Why Sjögren’s Disease Has Resisted Treatment for Decades

Sjögren’s disease is a systemic autoimmune condition characterised by lymphocytic infiltration of exocrine glands, resulting in the hallmark symptoms of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), alongside potentially serious extraglandular manifestations including fatigue, peripheral neuropathy, and lymphoma risk. Despite affecting an estimated 3–4 million people in the United States and between 0.1% and 0.6% of the global population, primary Sjögren’s disease has, as of 2025, no FDA-approved disease-modifying biologic therapy. Patients and clinicians have historically relied on symptomatic management—artificial tears, saliva substitutes, and off-label immunosuppressants such as hydroxychloroquine—none of which alter the underlying autoimmune cascade.

The therapeutic vacuum in Sjögren’s disease is not for lack of biological understanding. Researchers have known for decades that B cells are central to the disease’s pathogenesis: they produce the anti-Ro/SSA and anti-La/SSB autoantibodies that define the condition serologically, they accumulate in glandular infiltrates, and elevated levels of the B-cell survival cytokine BAFF (B-cell activating factor) are consistently observed in patient serum. The challenge has been translating that mechanistic understanding into a therapy that meaningfully reduces disease activity across the heterogeneous patient population—something that earlier candidates, including rituximab (anti-CD20) and the BAFF ligand–neutralising antibody belimumab, failed to demonstrate convincingly in Phase III trials for this specific indication.

The failure of earlier B-cell–directed therapies in Sjögren’s disease has been attributed to several factors: inadequate patient stratification, trial endpoints that did not capture the full burden of systemic disease, and—crucially—mechanistic gaps in how those drugs engaged the B-cell compartment. Ianalumab’s emergence represents a deliberate attempt to address the last of these by targeting a different node in the BAFF signalling axis: the receptor itself, rather than the ligand.

BAFF-R Blockade: The Science Behind Ianalumab’s Mechanism

Ianalumab (development code VAY736) is a fully human IgG1 monoclonal antibody engineered to bind BAFF-R (B-cell activating factor receptor, encoded by TNFRSF13C), the primary receptor through which the BAFF cytokine delivers pro-survival signals to mature B cells. Blocking BAFF-R at the receptor level is mechanistically distinct from the approach taken by belimumab, which neutralises the soluble BAFF ligand in circulation. This distinction matters because BAFF exists in both soluble and membrane-bound forms; a ligand-neutralising antibody may leave membrane-bound BAFF signalling partially intact, whereas receptor blockade interrupts all BAFF isoforms simultaneously.

Beyond receptor blockade, ianalumab’s IgG1 Fc region is engineered for enhanced antibody-dependent cellular cytotoxicity (ADCC), meaning that natural killer cells and macrophages expressing Fcγ receptors can recognise and eliminate BAFF-R–positive B cells coated with ianalumab. This dual mechanism—blocking survival signalling at the receptor while simultaneously flagging the B cell for immune-mediated destruction—is expected to produce deeper and more durable B-cell depletion than either mechanism alone. The approach is conceptually similar to the strategy that made obinutuzumab (an Fc-engineered anti-CD20 antibody) more effective than rituximab in certain B-cell malignancies, as reported in research published by Nature.

BAFF-R is expressed almost exclusively on B cells, which gives ianalumab a selectivity advantage over broad immunosuppressants and even over some anti-CD20 therapies that also deplete regulatory B cells with protective functions. In Sjögren’s disease specifically, elevated serum BAFF correlates with disease activity scores, hypergammaglobulinaemia, and autoantibody titres—making BAFF-R a biologically and clinically rational target. Regulatory agencies including the FDA have increasingly emphasised the importance of mechanistic rationale in biologic approvals for autoimmune indications, and the BAFF-R hypothesis in Sjögren’s disease is well-supported by translational data.

“Receptor-level blockade of BAFF-R interrupts all BAFF isoforms simultaneously—both soluble and membrane-bound—while Fc engineering enables ianalumab to additionally recruit ADCC-mediated B-cell elimination, a dual mechanism that prior BAFF-directed therapies lacked.”

Clinical Evidence and the Path to FDA Review

Ianalumab’s clinical development programme in Sjögren’s disease has been built around the TWINSS trial programme, a Phase II/III study evaluating the drug in patients with moderate-to-severe primary Sjögren’s disease who had inadequate responses to conventional therapy. The programme used the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) and the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) as co-primary endpoints—a dual-endpoint design that captures both physician-assessed systemic disease activity and patient-reported symptom burden, addressing one of the criticisms levelled at earlier Sjögren’s trials that relied on endpoints insensitive to the full disease spectrum.

Phase II data from the TWINSS programme demonstrated statistically significant reductions in ESSDAI scores versus placebo, accompanied by near-complete peripheral B-cell depletion, consistent with the drug’s mechanism. Patient-reported outcomes on ESSPRI also showed improvement, though the magnitude of effect on subjective symptoms—dryness, fatigue, and pain—was more variable across the patient population, reflecting the heterogeneity that has historically complicated Sjögren’s trials. Biomarker analyses showed reductions in immunoglobulin levels and rheumatoid factor, consistent with reduced B-cell activity.

The FDA’s acceptance of a Biologics License Application (BLA) for ianalumab in primary Sjögren’s disease—and the assignment of a Priority Review designation, reflecting the unmet medical need—places the drug on a regulatory timeline that could yield a decision in 2025. The EMA is conducting a parallel review under the European Medicines Agency’s centralised procedure, meaning that a positive outcome could open access across both major markets simultaneously. This dual-track regulatory strategy reflects the global burden of Sjögren’s disease and the commercial significance of being the first approved targeted therapy in this indication.

Patent Landscape: What Ianalumab’s Approval Would Trigger

The intellectual property landscape surrounding BAFF-R–directed therapeutics is poised for significant activity if ianalumab receives FDA approval. Novartis, the originator of ianalumab, holds a portfolio of patents covering the antibody composition of matter, its Fc-engineering modifications for enhanced ADCC, manufacturing processes, and specific formulations for subcutaneous administration. Composition-of-matter protection for a biologic of this type typically provides market exclusivity for the duration of the patent term (20 years from filing), supplemented in the US by 12 years of biologics data exclusivity under the Biologics Price Competition and Innovation Act (BPCIA) and potential patent term extensions under the Hatch-Waxman framework as applied to biologics through the USPTO.

Beyond Novartis’s originator portfolio, an approval in primary Sjögren’s disease is expected to catalyse a wave of follow-on patent activity in several adjacent areas. Companion diagnostic developers will seek IP protection around biomarkers—including serum BAFF levels, B-cell subset counts, and anti-Ro/SSA titres—that predict response to BAFF-R blockade. Patient stratification algorithms, dosing optimisation methods, and combination regimens pairing ianalumab with conventional immunosuppressants or other biologics represent further patentable innovations. According to data tracked through PatSnap‘s innovation intelligence platform, BAFF and BAFF-R–related patent filings have shown sustained growth over the past decade, with activity concentrated in the United States, Europe, China, and Japan.

Biosimilar developers will also be watching the ianalumab approval closely. The BPCIA’s 12-year data exclusivity clock begins at approval, meaning that biosimilar applicants cannot file an abbreviated BLA (aBLA) for at least four years post-approval, and cannot receive approval until the 12-year period expires. Given the complexity of manufacturing an Fc-engineered IgG1 antibody with consistent ADCC activity, biosimilar development for ianalumab will present substantial technical and analytical challenges, potentially extending the effective period of market exclusivity beyond the statutory minimum. IP teams at biosimilar developers should begin freedom-to-operate analyses now, particularly with respect to Novartis’s manufacturing and formulation patents, which may have filing dates and expiry timelines that differ from the composition-of-matter patents.

Implications for Autoimmune Drug Development and IP Strategy

A successful ianalumab approval in primary Sjögren’s disease would carry implications well beyond the immediate commercial opportunity. It would validate BAFF-R as an actionable therapeutic target in a systemic autoimmune disease where the target has been mechanistically implicated but not yet clinically confirmed at the Phase III level—a distinction that matters enormously for IP strategy, competitive intelligence, and pipeline prioritisation across the autoimmune space.

For drug developers, the BAFF-R validation in Sjögren’s disease raises the question of whether the same target could be pursued in related autoimmune conditions with overlapping B-cell pathology: primary biliary cholangitis, IgA nephropathy, systemic lupus erythematosus (in combination or as an alternative to belimumab), and ANCA-associated vasculitis are among the indications where elevated BAFF has been documented and where B-cell depletion has shown at least preliminary efficacy signals. Each of these represents a potential lifecycle management opportunity for Novartis and a competitive threat to other companies with B-cell–directed programmes.

“Ianalumab’s FDA review does not just open a single new indication—it validates an entire target class. BAFF-R blockade, if approved in Sjögren’s disease, will accelerate patent filings, biosimilar programmes, and combination-therapy research across the autoimmune landscape.”

For IP professionals, the ianalumab case illustrates a broader principle in biologic drug development: the most strategically valuable patents are often not the composition-of-matter claims on the antibody itself, but the method-of-treatment patents that define specific patient populations, dosing regimens, and biomarker-guided use. These method claims can be filed at any point during clinical development and can extend effective exclusivity significantly beyond the expiry of the originator composition patent. Monitoring continuation filings and divisional applications from Novartis in the period immediately following any approval will be essential for competitive intelligence teams. Organisations such as WIPO publish international patent applications through the PCT system, providing early visibility into global filing strategies before national phase entries occur.

The ianalumab FDA decision also has implications for clinical trial design standards in Sjögren’s disease. If the TWINSS dual-endpoint approach is accepted by regulators as a valid model for demonstrating efficacy, it will likely become the benchmark for subsequent trials in the indication—shaping how competitors design their own programmes and how regulatory agencies evaluate future applications. This creates an indirect but significant first-mover advantage for Novartis beyond the formal IP protections: the ability to define the evidentiary standard against which all future Sjögren’s therapies will be measured.