Belimumab use during pregnancy: a summary of birth defects and pregnancy loss from belimumab clinical trials, a pregnancy registry and postmarketing reports.

OBJECTIVE: Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab. METHODS: Data collected from belimumab clinical trials, the Belimumab Pregnancy Registry (BPR), and postmarketing/spontaneous reports up to 8 March 2020 were described. Belimumab exposure timing, concomitant medications and potential confounding factors were summarised descriptively. RESULTS: Among 319 pregnancies with known outcomes (excluding elective terminations), 223 ended in live births from which birth defects were identified in 4/72 (5.6%) in belimumab-exposed pregnancies and 0/9 placebo-exposed pregnancies across 18 clinical trials, 10/46 (21.7%) belimumab-exposed pregnancies in the BPR prospective cohort (enrolled prior to pregnancy outcome) and 0/4 belimumab-exposed pregnancies in the BPR retrospective cohort (enrolled after pregnancy outcome), and 1/92 (1.1%) in belimumab-exposed pregnancies from postmarketing/spontaneous reports. There was no consistent pattern of birth defects across datasets. Out of pregnancies with known outcomes (excluding elective terminations), pregnancy loss occurred in 31.8% (35/110) of belimumab-exposed women and 43.8% (7/16) of placebo-exposed women in clinical trials; 4.2% (2/48) of women in the BPR prospective cohort and 50% (4/8) in the BPR retrospective cohort; and 31.4% (43/137) of belimumab-exposed women from postmarketing/spontaneous reports. All belimumab-exposed women in clinical trials and the BPR received concomitant medications and had confounding factors and/or missing data. CONCLUSIONS: Observations reported here add to limited data published on pregnancy outcomes following belimumab exposure. Low numbers of exposed pregnancies, presence of confounding factors/other biases, and incomplete information preclude informed recommendations regarding risk of birth defects and pregnancy loss with belimumab use.

Efficacy of belimumab in patients with systemic lupus erythematosus from North East Asia: Results of exploratory subgroup analyses.

OBJECTIVES: To assess belimumab efficacy in patients from North East Asia (NEA) with systemic lupus erythematosus (SLE) in baseline demographic/disease characteristic subgroups. METHODS: This analysis of patient subgroups from BLISS-NEA (GSK Study 113750; NCT01345253) studied adults with SLE randomized to belimumab (10 mg/kg intravenous) or placebo. Primary endpoint, SLE Responder Index 4 (SRI-4) response rate at Week 52, was analysed in subgroups defined by gender, country, prednisone-equivalent dose, concomitant medications, Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, complement (C) levels, anti-double-stranded deoxyribonucleic acid (dsDNA) positivity, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score. RESULTS: Patients (overall population: N = 677; belimumab: n = 451, placebo: n = 226) were from China (76.4%), Korea (14.8%), and Japan (8.9%). The mean age was 32.1 years; 92.9% were female. In the overall population, more belimumab (53.8%) than placebo (40.1%) patients were SRI-4 Week 52 responders (p = .0001). SRI-4 response rates by subgroups were generally consistent with the overall population. A greater response with belimumab was seen in patients with a baseline SELENA-SLEDAI score ≥10 versus ≤9 and patients with low C3/C4 levels and anti-dsDNA positive at baseline versus those 'NOT' (low C3 and/or C4 and anti-dsDNA positive). CONCLUSIONS: These findings continue to support the efficacy of belimumab in SLE.

Safety of belimumab in adult patients with systemic lupus erythematosus: Results of a large integrated analysis of controlled clinical trial data.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that affects multiple organ systems. Belimumab, a targeted human monoclonal antibody, binds to and inhibits soluble B-lymphocyte stimulator. The safety and efficacy of belimumab has consistently been demonstrated in multiple clinical trials for the treatment of patients with active SLE. Integration of these data provides an additional opportunity to explore the safety of belimumab in a larger and more diverse population. This post hoc pooled analysis of clinical studies evaluated the safety profile of belimumab versus placebo in adults with SLE. METHODS: This was a pooled post hoc analysis of 52-week safety data from one Phase 2 and five Phase 3 belimumab trials in adult patients with SLE. Patients received ≥1 dose of placebo or belimumab (1, 4, or 10 mg/kg intravenous or 200 mg subcutaneous), plus standard therapy. Outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality. RESULTS: Across 4170 patients (placebo: N = 1355; belimumab: N = 2815), baseline demographics, disease characteristics, and treatment exposure were similar for placebo and belimumab. Most patients (placebo: 76.6%; belimumab: 81.0%) completed the protocol Week 52 visit. Overall, incidence of AEs, SAEs, severe AEs, AESI, and mortality were similar between groups. In both groups, the most commonly reported SAEs by system organ class were infections and infestations (placebo: 5.9%; belimumab: 5.4%) and renal and urinary disorders (placebo: 2.2%; belimumab: 1.7%). Additionally, a greater proportion of patients experienced AESI with belimumab versus placebo for post-infusion/injection systemic reactions (placebo: 8.1%; belimumab: 10.2%). Mortality rates were similar between groups (placebo: 0.4%; belimumab: 0.6%). CONCLUSIONS: These results are consistent with those of the individual studies, BASE, BLISS-LN, and long-term extension studies, making belimumab one of the most studied SLE treatments for safety. Collectively, this evidence continues to support a positive benefit-risk profile of belimumab in the treatment of adult patients with SLE.

Effect of intravenously administered reslizumab on spirometric lung age in patients with moderate-to-severe eosinophilic asthma.

Background: Spirometric lung age expresses lung function relative to chronological age. It has been effective in encouraging smoking cessation and has been used in the assessment of asthma. Reslizumab, a humanized anti-interleukin-5 monoclonal antibody, is approved as add-on therapy for adults with severe asthma and elevated blood eosinophils. Objective: To assess the effect of reslizumab versus placebo on the change in lung age over 52 weeks and the correlation between change in lung age and quality of life in moderate-to-severe asthma. Methods: This was a post hoc analysis of two randomized, double-blind, placebo-controlled trials. Patients ages 12-75 years with moderate-to-severe, inadequately controlled asthma and elevated blood eosinophils received intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Spirometry was performed every 4 weeks, and the Asthma Quality of Life Questionnaire (AQLQ) score was assessed at baseline and weeks 16, 32, and 52. Results: Mean improvement in lung-age deficit at week 52 was -8.73 years for reslizumab versus -3.80 years for placebo, a treatment difference of 5 years (p < 0.0001). A statistically significant effect was seen as early as 4 weeks. In AQLQ responders (a ≥ 0.5 increase in AQLQ score), a statistically significant inverse relationship between the change from baseline in lung age and AQLQ score at weeks 16, 32, and 52 was observed among patients treated with reslizumab only. Among lung-age responders (≥5 years' reduction), a statistically significantly greater proportion of patients on reslizumab achieved ≥0.5 increase in the AQLQ score versus placebo at all time points. Conclusion: Reslizumab reduced lung-age deficit by 5 years in patients with moderate-to-severe inadequately controlled eosinophilic asthma. Improvement in lung age correlated with improved quality of life. Lung age is a simple indication of pulmonary function and could be a valuable tool in asthma education.Clinical trials NCT01287039 and NCT01285323, www.clinicaltrials.gov.

Safety and efficacy of belimumab in older adults with SLE: results of an integrated analysis of clinical trial data.

OBJECTIVE: Assess the safety and efficacy of belimumab in older adults with SLE. METHODS: This post hoc integrated analysis (GSK Study 116559) included safety data from six randomised, placebo-controlled belimumab trials (BLISS-76, BLISS-52, BLISS-SC, North East Asia study, LBSL02, EMBRACE; n=4170). The BASE study provided additional safety data (n=4003). Efficacy data were from five of the trials. Older adults (≥65 years) were compared with the overall populations of patients with SLE. Patients who had received ≥1 treatment dose were included. RESULTS: Sixty-three older adults (1.5%) were included in the pooled safety analysis population and 156 (3.9%) in the BASE study. At baseline, older adults had lower disease activity but more organ damage than the overall populations. In the pooled safety analysis population, five (18.5%) placebo-treated and ten (27.8%) belimumab-treated older adults experienced ≥1 serious adverse event (SAE), as did 230 (17.0%) placebo-treated and 421 (15.0%) belimumab-treated patients overall. In the BASE study, nine (11.0%) placebo-treated and six (8.1%) belimumab-treated older adults experienced ≥1 SAE, as did 222 (11.1%) placebo-treated and 220 (11.0%) belimumab-treated patients overall. No clinically relevant differences in deaths and adverse events of special interest were observed between older adults and the overall populations. Older adults' SLE Responder Index response rates favoured belimumab versus placebo, consistent with the overall population. CONCLUSION: The safety and efficacy of belimumab in older adults were generally consistent with the overall populations, suggesting belimumab is a treatment option for older patients with SLE. Due to small numbers of older adults, findings should be interpreted with caution.

Belimumab use during pregnancy: Interim results of the belimumab pregnancy registry.

BACKGROUND: Belimumab is approved for active, autoantibody-positive systemic lupus erythematosus (SLE) and lupus nephritis, but limited data exist regarding its use in pregnancy. The Belimumab Pregnancy Registry (BPR, GSK Study BEL114256; NCT01532310) was created to evaluate pregnancy and infant outcomes following belimumab exposure. METHODS: Individuals with SLE exposed to belimumab from 4 months before and/or during pregnancy can enroll into the BPR. The primary outcome is major birth defects; secondary outcomes include miscarriages, stillbirths, elective termination, pre-term birth, neonatal death, small for gestational age, and adverse infant outcomes during the first year of life. Belimumab exposure timing, concomitant medications, and other potential confounding factors are also collected. Data up to March 8, 2021, are reported descriptively. RESULTS: From an expected sample size target of 500 prospective pregnancies with a known outcome, only 55 were enrolled in the study. Among these, two pregnancy losses and 53 pregnancies with a live birth outcome were reported. Ten of the 53 live birth pregnancies resulted in a major birth defect. Ten pregnancies were enrolled after the pregnancy outcome occurred and were examined retrospectively (four live births with no defects, four miscarriages, and two elective terminations). There was no indication or pattern of birth defects associated with belimumab. CONCLUSIONS: Low recruitment numbers for the BPR and incomplete information limit the conclusions regarding belimumab exposure during pregnancy. There was no pattern or common mechanism of birth defects associated with belimumab within the BPR data.

Identifying Barriers to Enrollment in Patient Pregnancy Registries: Building Evidence Through Crowdsourcing.

BACKGROUND: Enrollment in pregnancy registries is challenging despite substantial awareness-raising activities, generally resulting in low recruitment owing to limited safety data. Understanding patient and physician awareness of and attitudes toward pregnancy registries is needed to facilitate enrollment. Crowdsourcing, in which services, ideas, or content are obtained by soliciting contributions from a large group of people using web-based platforms, has shown promise for improving patient engagement and obtaining patient insights. OBJECTIVE: This study aimed to use web-based crowdsourcing platforms to evaluate Belimumab Pregnancy Registry (BPR) awareness among patients and physicians and to identify potential barriers to pregnancy registry enrollment with the BPR as a case study. METHODS: We conducted 2 surveys using separate web-based crowdsourcing platforms: Amazon Mechanical Turk (a 14-question patient survey) and Sermo RealTime (a 11-question rheumatologist survey). Eligible patients were women, aged 18-55 years; diagnosed with systemic lupus erythematosus (SLE); and pregnant, recently pregnant (within 2 years), or planning pregnancy. Eligible rheumatologists had prescribed belimumab and treated pregnant women. Responses were descriptively analyzed. RESULTS: Of 151 patient respondents over a 3-month period (n=88, 58.3% aged 26-35 years; n=149, 98.7% with mild or moderate SLE; and n=148, 98% from the United States), 51% (77/151) were currently or recently pregnant. Overall, 169 rheumatologists completed the survey within 48 hours, and 59.2% (100/169) were based in the United States. Belimumab exposure was reported by 41.7% (63/151) patients, whereas 51.7% (75/145) rheumatologists had prescribed belimumab to <5 patients, 25.5% (37/145) had prescribed to 5-10 patients, and 22.8% (33/145) had prescribed to >10 patients who were pregnant or trying to conceive. Of the patients exposed to belimumab, 51% (32/63) were BPR-aware, and 45.5% (77/169) of the rheumatologists were BPR-aware. Overall, 60% (38/63) of patients reported belimumab discontinuation because of pregnancy or planned pregnancy. Among the 77 BPR-aware rheumatologists, 70 (91%) referred patients to the registry. Concerns among rheumatologists who did not prescribe belimumab during pregnancy included unknown pregnancy safety profile (119/169, 70.4%), and 61.5% (104/169) reported their patients' concerns about the unknown pregnancy safety profile. Belimumab exposure during or recently after pregnancy or while trying to conceive was reported in patients with mild (6/64, 9%), moderate (22/85, 26%), or severe (1/2, 50%) SLE. Rheumatologists more commonly recommended belimumab for moderate (84/169, 49.7%) and severe (123/169, 72.8%) SLE than for mild SLE (36/169, 21.3%) for patients trying to conceive recently or currently pregnant. Overall, 81.6% (138/169) of the rheumatologists suggested a belimumab washout period before pregnancy of 0-30 days (44/138, 31.9%), 30-60 days (64/138, 46.4%), or >60 days (30/138, 21.7%). CONCLUSIONS: In this case, crowdsourcing efficiently obtained patient and rheumatologist input, with some patients with SLE continuing to use belimumab during or while planning a pregnancy. There was moderate awareness of the BPR among patients and physicians.

Phase 3, long-term, open-label extension period of safety and efficacy of belimumab in patients with systemic lupus erythematosus in China, for up to 6 years.

OBJECTIVES: To evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in China. METHODS: In this phase 3, open-label extension period, eligible completers of study BEL113750 (NCT01345253) received intravenous belimumab 10 mg/kg monthly for ≤6 years. The primary endpoint was safety. Secondary endpoints included the SLE Responder Index (SRI)-4 response rate, severe SLE flares and changes in prednisone use. Analyses were based on observed data from the first dose of belimumab through to study end. RESULTS: Of the 424 patients who received belimumab, 215 (50.7%) completed the study, 208 (49.1%) withdrew and 1 patient died. Overall, 359/424 (84.7%) patients had adverse events (AEs), and 96/424 (22.6%) had serious AEs. 26/424 (6.1%) patients discontinued study treatment/withdrew from the study due to AEs. Postinfusion systemic reaction rate was 1.5 events/100 patient-years. Herpes zoster infection rate was 3.0 events/100 patient-years, of which 0.4 events/100 patient-years were serious events. One papillary thyroid cancer and one vaginal cancer were reported in year 0-1 and year 3-4, respectively. There were no completed suicides/suicide attempts and no reports of serious depression. The proportion of SRI-4 responders increased progressively (year 1, week 24: 190/346 (54.9%); year 5, week 48: 66/82 (80.5%)). Severe flares were experienced by 55/396 (13.9%) patients. For 335 patients with baseline prednisone-equivalent dose >7.5 mg/day, the number of patients with a dose reduction to ≤7.5 mg/day increased over time (year 1, week 24: 30/333 (9.0%); year 5, week 48: 36/67 (53.7%)). CONCLUSIONS: Favourable safety profile and disease control appeared to be maintained in patients with SLE in China for ≤6 years, consistent with previous belimumab studies.

Long-term open-label continuation study of the safety and efficacy of belimumab for up to 7 years in patients with systemic lupus erythematosus from Japan and South Korea.

OBJECTIVES: To evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) from Japan and South Korea. METHODS: In this phase III, open-label continuation study (BEL114333; NCT01597622), eligible completers of BEL113750 (NCT01345253) or BEL112341 (NCT01484496) received intravenous belimumab 10 mg/kg every 28 days for ≤7 years. Primary endpoint was safety. Secondary endpoints: SLE Responder Index (SRI)4 response rate, proportion of patients meeting individual SRI4 criteria, SLE flares and prednisone use. Analyses were based on observed data from the first belimumab exposure (either in parent or current study) through to study end. RESULTS: Of 142 enrolled patients who received belimumab, 73.2% completed the study. The study population comprised patients with moderate SLE, mean (SD) Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) baseline score of 9.3 (3.9) and 98.6% receiving corticosteroids. Most patients (97.9%) experienced adverse events (AEs); 33.8% experienced serious AEs. Increase in SRI4 (Year 1, Week 24: 47.8%; Year 6, Week 48: 68.2%) and SELENA-SLEDAI responders suggested reductions in disease activity. Proportions of patients with no worsening in Physician Global Assessment/no new organ damage remained stable throughout. Severe SLE flares occurred in 14.8% of patients. Among patients with baseline prednisone-equivalent dose >7.5 mg/day (n=81), the median (min, max) number of days anytime post-baseline that the daily dose was ≤7.5 mg/day or had been reduced by 50% from baseline was 584 (0, 2267). CONCLUSIONS: Favourable safety profile and treatment responses were maintained for ≤7 years in patients with SLE from Japan and South Korea.