A recent study published in Annals of the Rheumatic Diseases evaluated ianalumab (VAY736), a fully human monoclonal antibody that combines B-cell depletion with BAFF receptor (BAFF-R) signaling blockade, in patients with moderate-to-severe systemic lupus erythematosus (SLE). When added to standard-of-care therapy, ianalumab significantly reduced disease activity, with clinical benefits sustained for up to one year.
B-cell depletion has long been recognized as an effective therapeutic strategy in autoimmune diseases such as SLE, with deeper and more sustained depletion correlating with improved clinical outcomes. Another important target in lupus is B-cell activating factor (BAFF), a cytokine essential for B-cell proliferation and survival. Elevated BAFF levels in SLE patients can protect autoreactive B cells from depletion, contributing to disease relapse. Preclinical and clinical evidence has suggested that combined targeting of BAFF signaling and B-cell depletion can produce synergistic benefits, including reductions in peripheral B-cell counts, serum autoantibody levels, and disease flares.
Ianalumab works through a dual mechanism. It depletes B cells via antibody-dependent cellular cytotoxicity (ADCC), enhanced by Fc afucosylation to maximize Fcγ receptor engagement, and concurrently blocks BAFF–BAFF-R signaling on B cells, disrupting a key pathway for B-cell survival and proliferation. This dual action represents a novel approach to B-cell-targeted therapy in SLE.
The phase 2, randomized, double-blind, placebo-controlled trial enrolled 67 patients with active SLE who were receiving standard-of-care therapy. Patients were randomized 1:1 to receive monthly subcutaneous ianalumab 300 mg or placebo through week 28. The primary endpoint was a composite SLE Responder Index (SRI)-4 response at week 28 among patients who successfully tapered corticosteroids. Following the blinded period, all participants entered an open-label extension with ianalumab through week 48, with exploratory efficacy assessments through weeks 52 and 68 and safety monitoring continuing until B-cell recovery.
At week 28, the primary composite endpoint was achieved in 44% of patients receiving ianalumab (15/34) compared with 9% in the placebo group (3/33). Sustained clinical benefits were observed through week 52, including in patients who transitioned from placebo to open-label ianalumab, with response rates of 45.5% and 40.6%, respectively. Secondary and exploratory endpoints, including SRI-6, Definition of Remission in SLE, Lupus Low Disease Activity State, flare rates, and corticosteroid use, also demonstrated consistent treatment effects that were maintained through weeks 52 and 68.
Ianalumab was generally well tolerated, with no increase in serious adverse events or serious infections compared with placebo. Non-serious local injection site reactions were more frequent in the ianalumab group, but overall tolerability supported continued therapy for up to one year.
These findings reinforce the therapeutic value of targeted B-cell depletion in SLE, particularly when combined with BAFF-R blockade. The study demonstrated that simultaneous B-cell depletion and BAFF-R signaling inhibition can reduce disease activity, lower flare incidence, and enable corticosteroid sparing. The open-label extension provided additional evidence for incremental clinical and laboratory improvements with prolonged ianalumab exposure, supporting further investigation in larger, long-term trials. Ianalumab represents a promising dual-mechanism therapy for patients with moderate-to-severe SLE, offering sustained clinical benefits with an acceptable safety profile and highlighting the potential for durable disease control through combined depletion and signaling blockade strategies.
Reference
Agmon-Levin N, Ignatenko S, Gordienko A, Cortés-Hernández J, Narongroeknawin P, Romanowska-Próchnicka K, et al. B cell depletion and BAFF receptor blockade with ianalumab (VAY736) for the treatment of moderate-to-severe systemic lupus erythematosus: a phase 2 randomised, double-blind, placebo-controlled trial with subsequent open-label treatment. Ann Rheum Dis. 2026 Mar;85(3):476-488.