Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial

Abstract

Objectives: This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE).

Methods: Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and '30 alternative' definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing.

Results: Ninety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL.

Conclusion: The belimumab intravenous pharmacokinetics and benefit-risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate.

Trial registration number: NCT01649765.

Keywords: DMARDs (biologic); systemic lupus erythematosus; treatment.

Figure 1

CONSORT diagram of patient disposition. *Initiate Cohort 2 after confirmed/adjusted dose from Cohort 1 PK review; ^†Cohort 3 was designed to have patient ages of 5 to 17 years, however overall study enrolment target was achieved before Cohort 2 PK analyses completion; ^‡Patients withdrawn from the study prior to Week 52 are considered treatment failures. CONSORT, CONsolidated Standards of Reporting Trials; PK, pharmacokinetics.

Figure 2

SRI4 response and severe flares. (A) SRI4 response by visit and at Week 52 (ITT population, n=93 for all time points). (B) Components of the SRI4 response at Week 52. (C) Severe flares over 52 weeks. *Defined as increase of<0.30 points from baseline. BILAG, British Isles Lupus Assessment Group; cSLE, childhood-onset systemic lupus erythematosus; ITT, intent-to-treat; PGA, Physician’s Global Assessment of cSLE activity; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index; SRI4, SLE Responder Index 4.

Figure 3

PRINTO/ACR at Week 52. (A) PRINTO/ACR responders at Week 52 by two definitions. (B) Percentage change from baseline in PRINTO/ACR cSLE core components at Week 52. *Defined as the proportion of patients with at least 30% improvement in three of five cSLE core components and no more than one of the remaining worsening more than 30%; ^†defined as proportion of patients with at least 50% improvement in any two of five cSLE core components and no more than one of the remaining worsening by more than 30%; ^‡mean (SD) change from baseline in PGA was –48.8 (42.04) for placebo and –56.5 (43.79) for belimumab; ^§mean (SD) change from baseline in SELENA-SLEDAI was –38.0 (39.50) for placebo and –43.3 (43.73) for belimumab. cSLE, childhood-onset systemic lupus erythematosus; Parent-global, Parent Global Assessment of patient overall well-being; PedsQL, Paediatric Quality of Life inventory generic core scale; PGA, Physician’s Global Assessment of cSLE activity; PRINTO/ACR, Paediatric Rheumatology International Trials Organisation/American College of Rheumatology; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index.