Abstract
Introduction
This study assessed pharmacokinetics and safety of subcutaneous (SC) belimumab in Chinese paediatric patients with systemic lupus erythematosus (cSLE) who previously received intravenous (IV) belimumab; only the IV form is approved for cSLE in China.
Methods
This single-arm, open-label, 12-week bridging study (GSK Study 217091) characterised belimumab 200 mg SC exposure in Chinese paediatric patients (5–17 years) with cSLE who completed the 48-week IV belimumab Phase 4 trial (GSK Study 213560). Safety and tolerability of SC belimumab on-treatment and in a 16-week follow-up period were also assessed. Patients were categorised based on weight; data were summarised using descriptive statistics.
Results
Overall, 16 patients were enrolled (≥ 15– < 30 kg, n = 1; ≥ 30– < 50 kg, n = 5; ≥ 50 kg, n = 10) with a mean age of 12.9 years. The geometric mean approximate Cmax (3 days post-administration) after the first and last dose were 92.44, 63.41 and 68.87 μg/mL, and 28.01, 85.11 and 88.61 μg/mL for the three weight groups, respectively. The geometric mean Ctrough at steady state were, 20.44, 71.57 and 85.55 μg/mL for the ≥ 15– < 30 kg, ≥ 30– < 50 kg and ≥ 50 kg weight groups, respectively. Thirteen patients (81%) reported ≥ 1 AE. No SAEs, severe AEs, AESIs, AEs resulting in belimumab discontinuation, deaths, or local injection site reactions were reported.
Conclusion
SC belimumab demonstrated expected steady-state exposure and tolerability in Chinese paediatric patients with SLE, supporting its use in this patient population.
Trial Registration
GSK Study 217091; NCT05917288.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40744-026-00878-7.
Keywords: Belimumab, Biological products, Lupus erythematosus, Subcutaneous injections, Systemic, Paediatrics, Pharmacokinetics
Plain Language Summary
Belimumab is a treatment for lupus, a disease where the immune system attacks healthy parts of the body. Doctors can give belimumab either as an infusion into a vein or as an injection under the skin. Most patients are happy getting belimumab as an infusion, but self-injection at home with an easy-to-use injection device may be more convenient and provide greater freedom. It also means patients wouldn’t need to go to the hospital for infusion treatments, which can help them stick to their treatment plan better. In China, only the infusion form is approved for children. To understand the safety and effect of the injection version of belimumab in China, this study looked at how the body tolerates belimumab when given as an injection under the skin in Chinese children with lupus who had already been treated with belimumab through infusion. Overall, 16 children between 5 and 17 years of age took part, after finishing almost 1 year of treatment with infusions. Each child got injections for 12 weeks; their weight determined how often they received injections: every week, every 10 days or every 2 weeks. After 10–12 weeks of injections, the amount of medicine in their blood became steady. Most children had at least one mild side effect, but none had serious problems or bad reactions at the injection site. Overall, this study found that giving belimumab as an injection under the skin has few side effects and works as expected in Chinese children with lupus.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40744-026-00878-7.
Key Summary Points
| Why carry out this study? |
| Childhood-onset systemic lupus erythematosus (cSLE) is associated with higher disease activity than adult-onset SLE, with a higher incidence in Asian populations compared with white populations |
| Intravenous (IV) belimumab is approved in China for paediatric patients (≥ 5 years) and is generally well accepted; however subcutaneous (SC) self-administration, which may improve convenience and adherence, has not yet been approved for patients with cSLE in China |
| Following a multinational Phase 2 study (GSK Study 200908; NCT04179032), this bridging study evaluated the pharmacokinetics and safety of SC belimumab in Chinese paediatric patients with cSLE previously treated with IV belimumab |
| What was learned from the study? |
| SC belimumab demonstrated expected steady-state exposure and tolerability in Chinese paediatric patients with SLE, supporting its use in this patient population |
| This is the first study to demonstrate the actual pharmacokinetics and safety of different belimumab formulations in the same paediatric population in China, indicating that SC belimumab may offer a convenient alternative treatment option to IV belimumab for paediatric patients with cSLE, which may improve treatment flexibility and adherence |
Introduction
Systemic lupus erythematosus (SLE) is a lifelong disease characterised by flares, organ damage accrual and increased risk of mortality [1, 2]. Approximately 15–20% of patients with SLE develop the disease before 18 years of age [3, 4], with prevalence and incidence rates reported to be higher in Asian populations compared with white populations [5]. In China, the incidence rate of childhood-onset SLE (cSLE) is reported to be 3.97% per 100,000 persons per year [6].
Patients with cSLE experience higher disease activity, greater risk of kidney, neurological and haematological involvement, and faster accumulation of organ damage compared with adults with SLE, even though the aetiology, pathogenesis and laboratory findings are similar [4, 7–10].
The treatment approach for children with SLE is similar to adults, with glucocorticoids and anti-malarial agents being the main standard of treatment for SLE, with conventional immunosuppressants and/or biologics recommended for patients with uncontrolled disease on glucocorticoids and antimalarials [8, 11, 12].
Belimumab, a B-cell modulator, targets the central immunopathogenic pathway in SLE by selectively inhibiting B lymphocyte stimulator (BLyS) and reducing the autoreactive B cells that drive disease activity [13, 14]. The efficacy and safety of belimumab have been demonstrated in several Phase 2 and 3 clinical trials in patients with active SLE [15–19], and it is available in both intravenous (IV) and subcutaneous (SC) formulations [9, 19–22].
The IV formulation of belimumab was approved by the China National Medical Products Administration as add-on therapy for adults with active SLE in 2019 and for paediatric patients (≥ 5 years of age) in 2020 [9, 23]. Approval for paediatric patients in China was based on data from studies conducted on Western paediatric patients, and global studies in adult patients, including those from North East Asia [15, 16, 19]. Additionally, the IV formulation has been investigated in Chinese paediatric patients with cSLE in a Phase 4 clinical trial of IV belimumab (GSK study 213560; NCT04908865 [‘precursor IV study’ hereafter]), which confirmed the efficacy and safety profile in this patient population [24].
While the majority of patients express satisfaction with IV belimumab [25], at-home self-administered SC belimumab using a pre-filled autoinjector device offers convenience, flexibility and independence, reduces the burden of IV infusions, may improve treatment adherence, and is the preferred administration route among patients with SLE [26]. However, the SC formulation of belimumab has not yet been approved for patients with cSLE in China.
Data on the pharmacokinetics (PK), pharmacodynamics and safety of SC belimumab in patients with cSLE are limited, and were recently investigated in a multinational Phase 2 study (GSK Study 200908; NCT04179032 [‘PLUTO SC’ hereafter]) [27]. To support the registration of the SC formulation in China, a bridging study has been conducted to assess the PK and safety of SC belimumab in Chinese paediatric patients with cSLE who had completed the precursor IV study, the results of which are reported here.
Methods
Study Design
This was a single-arm, open-label study (GSK Study 217091; NCT05917288) assessing the PK and safety of SC belimumab in Chinese paediatric patients with SLE who had previously completed the precursor IV study (48 weeks of IV belimumab treatment). This study was conducted at six centres in China between June 2023 and October 2024. Eligible patients received belimumab 200 mg SC for 12 weeks, with the first dose no more than 4 weeks after their last IV dose (administered at Week 48 of the precursor IV study). In line with the global paediatric PLUTO SC study [27], dosing schedules were determined by patient weight: every 2 weeks (≥ 15– < 30 kg); every 10 days (≥ 30– < 50 kg); and weekly (≥ 50 kg). The screening period (1–35 days prior to first SC belimumab dose) overlapped with the end of the precursor IV study. Post-treatment follow-up assessments were conducted at 8 and 16 weeks after the last dose of SC belimumab (Fig. 1).
Fig. 1.
Study design. aPatients rolled over from precursor IV study, thus the screening period of this study had an overlap with the precursor IV study. PK pharmacokinetics, SC subcutaneous
Patients
Eligible patients met the following criteria: 5–17 years of age with a body weight ≥ 15 kg at the time of informed consent; previously enrolled in the precursor IV study, and completed 48 weeks of IV belimumab treatment, with IV PK samples available (defined as the PK population); and were expected to benefit from continuing treatment with belimumab according to the investigator’s judgement. Female patients were eligible if they were not pregnant or breastfeeding or were using an effective contraceptive method if they were of childbearing potential.
Exclusion criteria included patients with clinical evidence of significant, unstable, or uncontrolled, acute or chronic disease not caused by SLE; development of other diseases, laboratory abnormalities or conditions that, based on the opinion of the principal investigator, made the patient unsuitable for the study; development of a positive test for HIV, hepatitis B or C after enrolment into the precursor IV study; and/or receipt of a live or live-attenuated vaccine within 30 days of Day 1 and during belimumab use. Patients who experienced an adverse event (AE) during the precursor IV study that placed the patient at undue risk, in the opinion of the principal investigator, were also excluded from the study. Inclusion and exclusion criteria for the precursor IV study have been published previously [24].
Objectives
The primary objective was to characterise SC belimumab exposure following 12 weeks of treatment. The measured exposure parameters included area under the curve at steady-state to the end of the dosing period (AUCss,0–t), average serum concentration at steady state (Cavg,ss), minimum serum concentrations at steady state (Cmin,ss), maximum serum concentrations during the dosing interval at steady state (Cmax,ss), and Cmax and trough serum concentration (Ctrough) at first dose (Week 0–2) and steady state (Week 10–12) of SC belimumab. Subgroup analyses by body weight groups (≥ 15– < 30 kg, ≥ 30– < 50 kg and ≥ 50 kg) were also conducted.
The secondary objective was to evaluate the safety and tolerability of SC belimumab treatment. The incidence of AEs, serious AEs (SAEs) and AEs of special interests (AESIs), categorised by system organ class (SOC) and preferred terms (PT), was assessed through the 12-week treatment and 16-week post-treatment periods. Additionally, clinical laboratory tests of haematology, chemistry, immunoglobulins, and urinalysis were conducted throughout the 12-week treatment period. A toxicity scale was consulted to assign a grade (Grade 1: mild, Grade 2: moderate, Grade 3: severe, and Grade 4: potentially life-threatening) for any laboratory test abnormalities (Table S1).
Statistical Analysis
For the primary endpoint, data were summarised using descriptive statistics, including mean and standard deviation (SD) for untransformed data, 95% confidence intervals (CI), median, 25th and 75th percentiles and geometric means. Belimumab exposure parameters for each weight group were summarised.
For the secondary endpoints, AEs, SAEs and AESIs were summarised using frequencies and percentages.
PK data collected for patients after treatment discontinuation were used in the analysis, with the exception of PK values recorded at the early withdrawal visit. To maximise the PK data to support the estimation of exposure parameters, data from the early withdrawal visit were included. If patients used prohibited medications, only the PK data before initiation of the prohibited medication were used.
The targeted sample size was 17 patients. If not enough patients from the precursor IV study had IV PK samples collected, additional patient(s) from the non-PK population in the precursor IV study (those who did not have PK samples collected; defined as the non-PK population) were also included to reach the required number.
Ethics
This study was approved by all relevant institutional review boards (IRBs) or ethics committees, and was conducted in accordance with the Declaration of Helsinki 2008 and its later amendments, Council for International Organisation of Medical Sciences (CIOM) International Ethical Guidelines, applicable International Organisation for Standardisation 14155 medical device guidelines, the European Medical Device Regulation 2017/745 for clinical device research and other applicable laws and regulations. The master ethics committee was the Medical Ethics Committee of Beijing Children’s Hospital, and all participating IRBs or ethics committees are listed in Table S2. Patients and their legal representatives were informed that study participation was voluntary. Prior to study enrolment, investigative sites obtained signed informed consent from patients that met the requirements of 21 Code of Federal Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, and the IRB/Independent Ethic Committee (IEC) or study centre.
Results
Patient Population
In total, 16 patients with cSLE were enrolled, of whom 15 were from the PK population, and one was from the non-PK population of the precursor IV study. Overall, 11 (69%) patients were female, mean (SD) age of patients was 12.9 years (2.6), and most patients were in the 12–17 years age group (n = 12, 75%) (Table 1). The median weight (range) of patients was 56.25 kg (25.0–77.5 kg). The total number of patients within each body weight group were 1, 5 and 10 in the ≥ 15– < 30 kg, ≥ 30– < 50 kg and ≥ 50 kg groups, respectively. Patient baseline demographics and clinical characteristics by body weight are available in Table S3.
Table 1.
General demographics and characteristics at baseline
| Belimumab 200 mg SC (N = 16) |
|
|---|---|
| Age (years), mean (SD) | 12.9 (2.6) |
| Age group (years), n (%) | |
| 5–11 | 4 (25) |
| 12–17 | 12 (75) |
| Sex, n (%) | |
| Male | 5 (31) |
| Female | 11 (69) |
| Ethnicity, n (%) | |
| Not Hispanic or Latino | 16 (100) |
| Race, n (%) | |
| Asian-East Asian Heritage | 16 (100) |
| Height (cm), median (IQR) | 160.00 (147.00, 166.50) |
| Weight (kg), median (IQR) | 56.25 (48.20, 64.75) |
| Body weight group, n (%) | |
| ≥ 15 kg– < 30 kg | 1 (6) |
| ≥ 30 kg– < 50 kg | 5 (31) |
| ≥ 50 kg | 10 (63) |
| Previous medical history, n (%) | |
| Cardiovascular risk factors | |
| Hypertension | 3 (19) |
| Serious infection | |
| Herpes virus infection | 1 (6) |
| Respiratory tract infection | 3 (19) |
| Allergic reactions drug | |
| Allergy | 1 (6) |
| Other (general) | 16 (100) |
| Concomitant medications, n (%) | |
| Immunosuppressants | 16 (100) |
| Mycophenolate mofetil | 14 (88) |
| Ciclosporin | 1 (6) |
| Methotrexate | 1 (6) |
| Tacrolimus | 1 (6) |
| Steroids | 16 (100) |
| Prednisone acetate | 14 (88) |
| Prednisolone | 1 (6) |
| Prednisone | 1 (6) |
| Antimalarials | 14 (88) |
| Hydroxychloroquine sulfate | 12 (75) |
| Hydroxychloroquine | 2 (13) |
| NSAIDS | 2 (13) |
| Aspirin | 1 (6) |
IQR interquartile range, NSAID nonsteroidal anti-inflammatory drug, SC subcutaneous, SD standard deviation
All patients had ≥ 1 prior medical history condition reported and had ≥ 1 allowable SLE medication usage at baseline. All patients were receiving immunosuppressants and steroids, 14 (88%) patients were receiving antimalarials, and two (13%) and one (6%) patient were receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, respectively.
Treatment Exposure and Compliance
The median duration of exposure to treatment was 84.0 days (range 79.0–89.0 days) and mean (SD) percentage compliance was 99.0% (2.85) (Table S4). The single patient in the ≥ 15– < 30 kg weight group received six injections of belimumab SC as per schedule over 85 days, and had a compliance rate of 100.0%. The patients in the ≥ 30– < 50 kg weight group received eight injections of belimumab SC as per schedule over a median of 80.0 days, with a mean (SD) compliance rate of 100.0% (0.0). Of the patients in the ≥ 50 kg weight group, eight patients received 12 injections as per schedule, and two patients received 11 injections with a mean (SD) compliance rate of 98.3% (3.51). Dose modifications were not reported during the study.
Pharmacokinetics
The geometric mean concentrations before the first dose were 38.47, 45.00 and 54.90 μg/mL for the ≥ 15– < 30 kg, ≥ 30– < 50 kg and ≥ 50 kg weight groups, respectively (Table 2). Cmax was observed approximately 3 days post-administration, as an estimated time that would reflect a maximum concentration in most patients. The geometric mean approximate Cmax after the first dose were 92.44, 63.41 and 68.87 μg/mL for the ≥ 15– < 30 kg, ≥ 30– < 50 kg and ≥ 50 kg weight groups, respectively, and geometric mean Ctrough after the first dose were 63.47, 54.55 and 61.71 μg/mL.
Table 2.
Summary of observed belimumab concentrations (µg/mL) at each timepoint by body weight groups
| Belimumab 200 mg SC | ||||
|---|---|---|---|---|
| ≥ 15 kg to < 30 kg (N = 1) |
≥ 30 kg to < 50 kg (N = 5) |
≥ 50 kg (N = 10) |
Total (N = 16) |
|
| First dose | ||||
| Pre-dose | ||||
| Geometric mean (GeoCV%) | 38.47 (NA) | 45.00 (43.19) | 54.90 (52.42) | 50.46 (47.74) |
| 95% CI of geometric mean | (NA, NA) | (26.93, 75.21) | (38.59, 78.10) | (39.64, 64.24) |
| Median (Min, Max) |
45.99 (22.92, 69.16) |
59.90 (18.88, 100.87) |
51.09 (18.88, 100.87) |
|
| Cmax after the first dose | ||||
| Geometric mean (GeoCV%) | 92.44 (NA) | 63.41 (31.66) | 68.87 (36.79) | 68.36 (34.04) |
| 95% CI of geometric mean | (NA, NA) | (43.20, 93.07) | (53.37, 88.86) | (57.30, 81.55) |
| Median (min, max) |
73.32 (38.71, 83.21) |
75.44 (38.44, 109.16) |
74.65 (38.44, 109.16) |
|
| Ctrough after the first dose | ||||
| Geometric mean (GeoCV%) | 63.47 (NA) | 54.55 (29.07) | 61.71 (38.47) | 59.48 (33.79) |
| 95% CI of geometric mean | (NA, NA) | (38.30, 77.69) | (47.31, 80.50) | (49.92, 70.87) |
| Median (min, max) |
54.87 (34.89, 76.55) |
67.27 (31.88, 100.52) |
61.67 (31.88, 100.52) |
|
| Steady state | ||||
| Pre-dose | ||||
| Geometric mean (GeoCV%) | 22.75 (NA) | 76.37 (19.18) | 83.94 (27.53) | 75.11 (41.22) |
| 95% CI of geometric mean | (NA, NA) | (60.32, 96.70) | (69.18, 101.85) | (60.82, 92.76) |
| Median (min, max) |
80.38 (54.94, 88.64) |
87.69 (49.52, 118.44) |
85.14 (22.75, 118.44) |
|
| Cmax at steady state | ||||
| Geometric mean (GeoCV%) | 28.01 (NA) | 85.11 (28.71) | 88.61 (27.68) | 81.42 (39.76) |
| 95% CI of geometric mean | (NA, NA) | (60.01, 120.70) | (72.96, 107.62) | (66.39, 99.86) |
| Median (min, max) |
92.11 (52.22, 107.83) |
92.70 (52.39, 121.20) |
91.42 (28.01, 121.20) |
|
| Ctrough at steady state | ||||
| Geometric mean (GeoCV%) | 20.44 (NA) | 71.57 (36.72) | 85.55 (33.52) | 73.99 (49.91) |
| 95% CI of geometric mean | (NA, NA) | (46.02, 111.31) | (67.74, 108.04) | (57.55, 95.12) |
| Median (min, max) |
82.12 (37.98, 87.75) |
85.20 (53.35, 154.23) |
83.53 (20.44, 154.23) |
|
CI confidence interval, Cmax maximum concentration, Ctrough trough serum concentration, NA not applicable, SC subcutaneous
PK exposure approached steady state after 10 to 12 weeks of treatment. At steady state, the geometric mean pre-dose concentrations were 76.37 and 83.94 μg/mL for the ≥ 30– < 50 kg and ≥ 50 kg weight groups, respectively. The geometric mean approximate Cmax were 85.11 and 88.61 μg/mL, and the geometric mean Ctrough were 71.57 and 85.55 μg/mL for the ≥ 30– < 50 kg and ≥ 50 kg weight groups, respectively. For the single patient within the ≥ 15– < 30 kg weight group, geometric mean pre-dose concentration was 22.75 μg/mL, the geometric mean approximate Cmax was 28.01 μg/mL, and the geometric mean Ctrough was 20.44 µg/mL (Table 2).
Safety
During the 12-week treatment period, 13 patients (81%) reported ≥ 1 AEs and nine patients (56%) reported ≥ 1 AE related to belimumab (Table 3). No SAEs, severe AEs, AESIs, AEs resulting in belimumab discontinuation, or deaths were reported during the 12-week treatment period and the 16-week post-treatment follow-up period.
Table 3.
Summary of AEsa during the 12-week on-treatment period and 16-week follow-up
| Events (n) | Patients, n (%) N = 16 |
|
|---|---|---|
| 12-week on-treatment, n (%) | ||
| At least 1 AE | 32 | 13 (81) |
| At least 1 related AE | 18 | 9 (56) |
| At least 1 SAE | 0 | 0 |
| At least 1 severe AE | 0 | 0 |
| At least 1 SAE and/or severe AE | 0 | 0 |
| At least 1 AE resulting in study intervention discontinuation | 0 | 0 |
| Death | 0 | 0 |
| 12-week on-treatment and 16-week follow-up, n (%) | ||
| At least 1 AE | 40 | 13 (81) |
| At least 1 related AE | 19 | 9 (56) |
| At least 1 SAE | 0 | 0 |
| At least 1 severe AE | 0 | 0 |
| At least 1 SAE and/or severe AE | 0 | 0 |
| At least 1 AE resulting in study intervention discontinuation | 0 | 0 |
| Death | 0 | 0 |
AE adverse event, SAE serious adverse event
aPatients were counted once in each row for which they had any AE that met the criterion
Common AEs (≥ 2 patients) by SOC were infections and infestations (n = 11, 69%), gastrointestinal disorders (n = 2, 13%), hepatobiliary disorders (n = 2, 13%) and respiratory, thoracic and mediastinal disorders (n = 2, 13%) (Table 4). AEs by PT occurring in at least two patients were upper respiratory tract infection (n = 9, 56%), bronchitis (n = 3, 19%) and abnormal hepatic function (n = 2, 13%) (Table 4). No local injection site reactions were reported as an AE.
Table 4.
All adverse events by SOC and PTa in 12-week on-treatment period and 16-week post-treatment follow-up
| System organ class | Events (n) | Patients, n (%) |
|---|---|---|
| Preferred term | (N = 16) | |
| Any event, number of events, n (%) | 40 | 13 (81) |
| Infections and infestations | ||
| Any event | 26 | 11 (69) |
| Upper respiratory tract infection | 17 | 9 (56) |
| Bronchitis | 3 | 3 (19) |
| Bacterial infection | 1 | 1 (6) |
| Conjunctivitis | 1 | 1 (6) |
| Mycoplasma infection | 1 | 1 (6) |
| Tinea versicolour | 1 | 1 (6) |
| Tonsillitis | 1 | 1 (6) |
| Viral infection | 1 | 1 (6) |
| Gastrointestinal disorders | ||
| Any event | 3 | 3 (19) |
| Diarrhoea | 1 | 1 (6) |
| Lip swelling | 1 | 1 (6) |
| Noninfective gingivitis | 1 | 1 (6) |
| Hepatobiliary disorders | ||
| Any event | 3 | 2 (13) |
| Hepatic function abnormal | 3 | 2 (13) |
| Respiratory, thoracic and mediastinal disorders | ||
| Any event | 2 | 2 (13) |
| Cough | 1 | 1 (6) |
| Rhinitis allergic | 1 | 1 (6) |
| Skin and subcutaneous tissue disorders | ||
| Any event | 2 | 2 (13) |
| Acne | 1 | 1 (6) |
| Rash | 1 | 1 (6) |
| Investigations | ||
| Any event | 2 | 1 (6) |
| White blood cell count decreased | 2 | 1 (6) |
| Metabolism and nutrition disorders | ||
| Any event | 1 | 1 (6) |
| Weight fluctuation | 1 | 1 (6) |
| Musculoskeletal and connective tissue disorders | ||
| Any event | 1 | 1 (6) |
| Growth retardation | 1 | 1 (6) |
PT preferred term, SOC system organ class
aPatients only counted once per SOC and per PT
Clinical Laboratory Tests
Overall, there were no Grade 3 or 4 post-baseline values for any haematological parameters. One patient experienced a 2-grade shift in lymphocyte count from Grade 0 at baseline to 2. There were no Grade 2, 3 or 4 post-baseline values in clinical chemistry parameters assessed, nor any shifts of ≥ 2 grades.
One patient had a Grade 3 post-baseline value for immunoglobulin G (IgG) levels, with this patient reporting low IgG values at screening (Grade 2) and at baseline (Day 1, Grade 3). They reported no further worsening from screening after dosing nor any AEs related to immunoglobulins. One patient had a Grade 1 post-baseline value, and reported low IgG values at screening (Grade 2) with no further worsening post-baseline after dosing, and no AEs related to the study intervention reported. No patients experienced immunoglobulin A or immunoglobulin M post-baseline decrease from normal or high to below the lower limit of normal.
Maximum grade increases post-baseline for liver function tests were either Grade 1 (five cases) or Grade 2 (three cases). Two patients reported Grade 2 liver toxicity—an elevation of alanine aminotransferase and gamma glutamyl transferase in one patient and an elevation of bilirubin in the other patient. Urinalysis results demonstrated maximum grade increase post-baseline of either Grade 1 or Grade 2. No patients experience a ≥ 2 grade shift for any urinalysis parameter.
Discussion
This single-arm, open-label study demonstrated expected PK parameters with no new safety signals identified in paediatric patients with SLE in China, suggesting that SC belimumab is an appropriate treatment option in this patient population.
We characterised SC belimumab exposure following 12 weeks of treatment in patients who had previously completed the precursor IV study to directly observe PK activity. As expected, based on PK characteristics studied in previous trials, PK exposure approached steady state after 10 to 12 weeks of treatment [27, 28]. The slightly higher concentration observed in the higher body weight groups (≥ 30–50 kg and ≥ 50 kg) before the first dose reflects the higher weight-based IV dose amount before SC treatment and the allometric effect on PK. At steady state, the concentration of SC belimumab in these two weight groups were generally comparable, indicating patients reached similar PK steady state after repeated SC doses. Therefore, these results indicate that the chosen weight-based dosing schedules may be appropriate for this patient population.
For the single patient in the ≥ 15– < 30 kg weight group, the concentrations observed after the last dose did not match well with the other weight groups. Interpretation of the data are limited due to the difficulties in recruiting for this subgroup and this highlights the need for a more comprehensive analysis of the dosing regimen in this subgroup of patients through further studies. Since the concentrations after the first dose in the single patient were in line with expected values, the unexpectedly lower concentration after the last dose is not likely to be attributed to inter-patient variability. The timing of sample collection relative to dosing could influence observed Cmax values. In the ≥ 15– < 30 kg group, which consisted of only a single patient, variability in sampling times may have contributed to the unexpected pattern seen. Therefore, caution is warranted when interpreting these results, as both sampling timing and small sample size may have affected the observed Cmax values, in addition to variability arising from sample handling, bioanalysis, or investigational product. There were no issues with administration, storage of belimumab, or sample processing that could explain the observed lower concentration.
Belimumab’s efficacy in patients with SLE has been demonstrated in Chinese adults through the North East Asia study (GSK study BEL113750; NCT01345253) [19], showing comparable results to overseas studies [15, 16, 29]. The PK, efficacy and safety of IV belimumab in patients with cSLE have also been demonstrated in the PLUTO IV study [27, 30], and, for a Chinese paediatric population, in the precursor IV study, which demonstrated achievement of SELENA-SLEDAI response and decrease from baseline in daily GC dose in two-thirds of patients or more, and three-quarters of patients seeing an improvement in Physician Global Assessment (PGA) scores; a trend for decreasing Parent Global Assessment (ParentGA) was also observed over time [24, 27]. Additionally, the PLUTO SC study has demonstrated that the SC formulation of belimumab had consistent exposure in paediatric patients compared with adult patients with SC from the BLISS-SC trial (GSK study 112,341; NCT01484496) [17, 27]. Furthermore, SC belimumab has been shown to demonstrate concentration–time profiles in healthy Chinese volunteers similar to those of previous studies in the USA and Japan, further supporting the use of a SC formulation in Chinese patients with SLE [27, 31].
The observed PK exposure reported in the current analysis is lower than that observed in the PLUTO SC study and the BLISS-SC adult trial [17, 27], and the population PK model analysis also demonstrated lower systemic exposure in the Chinese paediatric population compared with non-Chinese paediatric studies. Of note, the lower treatment duration may not explain the lower exposure since steady state had been reached. Despite this lower exposure, an exposure–response analysis indicated that belimumab still reached the plateau phase and that a similar predicted rate of SLE responder index (SRI) response compared with white patients would be achieved [32]. As such, the lower exposure seen in Chinese patients is not expected to affect efficacy, and it can be reasonably inferred that the SC dose will achieve similar efficacy to that seen in the precursor IV study [24]. The safety findings in this study are in line with those previously reported in the PLUTO SC and precursor IV studies, suggesting that no new safety signals were seen in the Chinese population receiving SC belimumab [24, 27]. Additionally, no injection site reactions were reported during the 12-week treatment period, nor were any SAEs, severe AEs, AEs resulting in study treatment discontinuation, death or AESI reported over the entire study period. However, it should be noted that the relatively short length of the study and the small population size limit the interpretation of these findings and may not be sufficient to identify rare AEs.
This study leverages the precursor IV study by enabling patients who have completed 48 weeks of IV treatment to transition to SC treatment. This innovative study design uses a separate bridging PK study (Phase 1) that extends from the precursor IV study. By collecting PK samples from the same patients who previously received belimumab IV, this study could precisely estimate the bioavailability of each patient while minimising any impact due to between-patient variability, which is a key advantage considering the small population size. The findings presented in this study can therefore aid in updating existing population PK models, with an analysis estimating the population PK parameters using data from this study, the precursor IV study and two global paediatric studies currently ongoing. This analysis could then inform the development of an appropriate dosing regimen of SC belimumab in paediatric patients with cSLE in China.
The 3-weight-group dosing regimen used in this study was originally proposed to minimise overexposure in paediatric patients in both the global and Chinese studies. However, in the global paediatric study, modelling and simulation showed that a 2-weight-group regimen can achieve exposures comparable to the 3-weight-group regimen, supporting similar efficacy and safety while eliminating the inconvenient dosing schedule of every 10 days for the ≥ 30– < 50 kg weight group [27]. This approach has been approved by the FDA and a similar modelling and simulation strategy will be applied in Chinese paediatric patients to support dose-regimen selection in China.
Beyond the small sample size, particularly for the ≥ 15– < 30 kg weight group, it should be noted that data collection was limited to patients who enrolled in the precursor IV study, and who consented to take part in the open-label extension SC belimumab study. The inclusion of only patients who had successfully completed 48 weeks of IV belimumab treatment may introduce selection bias, as this cohort likely represents individuals with favourable tolerability and response to belimumab. As a result, the safety and pharmacokinetic findings observed in this study may not be fully generalisable to all patients with cSLE, particularly those who are initiating SC belimumab therapy or who may have experienced adverse events during prior IV treatment. This limitation should be considered when interpreting the results and their applicability to broader patient populations. In addition, although the subgroup analysis was based on body weight, the data reported within each subgroup may not adequately represent the overall population due to small sample size.
Conclusion
Paediatric patients and their families could benefit from an additional treatment choice of self-administered SC belimumab versus IV belimumab. This study demonstrated expected steady-state exposure parameters and tolerability of belimumab administered via an SC formulation in Chinese paediatric patients with SLE. While results across different weight groups were generally consistent, caution is warranted in interpreting comparisons among weight groups, as one subgroup consisted of only a single patient. This is the first study to demonstrate the actual PK and safety of different belimumab formulations in the same individuals in China and supports the use of SC belimumab as a suitable treatment option for Chinese paediatric patients.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank the participating patients and their families, clinicians and study investigators. The authors would also like to thank Deepak Assudani for his contributions to the conception or design of the study and to data interpretation.
Medical writing/editorial assistance
Medical writing support was provided by Philip Chapman, BSc, CMPP, Fishawack Indicia Ltd, UK, part of Avalere Health, and was funded by GSK.
Author Contribution
Caifeng Li, Jane Chen, Junyi Wu, Xuan Zhou and Haomin Qiu contributed to the conception or design of the study. Caifeng Li, Junmei Zhang, Meiping Lu, Haiguo Yu, Li Sun, Qihua Feng and Zhihui Li contributed to the acquisition of data. Jane Chen, Tiantian Liu, Junyi Wu and Haomin Qiu contributed to data analysis. Caifeng Li, Junmei Zhang, Jane Chen, Tiantian Liu, Junyi Wu, Xuan Zhou and Haomin Qiu contributed to data interpretation. All authors critically reviewed and approved this manuscript.
Funding
This study was funded by GSK (GSK Study 217091; NCT05917288). All costs related to the development of the publication, including the journal’s Rapid Service Fee, were funded by GSK.
Data Availability
The datasets generated and/or analysed during the current study are available in ClinicalTrials.gov repository, https://clinicaltrials.gov/study/NCT05917288?id=217091&rank=1&tab=results. Please refer to GSK weblink to access GSK’s data sharing policies and, as applicable, seek anonymised subject level data via the link https://www.gsk-studyregister.com/en/.
Declarations
Conflict of interest
Caifeng Li, Junmei Zhang, Meiping Lu, Haiguo Yu, Li Sun, Qihua Feng, and Zhihui Li have nothing to disclose. Jane Chen and Haomin Qiu are employed by GSK and hold financial equities in GSK. Tiantian Liu is employed by GSK. Junyi Wu was employed by GSK at the time of the study and holds financial equities in GSK. Xuan Zhou was employed by GSK at the time of the study. This study is independent of the current affiliations for Junyi Wu and Xuan Zhou, with no further conflicts of interest.
Ethical approval
This study was approved by all relevant institutional review boards (IRBs) or ethics committees and was conducted in accordance with the Declaration of Helsinki 2008 and its later amendments, Council for International Organisation of Medical Sciences (CIOM) International Ethical Guidelines, applicable International Organisation for Standardisation 14155 medical device guidelines, the European Medical Device Regulation 2017/745 for clinical device research and other applicable laws and regulations. The master ethics committee was the Medical Ethics Committee of Beijing Children’s Hospital, and all participating IRBs or ethics committees are listed in Table S2. Patients and their legal representatives were informed that study participation was voluntary. Prior to study enrolment, investigative sites obtained signed informed consent from patients or their legally authorized representative that met the requirements of 21 Code of Federal Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act requirements, where applicable, and the IRB/Independent Ethic Committee (IEC) or study centre.
Footnotes
Junyi Wu and Xuan Zhou: Affiliation at the time of the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analysed during the current study are available in ClinicalTrials.gov repository, https://clinicaltrials.gov/study/NCT05917288?id=217091&rank=1&tab=results. Please refer to GSK weblink to access GSK’s data sharing policies and, as applicable, seek anonymised subject level data via the link https://www.gsk-studyregister.com/en/.