ACR classification criteria for systemic sclerosis and meet diffuse manifestations;

  2. Combined interstitial pneumonia: interstitial changes with ground-glass exudate detected by chest high-resolution computed tomography (HRCT);

     Needs to be met c. or d.:

  3. Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (Above 0.5 mg/kg/d) and cyclophosphamide, and any of the following immunomodulatory drugs for more than 6 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as rituximab and belimumab.

  4. Meet the definition of progression: 1) Definition of skin progression: mRSS increases b > 25%; 2) Definition of lung disease progression: FVC decreased by 10%, or FVC decreased by 5% and DLCO decreased by 15%.

• Criteria for inflammatory myopathy:

  1. The classification criteria for inflammatory myopathy comply with the 2017 EULAR/ACR (including DM, PM, ASS and NM);

  2. For patients with muscle involvement, the MMT-8 score is less than 142 and abnormalities are found in at least two of the following five core measures (PhGA, PtGA, or extramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscle enzyme level is 1.5 times upper limit of normal);

  3. Myositis antibody positive;

     Needs to be met d. or e.:

  4. Definition of relapse/refractory: Failure of conventional treatment or relapse of disease activity after response. Definition of conventional treatment: Use of glucocorticoids (greater than 1 mg/kg/d) and cyclophosphamide, and any of the following immunomodulatory drugs for more than 6 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as rituximab and belimumab.

  5. Meet the definition of progression: Interstitial pneumonia progresses rapidly over a short period of time.

• Criteria for ANCA-associated vasculitis:

  1. Meet the diagnostic criteria for ANCA-associated vasculitis in the 2022 ACR/EULAR, including microscopic polyangiitis, granulomatous polyangiitis, eosinophilic granulomatosis with polyangiitis;
  2. ANCA-related antibody positive (MPO-ANCA or PR3-ANCA positive);
  3. Birmingham Vasculitis Activity Scale (BVAS) ≥ 15 points (out of a total of 63 points), indicating activity of vasculitis;
  4. Must have at least one major item, at least three minor items, or at least two renal items, hematuria and proteinuria, in the BVAS assessment;
  5. Definition of relapse/refractory: Failure of conventional treatment or relapse of disease activity after response. Definition of conventional treatment: Use of glucocorticoids (greater than 1 mg/kg/d) and cyclophosphamide, and any of the following immunomodulatory drugs for more than 6 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biologics such as rituximab and belimumab.

Exclusion Criteria:

• Prohibited medications and treatments:

  • Any RNA-LNP products or other LNP drugs received within the past two years.
  • Received intravenous gamma immunoglobulin within 24 weeks prior to screening.
  • Received plasmapheresis therapy within 12 weeks prior to screening.
  • Subjects who have not fully recovered from surgery within 4 weeks prior to screening.
  • Epilepsy or use of psychotropic or sedative drugs during the screening period (except medications for sleeping).
  • Received any live or live attenuated vaccine within 12 weeks prior to screening, or requiring vaccination at any time during clinical trial treatment.
  • Participated in clinical trial of other drugs or medical devices within 12 weeks prior to screening (except for those whose screening failed).

• Concomitant diseases or clinical condition:

  • History of lupus nephropathy requiring hemodialysis or treatment with high-dose corticosteroids (> 100 mg/d prednisone or equivalent) within 90 days prior to baseline.
  • Epilepsy or use of psychotropic or sedative drugs during the screening period (except medications for sleeping).
  • Received any live or live attenuated vaccine within 12 weeks prior to screening, or requiring vaccination at any time during clinical trial treatment.
  • Participated in clinical trial of other drugs or medical devices within 12 weeks prior to screening (except for screen failures).
  • Have active central nervous system lupus, including meningitis aseptic, cerebral vasculitis, demyelinating syndrome, myelopathy, acute demented, psychosis, acute inflammatory demyelinating polyradiculoneuropathy, mononeuropathy (single/multiple), cranial neuropathy, plexopathy, status epilepticus or cerebellar ataxia.
  • Presence of other systemic inflammations such as, but not limited to, rheumatoid arthritis, juvenile chronic arthritis, spondyloarthritis, Crohn's disease, ulcerative colitis, or psoriatic arthritis within 12 weeks prior to screening (except for those with secondary Sjögren's syndrome, who should not be excluded).
  • Subjects who have Grade III or above congestive heart failure (NYHA grade), unstable angina or myocardial infarction, poorly controlled hypertension (hypertension is diagnosed as Grade 2 or above, risk factor stratified as high-risk, systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg when taking one or two antihypertensive drugs, cerebrovascular accidents, or arrhythmias requiring treatment within 6 months prior to screening.
  • Presence of active or uncontrolled infection requiring treatment; or have known or suspected ongoing, chronic, or recurrent infectious diseases (including but not limited to opportunistic infections such as pulmonary tuberculosis, atypical mycobacterosis, listeriosis or aspergillosis, HIV, hepatitis B or hepatitis C, etc.).
  • Subjects with suspected allergy to TI-0032-III or similar drugs or a history of severe allergy or hypersensitivity reactions.
  • History of thyrotoxicosis, including but not limited to diffuse toxic goitre, multinodular toxic goiter, thyroid autonomic high-function adenoma, and subacute thyroiditis, or thyroid color ultrasound suggests thyroid nodules TI-RADS classification as category 4 or 5.
  • Previous history of splenectomy or loss of spleen function after splenic infarction or splenic vein thrombosis leading to direct vascular injury; or major surgery within 2 months prior to screening; or have planned surgery before the end of the trial.
  • Have other serious/severe acute or chronic mental illness, including recent (within the past 1 year) or current suicidal ideation or behavior; or a history of alcohol, drug, or chemical abuse within 1 year prior to screening.
  • History of major organ transplant (e.g., heart, lung, liver, kidney) or bone marrow/hematopoietic stem cell transplantation.
  • History of malignancy, regardless of evidence of local recurrence or metastasis and regardless of treatment; or accompanied by a history of other major diseases, such as liver disease under treatment, including but not limited to acute or chronic hepatitis, liver cirrhosis or liver failure, etc.
  • HIV positive, or active hepatitis B virus test positive (HBsAg positive, HBV-DNA ≥ 200 copies/mL is required (conversion is required if HBV-DNA is in IU/mL)), or anti-HCV antibody positive and HCV-RNA positive.
  • Women who plan to become pregnant or are pregnant or breastfeeding; or blood pregnancy test positive during screening; or unable to take effective contraceptive measures within 12 months after the last infusion of investigational drug; or planned sperm/egg donation within 12 months after the last dose of the investigational drug.
  • Other clinically significant abnormal laboratory tests or imaging tests judged by the investigator or considered unsuitable for clinical the trial for other reasons.