A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis.

Funder: GlaxoSmithKline; doi: http://dx.doi.org/10.13039/100004330BACKGROUND: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). METHODS: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. RESULTS: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. CONCLUSIONS: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016

EMBRACE: One Small Story in Lupus—One Giant Challenge in Clinical Trials

Clinical trials of novel therapeutics in the United States have not been adequately representative of diverse populations, particularly racial and ethnic minorities. The challenges and consequences of underrepresentation in clinical trial recruitment are exemplified by the case of belimumab, a biologic treatment for systemic lupus erythematosus (SLE), a disease that is more prevalent in patients of Black African ancestry and of Hispanic/Latino ethnicity than in other patient populations. Although belimumab was found to be effective in phase 2 and 3 clinical trials in the general population, post hoc analyses of efficacy data in patients of Black African ancestry showed inconsistent results. Consequently, a cautionary statement regarding belimumab use in this population was added to the product label. To alleviate concerns that belimumab may not be safe and effective for patients of Black African ancestry, the Efficacy and Safety of Belimumab in Black Race Patients with SLE (EMBRACE) study was conducted in a post‐marketing commitment to the Food and Drug Administration. The study recruited only patients who self‐identified as being of Black race; its findings led to the removal of the cautionary labeling of belimumab use in patients of Black African ancestry. Our manuscript highlights the critical lessons learned from the successes and failures of the EMBRACE study. It also provides suggestions for overcoming health disparities, highlighting strategies for conducting well‐designed clinical trials to overcome systematic barriers to diversity in recruitment, with a focus on enacting long‐term support to ensure equity in the process, products, and benefits from drug development and clinical trials

Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.

BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.)

EMBRACE: Phase 3/4, Randomized, 52-Week Study of Belimumab Efficacy and Safety in Patients of Black African Ancestry With Systemic Lupus Erythematosus

OBJECTIVE: Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in Phase 2 and 3 belimumab trials was not reflective of the racial distribution observed in the lupus population. This study assessed efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified black race. METHODS: EMBRACE (GSK Study BEL115471; NCT01632241): 52-week multicenter, double-blind (DB), placebo-controlled trial in adults of self-identified black race with active SLE, receiving monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the DB phase. The primary endpoint was SLE Responder Index response rate at Week 52 with modified proteinuria scoring adapted from the SLEDAI-2K (SRI-S2K). Key secondary endpoints included: Week 52 SRI response rate, time to first severe flare, and reductions in prednisone dose. RESULTS: The modified intention-to-treat population comprised 448 patients (96.9% female; mean [standard deviation] age: 38.8 [11.42] years). The primary endpoint (SRI-S2K response rate at Week 52) was not achieved (belimumab 48.7%, placebo 41.6%; p=0.1068); however, numerical improvements favoring belimumab were observed, especially in patients with high baseline disease activity or renal manifestations. The safety profile of belimumab was generally consistent with previous SLE trials. Adverse events were the primary reason for DB phase withdrawals (belimumab 5.4%; placebo 6.7%). CONCLUSIONS: The primary endpoint of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry