Background/Purpose: VAY736 is a novel, defucosylated, human IgG1 mAb targeting the receptor for B cell activating Factor of the TNF family (BAFF-R), providing both enhanced antibody-dependent cellular cytotoxicity-mediated depletion of B cells and blockade of BAFF:BAFF-R signaling that drives B cell differentiation, proliferation and survival. We evaluate here safety and efficacy of the dual mechanisms of action of VAY736 in patients with pSS, a highly BAFF-driven, systemic autoimmune disease involving lymphocytic infiltration and progressive dysfunction of exocrine glands along with various extra-glandular manifestations.

Methods: A single center, randomized, parallel group, double-blind, placebo-controlled trial recruited 27  seropositive pSS patients with EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) ≥6 over a 10-month period for treatment with intravenous VAY736 at either a single high dose, (n=12), a single lower dose (n=6), or with placebo (n=9). Outcomes were measured at baseline and at weeks (w)6, 12 and 24. The primary outcome was change in ESSDAI at w12. Secondary outcomes included the EULAR Sjögren‘s Syndrome Patient Reported Index (ESSPRI), Short Form-36 (SF-36), Multidimensional Fatigue Inventory (MFI), physician/patient global VAS assessments, salivary flow rate, Ocular Staining Score (OSS), high resolution salivary gland ultrasound (US) de Vita scores/perfusion and elastography, serum markers of B cell hyperactivity and flow cytometry-determined lymphocyte subsets.

Results: Analyses to w24 included all 27 patients. VAY736 was safe and well-tolerated with no drug-related SAE, drop outs or discontinuations. Mean age was 50.5 years with 4 males, 2 in placebo and 1 in each treated arm. Baseline mean ESSDAI scores (range) were 11.5 (6-18), 14.5 (6-31) and 11.1 (6-19) in the high dose, lower dose and placebo arms, respectively. Target engagement was confirmed by serum BAFF levels and rapid, profound depletion of circulating B cells in all VAY736-treated patients; up to 99% by 24h and remaining so to 12-24w and beyond. The primary endpoint of ESSDAI was reduced within 12w but did not reach clinical or statistical significance versus placebo. However, improvements for VAY736-treated subjects were seen across clinical secondary outcomes, particularly for patient and physician global assessments and SF-36 physical. Reductions in parotid gland stiffness by US suggest early signs of salivary gland improvement. B cell hyperactivity markers were also reduced in treated patients. There were no consistent changes in salivary flow rate or OSS.

Conclusion: Despite a limited, single infusion, VAY736 achieved in this early phase trial trends for improvement in the primary outcome and across all secondary outcomes. Thus, this treatment was safe and suggests a positive therapeutic effect for this dual mechanisms of action in pSS that warrant further evaluation.