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
- PMID: 34861168
- DOI: 10.1016/S0140-6736(21)02251-0
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
Abstract
Background: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome.
Methods: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895.
Findings: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group).
Interpretation: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future.
Funding: Novartis.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests SJB and BAF have received support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and the NIHR/Wellcome Trust Birmingham Clinical Research Facility. SJB has received consultancy funding from Abbvie, AstraZeneca, Galapagos, and Novartis in the past 36 months. RF has received consultancy funding from Pfizer and Eli Lilly. TD has received grants and consultancy funding from AbbVie, Celgene, Eli Lilly, EMD MerckSerono, GSK, Janssen, Novartis, and Roche; grants from UCB, Sanofi, Deutsche Forschungsgemeinschaft, and EU Horizon2020 HarmonicSS; and consultancy funding from Gilead/Galapagos. XM received consultancy funding from BMS, Galapagos, GSK, Novartis, and Servier and grants from Servier. AP received grants and consultancy funding from Novartis. TG-B has received consultancy fees from Eli Lilly and Novartis. BAF has received consultancy fees from BMS, Galapagos, Novartis, Roche, and Servier. HS-K received grants and consulting fees from Novartis. RJM received grants from Aintree University Hospital and Novartis. GJ, JNW, MAS, W-LL, and WH are employees of Novartis. All other authors declare no competing interests. The views expressed in this publication are those of the authors and not necessarily those of the institutions they are associated with.
Comment in
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Primary Sjögren's syndrome: new beginning for evidence-based trials.Lancet. 2022 Jan 8;399(10320):121-122. doi: 10.1016/S0140-6736(21)02644-1. Epub 2021 Nov 30. Lancet. 2022. PMID: 34861169 No abstract available.
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New hope for B cell-targeting therapy in pSS.Nat Rev Rheumatol. 2022 Feb;18(2):61. doi: 10.1038/s41584-021-00740-w. Nat Rev Rheumatol. 2022. PMID: 34931061 No abstract available.
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