Update on Clinical Trials in Systemic Lupus Erythematosus

Sonali Narain; Richard Furie

Disclosures

Curr Opin Rheumatol. 2016;28(5):477-487. 

In This Article

Targeting B-cell Growth and Survival Factors

Belimumab is a human immunoglobulin (Ig)-G1λ monoclonal antibody (mAb) that inhibits soluble B lymphocyte stimulator (BLyS; also known as B-cell activating factor).[3] Pivotal trials in SLE established belimumab as an effective and well tolerated drug that reduces disease activity and improves serologies.[4–6,7] Two abstracts on the subcutaneous belimumab formulation were presented at the European League Against Rheumatism and American College of Rheumatology 2015 Annual Scientific Meetings.[8,9] Belimumab International SLE Study – Subcutaneous,[9] a randomized double-blind placebo-controlled trial of subcutaneous belimumab in SLE patients (n = 839), achieved its primary end point of SLE responder index (SRI) 4 response (drug: 61.4% versus placebo: 48.7%; odds ratio: 1.65, P = 0.0009) as early as 16 weeks and sustained to week 52.

Controversy over belimumab's effectiveness in African American arose at the FDA Advisory Committee hearing in 2010. Since that time, observational studies[10,11] have demonstrated efficacy in all ethnic groups, including African Americans. Although the registrational trials excluded patients with active lupus nephritis, recent observational studies[12,13] have also noted improvement in renal outcomes in patients on belimumab with background mycophenolate mofetil (MMF). Trials to better assess the safety and efficacy of belimumab in lupus nephritis and in African Americans are ongoing.

Atacicept is a human recombinant fusion protein that inhibits B-cell activation by blocking both BLyS and APRIL (a proliferation-inducing ligand).[14] Initial studies[14,15] in SLE demonstrated a dose-dependent reduction in B cells and immunoglobulin levels with minimal adverse events. Subsequently, a study[16] in patients with class III or intravenous lupus nephritis on background MMF was prematurely terminated when three of six patients developed severe hypogammaglobulinemia and serious infections. Atacicept Phase 2/3 in Generalized SLE[17] recruited 461 patients with moderate-to-severe SLE. Although the study did not meet its primary end point of reduction in SLE flares, a posthoc analysis showed benefit in the 150 mg arm with a significant delay in time to first flare. However, this arm was prematurely terminated because of two deaths (n = 145) from respiratory infections. Despite setbacks, regulatory approval is being pursued.

Blisibimod is a high affinity fusion protein BLyS antagonist that, unlike belimumab, binds to both cell membrane-bound and soluble BLyS. Two trials of blisibimod published thus far[18,19] have shown acceptable safety and tolerability. Blisibimod has entered phase III development.

Tabalumab is a human IgG4 mAb that binds both soluble and membrane-bound BLyS.[20] ILLUMINATE 1 (n = 1164) evaluated two doses of tabalumab in SLE patients on standard of care (SoC).[20] The primary outcome, SRI 5 response at week 52, was not met in either treatment arm, although the response rates were higher than placebo (120 mg Q2W: 31.8%, 120 mg Q4W: 35.2%, placebo: 29.3%; P > 0.05). Improvements in antidsDNA antibodies, total B cells, immunoglobulins and complement levels were also noted. The sister study,[21] ILLUMINATE 2 (n = 1124), studied identical dosing regimens. This trial did meet its primary end point of SRI 5 response at week 52 in the tabalumab 120 mg q2W versus placebo groups (38.4 versus 27.7%, P = 0.0002), but not with the 120 mg q4W regimen (34.8 versus 27.7%, P = 0.051). The treatment groups had more adverse events of depression and suicidal ideation. Being similar studies with respect to design, geography and patient demographics, the difference in outcomes between ILLUMINATE 1 and 2 was attributed, in part, to the former study classifying immunosuppressive tapering as nonresponse. Dooley et al.[22] reported no differences in renal outcomes in both ILLUMINATE 1 and 2 trials.

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