OP0041 Treatment of primary Sjögren's disease by blocking FcRn: clinical and translational data from RHO, a phase 2 randomized, placebo controlled, double-blind, proof-of-concept study with efgartigimod

Abstract

<h2>Abstract</h2><h3>Background:</h3> Primary Sjögren's disease (pSjD) is a chronic, systemic autoimmune disease, characterized by lymphocytic infiltration and progressive, immune-mediated dysfunction of the exocrine glands. B-cell activation plays a pivotal role in the development of the disease, resulting in the production of immunoglobulin (Ig) G autoantibodies, especially those that target Sjögren's syndrome–related antigens A/Ro and B/La ribonuclear complexes, and rheumatoid factor (RF), as well as elevated levels of serum IgG. There are no systemic disease-modifying treatments approved for pSjD. Current therapies focus on the management of symptoms, and treatment of systemic disease manifestations, including oral and ocular mucosal dryness, and have limited efficacy in preventing glandular damage or suppressing systemic disease activity. Efgartigimod is an IgG1 antibody Fc fragment that has been engineered for increased affinity to the neonatal Fc receptor (FcRn), and uniquely contains only that part of the IgG antibody that normally binds FcRn. Efgartigimod selectively reduces IgG by blocking FcRn-mediated IgG recycling without impacting antibody production, albumin levels, or other parts of the immune system. In phase 2 and 3 studies across a range of indications, efgartigimod decreased serum concentrations of total IgG, including pathogenic autoantibodies, without reducing albumin levels. In those studies, efgartigimod was well tolerated, and most adverse events were mild. <h3>Objectives:</h3> We hypothesize that efgartigimod may successfully reduce disease activity and symptoms in patients with pSjD due to reduction in IgG, including disease-specific IgG autoantibodies, thereby targeting the underlying pathogenesis of pSjD. We present results of RHO, a phase 2, multicenter, randomized, placebo-controlled, double-blind, proof-of-concept study initiated to explore the safety and efficacy of efgartigimod in adult participants with pSjD (NCT05817669). <h3>Methods:</h3> Patients met ACR/EULAR 2016 primary Sjogren's syndrome criteria ≤7 years before screening, had EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥5, were anti-Ro/SSA positive, and had residual salivary flow. Patients were randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. The primary endpoint was the proportion of responders to the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS; response on ≥3 out of 5 items) at Week 24. Key secondary endpoints were proportion of responders to the candidate Sjögren's Tool for Assessing Response (cSTAR), change from baseline in ESSDAI, Clinical ESSDAI (ClinESSDAI), and EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) scores, as well as safety. Additional endpoints include exploratory biomarkers to understand the effects of efgartigimod on pSjD disease pathology. <h3>Results:</h3> Thirty-four patients were randomized in the study. Three did not meet eligibility criteria and were removed from the efficacy analysis. The study met its primary endpoint, with more responders to ≥3 of 5 CRESS items in the efgartigimod group (45.5%; 10/22) compared with the placebo group (11.1%; 1/9) at Week 24. For 4 of the 5 individual CRESS items (systemic disease activity, salivary gland function, tear gland function, and serology), a positive signal was observed for efgartigimod versus placebo (Figure 1). 54.5% (12/22) of efgartigimod-treated participants were cSTAR responders at Week 24, compared with 33.3% (3/9) of those treated with placebo. Strong improvements from baseline were seen in both treatment arms in disease activity (ESSDAI and ClinESSDAI scores). No relevant changes in ESSPRI score were observed. Efgartigimod was safe and well tolerated, with no new safety signals observed. Efgartigimod rapidly reduced IgG and anti-Ro52 autoantibodies with a mean (SE) reduction of 58.3% (2.4) and 63.8% (3.9) from Week 4 onward. In line with this effect, C1Q immune complexes showed a mean (SE) reduction of 4.0 (1.3) μg Eq/mL after 4 weeks, while no effect was observed in the placebo arm (0.1 [0.6]). There was also a notable effect on RF, with a mean (SE) reduction of 19.6% (4.1) with efgartigimod as opposed to placebo (6.3% [3.0]) at the end of the study. Additional exploratory and parotid biomarker data will be presented. <h3>Conclusion:</h3> Proof-of-concept was demonstrated using efgartigimod in patients with pSjD, which was generally well tolerated. The phase 3 UNITY trial (NCT06684847) is currently underway to assess efficacy and safety of efgartigimod in patients with pSjD with clinESSDAI ≥6 (moderate-to-severe systemic disease activity). <h3>REFERENCES:</h3> <b>NIL</b>. Figure 1Proportion of CRESS responders (≥3 of 5 CRESS items; primary endpoint) (A) and responders to individual CRESS items at Week 24 (B) <h3>Acknowledgements:</h3> Medical writing support was provided by Envision Pharma Group and was funded by argenx. <h3>Disclosure of Interests:</h3> Isabelle Peene argenx, BMS, Gwenny M. Verstappen argenx, Joke Deprez: None declared, Frans G.M. Kroese argenx, Suzanne Arends argenx, BMS, Novartis, Andrew Kelly argenx, Lana Vandersarren argenx, Edward Bowen IQVIA, Julie Jacobs argenx, Paul Meyvisch argenx, Dirk Elewaut argenx, Hendrika Bootsma BMS, AstraZeneca, Novartis, Roche, UCB, Servier, Galapagos, BMS, AstraZeneca, Novartis, Roche. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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