Clinical Study of (A-319) in the Treatment of Active Rheumatoid Arthritis

Clinical Study of Recombinant Anti-CD19m-CD3 Antibody Injection (A-319) in the Treatment of Active Rheumatoid Arthritis

The primary objective of the study was to evaluate the safety and tolerability of A-319 in patients with active rheumatoid arthritis.

Active rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis as its primary clinical manifestation. A-319 is a recombinant CD19xCD3 bispecific antibody that activates T cells in vivo and targets and kills pathogenic B cells. A-319 is currently in clinical trials for B-cell hematologic malignancies. Preclinical results in animal models of systemic lupus erythematosus (SLE) and RA have also demonstrated that A-319 can alleviate or eliminate autoimmune disease-related symptoms and progression by depleting pathogenic B cells in individuals with autoimmune diseases. This investigator-initiated trial (IIT) evaluated the safety, tolerability, pharmacokinetic profile, biological markers, and preliminary efficacy of A-319 in the treatment of patients with rheumatoid arthritis (RA) who have refractory responses to at least two different therapies with different mechanisms of action.

Inclusion Criteria:

1. Age 18-70 years (inclusive), gender unrestricted.
2. Meet the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria, with a diagnosis of rheumatoid arthritis for at least 24 weeks.
3. Patients with rheumatoid arthritis who have previously responded inadequately to at least one csDMARD and who have not responded to 12 weeks of combined treatment with at least one bDMARD or/and tsDMARD with a different mechanism of action in addition to their original csDMARD, such as those with insignificant improvement in swollen/tender joints, physical condition, or disease activity.
4. Experiencing at least one of the following clinical manifestations suggestive of moderate to severe RA disease activity:

1) C-reactive protein-based 28-joint disease activity index (DAS28-CRP) >3.2 or clinical disease activity index (CDAI) >10; 2) Clinical manifestations and/or symptoms suggestive of disease activity, including acute inflammatory markers (ESR, CRP) and imaging findings, and joint-related or other symptoms. 5. At the screening and baseline visits, patients must have ≥ 6 tender joints (TJCs) per 68 units and ≥ 4 swollen joints (SJCs) per 66 units.

6. If the patient is taking oral glucocorticoids, the dose of prednisone or its equivalent must be ≤ 7.5 mg/day and maintained stable for at least 2 weeks before the first dose.

7. Patients must have voluntarily signed the informed consent form, communicated well with the investigator, and completed all visits as required by the protocol.

Exclusion Criteria:

Subjects with other autoimmune diseases that the investigator considers would not potentially benefit from A-319 treatment; or conditions that interfere with the assessment of joint swelling and pain. 2. Use of abatacept, infliximab, adalimumab, or tocilizumab within 6 weeks prior to the first treatment with the study drug; use of etanercept, anakinra, immune globulin, or blood products within 4 weeks prior to the first treatment with the study drug; or use of a JAK inhibitor (e.g., tofacitinib, baricitinib, or upadacitinib), mycophenolate mofetil, cyclosporine, or iguratimod within 2 weeks prior to the first treatment with the study drug.

3. Use of B-cell depleting therapy, such as rituximab, within 3 months prior to the first treatment with the study drug; cell counts must have returned to acceptable levels or baseline.

4. Subjects with any periprosthetic joint infection. 5. Patients with immunodeficiency (defined as immunoglobulin G ≤ 5g/L). 6. History of demyelinating diseases, including, but not limited to, multiple sclerosis, Guillain-Barré syndrome, and neuromyelitis optica (Devic's disease). 7. Laboratory values: Hemoglobin level < 9.0 g/dL, absolute white blood cell (WBC) count < 3.0 × 109/L (< 3000/mm3), or absolute neutrophil count < 1.2 × 109/L (< 1200/mm3), or absolute lymphocyte count < 0.8 × 109/L (< 800/mm3); thrombocytopenia, defined as a platelet count < 100 × 109/L (< 100,000/mm3); age-appropriate estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2, proteinuria ≥ 3+; total bilirubin (T-bili), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) exceeding 1.5 times the upper limit of normal (ULN). 8. Receipt of live or live attenuated vaccines within 30 days prior to first medication use.

9. Active hepatitis during the screening period, or positive hepatitis B virus surface antigen (HBsAg), or positive hepatitis B virus core antibody (HBcAb) plus hepatitis B virus (HBV) deoxyribonucleic acid (DNA), or positive hepatitis C virus (HCV) antibody plus HCV RNA; history of human immunodeficiency virus (HIV) infection, or positive HIV antibody during the screening period; or positive Treponema pallidum antibody during the screening period.

10. Chronic active infection or acute infection requiring systemic treatment with antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks prior to screening, or superficial skin infection requiring treatment within 1 week prior to screening (Note: Patients can be rescreened after the infection is resolved). 11. Major surgical procedure (craniotomy, thoracotomy, or laparotomy) or unhealed wounds, ulcers, or fractures within 4 weeks prior to the first dose of study drug, or plans for major surgery during the study.

12. A history of a major clinical illness (such as circulatory system disorders, endocrine system disorders, nervous system diseases, respiratory system diseases, hematologic diseases, immune system diseases, psychiatric disorders, and metabolic instability) that the investigator believes will pose a risk to the patient's safety, or that may affect safety or efficacy analysis if the disease/symptom worsens during the study. For example: Cardiovascular disease: history of acute myocardial infarction, unstable angina, or severe arrhythmias (multi-source frequent premature ventricular contractions, ventricular tachycardia, or ventricular fibrillation) within 6 months prior to screening; New York Heart Association (NYHA) class III-IV.

13. Possible active Mycobacterium tuberculosis infection, defined as: positive sputum smear/sputum culture within 3 months prior to screening/during the screening period, or chest X-ray (anteroposterior and lateral)/lung CT indicating active tuberculosis infection (tuberculosis testing will be performed according to the site's protocol if ethically required).

14. Subjects with a malignancy within 5 years prior to screening (excluding completely cured in situ cervical cancer, non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma).

15. History of major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/or bone marrow transplant).

16. Participation in any clinical trial within 4 weeks prior to the first dose of study drug or within 5 half-lives of the study drug in the clinical trial (whichever is longer, unless otherwise specified).

17. Patients undergoing acute or consolidation medication for depression and experiencing suicidal thoughts within 6 months. 18. Women who are pregnant or breastfeeding, or who plan to become pregnant or breastfeed during the study; or men whose partners plan to become pregnant during the study.

19. Any reason that the researcher deems would prevent the subject from participating in the study.