Belimumab: China's First Approved Biologic for Systemic Lupus Erythematosus Marks a Therapeutic Milestone

Author: Johnson

Recently, Belimumab, the first biologic agent developed by GSK for the treatment of systemic lupus erythematosus (SLE), has finally been approved in China. This provides domestic SLE patients with an important additional therapeutic option, marking the introduction of monoclonal antibody therapy into the treatment landscape. Prior to this approval, the standard of care for SLE patients in China relied primarily on “conventional corticosteroids” combined with “older immunosuppressive agents.” Therefore, the approval of Belimumab holds significant importance for the management of SLE in China.

Part 1 Introduction to Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a typical autoimmune disease with diverse clinical manifestations, ranging from classic organ involvement (joints, skin, and kidneys) to rare limb deformities (such as constrictive lung syndrome). It predominantly affects women of childbearing age. The global prevalence of SLE is approximately 1–5 per 100,000 individuals, with a male-to-female ratio of 1:9.

Currently, the survival rate of patients with systemic lupus erythematosus (SLE) has improved. However, its pathogenesis remains unclear and involves multiple factors, including genetics, epigenetics, environment, and hormones. In SLE patients, T lymphocytes are abnormally activated, while B lymphocytes produce various autoantibodies, leading to multi-system and multi-organ damage involving the skin, heart, joints, serous membranes, kidneys, nervous system, and lungs, resulting in diverse clinical manifestations.

Figure 1: Body Systems Commonly Affected by SLE

Part 2 SLE Diagnostic Criteria & Immunological Criteria

Diagnostic Criteria for SLE

Currently, the diagnostic criteria for systemic lupus erythematosus (SLE) in China consist of 11 items, namely malar rash, photosensitivity, discoid rash, oral ulcers, serositis, renal disorder, arthritis, neurological disorder, immunological disorder, hematological disorder, and antinuclear antibody abnormality.

In China, the clinical diagnosis and treatment of systemic lupus erythematosus (SLE) patients using this classification standard demonstrate high specificity and sensitivity, reaching approximately 96%. However, it should be noted that this standard does not yield optimal diagnostic efficacy in the early stages of disease onset. Consequently, the American College of Rheumatology (ACR) revised the SLE classification criteria at its 2009 meeting. The revised criteria categorize manifestations into acute or subacute cutaneous lupus, oral or nasopharyngeal ulcers, chronic cutaneous lupus, inflammatory synovitis, non-scarring alopecia, renal involvement, serositis, leukopenia, and hemolytic anemia. This approach facilitates better observation and analysis of symptoms during the early phase of the disease, thereby improving diagnostic accuracy for SLE patients.

Immunological Criteria for SLE

Immunological Diagnostic Criteria for SLEThe immunological diagnostic criteria for systemic lupus erythematosus (SLE) consist of the following six items:1) Anti-double-stranded DNA (anti-dsDNA) antibody titers meet or exceed the laboratory reference standard;2) Anti-Smith (anti-Sm) antibodies are positive;3) Antinuclear antibody (ANA) titers exceed the laboratory reference standard;4) Complement levels are decreased;5) Lupus anticoagulant is positive, serological tests for syphilis yield false-positive results, or anticardiolipin antibody levels are at least twice the upper limit of normal;6) Regarding definitive diagnosis: if a patient is diagnosed with lupus nephritis based on renal pathology and tests positive for either anti-dsDNA antibodies or ANA, a definitive diagnosis of SLE can be established.

Furthermore, if a patient meets four of the diagnostic criteria, they can also be diagnosed with SLE. The sensitivity and specificity of the immunological diagnostic criteria are both high, exceeding 90%, which provides good diagnostic performance in clinical practice.

Part 3 Hormonal Medications for SLE

For patients with systemic lupus erythematosus (SLE), glucocorticoids are among the first-line therapeutic agents and can achieve favorable treatment outcomes. However, glucocorticoid therapy should be individualized as much as possible, typically administered as a single oral dose in the morning. In cases involving major organ involvement, the dosage may be increased. Given that glucocorticoids can cause numerous adverse reactions, it is essential to closely monitor changes in clinical symptoms during actual treatment. If adverse reactions occur, the medication should be discontinued immediately, and targeted management of these adverse effects should be implemented to prevent their worsening.

Part 4 Immunosuppressants for SLE

Immunosuppressants are currently the most commonly prescribed class of medications for patients with systemic lupus erythematosus (SLE). They effectively control disease activity, reduce SLE flares, and allow for lower dosages of corticosteroids. Commonly used immunosuppressants include azathioprine, mycophenolate mofetil, hydroxychloroquine, cyclosporine, total glucosides of Tripterygium wilfordii, and cyclophosphamide. Previous studies have demonstrated that these agents provide favorable therapeutic outcomes in SLE patients. However, they may be less effective in patients with refractory symptoms, and their adverse effects warrant careful monitoring.

Appendix 1: Globally Marketed Drugs for Lupus-Related Diseases

Part 5 Belimumab Monoclonal Antibody Recently Approved for Market Launch in ChinaP

Belimumab is the first biologic agent approved by the U.S. FDA (in 2011) for the treatment of systemic lupus erythematosus (SLE), and remains the only one to date, indicated for adult patients with autoantibody-positive SLE. As a fully human monoclonal antibody targeting BAFF, belimumab binds to soluble BAFF, thereby reducing the number of activated B cells and plasma cells.

Figure 2: Pathogenesis and Therapeutic Targets of SLE

Both Phase III clinical trials of belimumab (BLISS-52 and BLISS-76) met their primary endpoints, as evaluated by the Systemic Lupus Erythematosus Responder Index-5 (SRI-5). The BLISS-52 trial demonstrated that the SRI-5 response rates for the two belimumab dosage groups (1 mg/L and 10 mg/L) were 51% and 58%, respectively, both significantly higher than that of the placebo group (44%). Belimumab can alleviate symptoms and improve prognosis in patients with systemic lupus erythematosus (SLE), reduce anti-double-stranded DNA (anti-dsDNA) antibody levels, and increase complement levels. Similar results were observed in the BLISS-76 trial. Furthermore, patients with high disease activity, elevated anti-dsDNA antibody levels, or low complement levels exhibited greater sensitivity to belimumab. Long-term follow-up of SLE patients receiving belimumab in combination with standard therapy revealed that the incidence of adverse events, such as infections, allergic reactions, and malignancies, remained stable or decreased over a treatment period of up to seven years, indicating a favorable safety profile for long-term use of belimumab.

Appendix Table 2: Selected Clinical Trials of Belimumab Conducted in China in Recent Years

Part 6 Drug Development for SLE by Domestic Companies

A search reveals that there are no more than 10 drug candidates for systemic lupus erythematosus (SLE) under development in China with clearly documented information. The highest clinical development stage reached is Phase II, achieved by RCT-18 (targeting BAFF/BLyS) from Rongchang Pharmaceutical and AC-0058TA (targeting BTK) from Eisun Biopharma. All other candidates have advanced only to Phase I clinical trials for SLE. Relevant details are provided in the table below.

Appendix 3: Development Status of SLE Drugs in China

Reference:

1. https://ghr.nlm.nih.gov/condition/systemic-lupus-erythematosus

2. Pharmacodia/CNKI Database

3. Progress in the Treatment of Systemic Lupus Erythematosus with Biologics. Advances in Pharmaceutical Sciences. 2018

4. Advances in Diagnostic Criteria and Treatment of Systemic Lupus Erythematosus. Journal of Clinical Medical Literature. 2017

5. Advancesin the treatment of systemic lupus erythematosus: From back to the future, tothe future and beyond. Doi.org/10.1016/j.jbspin.2018.09.004.

6. SystemicLupus Erythematosus. Doi.org/10.1016/B978-0-12-801238-3.65663-5.

7. Advancesin systemic lupus erythematosus. Doi.org/10.1016/j.mpmed.2017.11.010.

Original Title: From the Domestic Approval of the First Biologic for Lupus, to Understanding SLE and Its Drug Development!