Joint Ventures: The B-Cell Story, Part 2 — Ianalumab and the Next Chapter in Sjögren's and Lupus

In the second part of this Joint Ventures episode on B cell therapies in rheumatic disease, hosts Jack Arnold, MBBS, PhD, and Rihards Buss, MD, return with guest Lucy Carter, MBBS, PhD, to move beyond the question of how to deplete B cells and toward the more conceptually challenging problem of what happens after depletion — and whether ianalumab's dual mechanism of action represents the most rational answer yet developed.

The conversation opens by examining the biological rationale for combining rituximab with belimumab as a way to suppress pathological B cell repopulation. Carter reviews three trials that explored this principle — CALIBRATE in lupus nephritis, BLISS-BELIEVE in non-renal systemic lupus erythematosus (SLE), and the academically initiated BEAT-LUPUS trial — noting that while none delivered unambiguous positive primary endpoint results, BEAT-LUPUS demonstrated suppression of serological disease activity and a reduction in severe flares with the combination, lending meaningful biological support to the concept that controlling what repopulates after depletion is as important as depletion itself.

Ianalumab is then framed as the attempt to encode that concept into a single agent. A fully human, afucosylated IgG1 monoclonal antibody, it depletes B cells through enhanced antibody-dependent cellular cytotoxicity via the BAFF receptor — achieving in vitro depletion estimated at approximately 70-fold greater than rituximab — while simultaneously blocking BAFF-R signaling to prevent the BAFF-driven maturation and proliferation that drives pathological reconstitution. Buss draws the mechanistic distinction clearly: ianalumab targets the BAFF receptor, whereas belimumab neutralizes circulating BAFF itself, and its depletion route is entirely separate from CD20.

The NEPTUNUS-1 and NEPTUNUS-2 phase 3 trials in Sjögren's disease are then the focus, having met their primary endpoint of ESSDAI improvement from baseline to week 48 — a first for any targeted therapy in this indication. In the pooled analysis, the mean ESSDAI reduction was 6.5 points with ianalumab 300 mg monthly versus 5.3 with placebo (P = .0031), with benefit emerging as early as week 8. The group engages in a candid discussion about the magnitude of the separation, with Buss raising the high placebo response and the question of which ESSDAI domains were driving the improvement — noting that renal, CNS, and musculoskeletal domains were excluded in earlier phase work, and that patient-reported outcomes including dryness and fatigue, which carry the highest day-to-day symptom burden, showed less dramatic improvement on ESSPRI. Carter contextualizes this as entirely consistent with how lupus trials are powered — skin and joint dominant — and notes that real-world use will inevitably expand into manifestations the trials were not designed to address. The unresolved question of whether B cell–targeted therapy might reduce the excess lymphoma risk in Sjögren's is acknowledged but remains unanswerable from current trial data.

“The other interesting thing is, obviously, in the context of Sjögren's disease, the increased risk of non Hodgkin lymphoma, and where the B-cell depleting therapies that are specifically targeted or licensed specifically in Sjögren's fit into this pathway,” Arnold said. “How is that going to affect the stewardship regarding this, you know, these medications, and where do we go?”

The episode closes with a look at the broader therapeutic horizon: phase 2 SLE data for ianalumab showing improvements in SRI-4 and steroid taper at week 28, and the prospect of a rapidly crowding field — including CD40/CD40L costimulatory blockade advancing to phase 3 — that will eventually require head-to-head comparisons or validated biomarkers to guide patient selection. The safety profile of ianalumab across trials to date, including injection-site reactions and transient neutropenia without serious infection signals, is judged as reassuring, with Carter emphasizing that steroid reduction remains the primary lever for managing infection risk across all of these agents.

References

1. Furie RA, Aroca G, Cascino MD, et al; CALIBRATE Trial Investigators. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100-107. doi:10.1136/annrheumdis-2021-220920

2. Aranow C, Allaart CF, Amoura Z, et al; BLISS-BELIEVE Study Investigators. Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study. Ann Rheum Dis. 2024;83(11):1502-1512. doi:10.1136/ard-2024-225686

3. Bowman SJ, Fox R, Dörner T, et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet. 2022;399(10320):161-171. doi:10.1016/S0140-6736(21)02251-0

4. Dörner T, Bowman SJ, Fox R, et al. Safety and efficacy of ianalumab in patients with Sjögren's disease: 52-week results from a randomized, placebo-controlled, phase 2b dose-ranging study. Arthritis Rheumatol. 2025;77(5):560-570. doi:10.1002/art.43059

5. Grader-Beck T, Mariette X, Finzel S, et al. Ianalumab demonstrates significant reduction in disease activity in patients with Sjögren's disease: efficacy and safety results from two global phase 3, randomized, placebo-controlled double-blind studies (NEPTUNUS-1 and NEPTUNUS-2) [abstract]. Arthritis Rheumatol. 2025;77(suppl 9). https://acrabstracts.org/abstract/ianalumab-demonstrates-significant-reduction-in-disease-activity-in-patients-with-sjogrens-disease-efficacy-and-safety-results-from-two-global-phase-3-randomized-placebo-controlled-double-blind-s/