Background/Purpose: Sjögren’s disease (SjD) is a systemic, heterogeneous, autoimmune disease with substantial disease burden, high unmet need, and no approved systemic treatments. B cell hyperactivity and dysregulated B cell–activating factor/receptor (BAFF/BAFF-R) signalling are a hallmark of SjD pathogenesis. Ianalumab is a fully human IgG1 mAb with a novel dual mechanism of action that depletes B cells through enhanced antibody-dependent cellular cytotoxicity (ADCC) and also inhibits their activation and survival via BAFF-R blockade. NEPTUNUS-1 (NCT05350072) and NEPTUNUS-2 (NCT05349214) are Phase 3 studies designed to assess the efficacy and safety of ianalumab in patients with active SjD.

Methods: NEPTUNUS-1 and NEPTUNUS-2 are complementary, 52-week (Wk), global, multicenter, randomized, double-blind, placebo-controlled studies that enrolled adult patients with SjD meeting ACR/EULAR 2016 classification criteria with a EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score ≥5 across 8 pre-selected domains, and stimulated salivary flow rate of ≥0.05 mL/min. Background immunosuppressants, including MTX (≤25 mg/Wk), HCQ (≤400 mg/day), AZA (≤150 mg/day), and prednisone ≤10 mg/day were allowed alone or in combination in both studies. In NEPTUNUS-1, patients were randomized (1:1) to monthly (QM) subcutaneous (s.c.) ianalumab 300 mg or placebo (PBO); in NEPTUNUS-2, patients were randomized (1:1:1) to either ianalumab 300 mg QM, every 3 months (Q3M) or PBO. The primary objective of both studies was to demonstrate superiority of ianalumab over PBO based on change from baseline (CFB) in ESSDAI at Wk 48. Key secondary endpoints included disease activity measures as well as physician- and patient-reported outcomes at Wk 48. Safety was assessed up to Wk 52.

Results: In NEPTUNUS-1, 275 patients and in NEPTUNUS-2, 504 patients were randomized. In both studies, baseline characteristics were generally balanced across treatment arms. Both studies met their primary objective. Ianalumab QM demonstrated statistically significant improvement in ESSDAI CFB at Wk 48 compared to PBO (Fig 1). Patient’s Global Assessment (PaGA; LS mean difference [∆]: -6.6; 95% CI: -11.4, -1.8, p=0.007) and Physician’s Global Assessment (PhGA; ∆: -5.5; 95% CI: -10.1, -0.9, p=0.018) reached nominal statistical significance in NEPTUNUS-1. Additional secondary endpoints showed a trend towards improvement in both studies. Ianalumab showed favorable safety with an overall incidence of adverse events and serious adverse events comparable to placebo in both studies (Table 1).

Conclusion: NEPTUNUS-1 and NEPTUNUS-2 are the first replicate Phase 3 studies in SjD to meet their primary endpoint, with ianalumab 300 mg QM demonstrating significant improvement in disease activity measured by ESSDAI. In addition, secondary endpoints including PaGA and PhGA indicate symptom reduction and patient benefit beyond improvement in disease activity. Ianalumab also demonstrated a favorable safety profile, reinforcing its positive benefit-risk profile in the treatment of SjD.

Figure 1: Change from baseline in ESSDAI score over 52 weeks#: A) NEPTUNUS-1 B) NEPTUNUS-2

 

Table 1: Safety summary through Week 52

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ACR Meeting Abstracts - 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/