Ianalumab (VAY736), a Dual Mode of Action Biologic Combining BAFF Receptor Inhibition with B Cell Depletion, for Treatment of Primary Sjögren’s Syndrome: Results of an International Randomized, Placebo Controlled Dose Range Finding Study in 190 Patients
Simon Bowman, PhD, FRCP
University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
Primary Sjogren’s syndrome (pSS) is a multi-organ autoimmune disease primarily affecting excretory glands and characterized by B-cell hyperactivity, with no approved systemic treatments available. Ianalumab (VAY736) is an anti-B-cell activating factor (BAFF) receptor fully human IgG1 monoclonal antibody, engineered for direct ADCC-mediated B-cell depletion, thus providing a dual mode of action and targeted approach to treat pSS. A single-dose study suggested potent and sustained B cell depletion by ianalumab, which could provide therapeutic benefits in patients with pSS without major side effects.  This phase 2b study aims at establishing a dose-response relationship over a wide range of ianalumab doses, using change from baseline in the EULAR Sjogren’s Syndrome Disease Activity index (ESSDAI) over 24 weeks as the primary endpoint.
190 patients with pSS were randomized 1:1:1:1 to monthly s.c. administrations of placebo (n =49) or one of three ianalumab doses; 5 mg (n =47), 50 mg (n =47), or 300 mg (n =47).
First-dose premedication was 250 mg IV methylprednisolone.
To be eligible, patients had to fulfil the American European Consensus Group (AECG) classification criteria for pSS, be anti-Ro/SSA positive, have an ESSDAI ≥6 (on 7/12 domains: glandular, articular, lymphadenopathy, constitutional, cutaneous, hematologic, biologic), and a EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) ≥5.
The primary endpoint was the ESSDAI change from baseline to week 24.
Secondary endpoints included ESSPRI, Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Physician’s (PhGA) and Patient’s Global Assessments (PGA), SF-36, stimulated salivary flow (sSF) and Schirmer’s testStatistical methods included MCP-Mod to assess the dose-response on change of ESSDAI (12 domains) from BL and responder analysis to calculate the proportion of patients with ≥3 points improvement on ESSDAI as secondary analysis.
The primary endpoint of the study was met with a statistically significant dose-response for ESSDAI (Figure).
The largest reduction in ESSDAI was 1.92 points over placebo for ianalumab 300 mg at week 24.
Secondary analysis on ESSDAI revealed responder rates of 89.4% vs. 61.2%, for ianalumab 300 mg vs. placebo with a difference of 28.1% (p = 0.0019): no differences were observed for ianalumab 5 mg and 50 mg vs placebo.
In line with the results of the ESSDAI, the PhGA change from baseline was significantly different between ianalumab 300 mg and placebo (p = 0.022).
The secondary efficacy endpoints ESSPRI and FACIT-F showed no benefits over placebo for improvements in the patient reported symptoms such as dryness, fatigue, and pain.
Placebo responses were generally high.
Incidence of treatment emergent adverse events were comparable across placebo and ianalumab groups, whereby local injection reactions were most frequent, mostly mild and were more frequent with higher ianalumab doses.
Dörner T, Posch MG, Li Y, et al. Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019 May;78(5):641-7.
Presenter disclosure: The presenter has reported relationships with AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Celgene, Fox, Glaxo Smith and Klein, Janssen, Lilly, Medimmune, MTPharma, Novartis, ONO, Pfizer, Roche, Samsung, Sanofi, T. Dörner, UCB, Xtlbio, R.