Written By: Shreya Bendsure and Sheetal Barbade BPharm
Reviewed By: Pharmacally Editorial Team
The phase 2 DAHLIAS trial, recently published in The Lancet (October 2025), marks a pivotal milestone in autoimmune research, demonstrating that Nipocalimab, Johnson & Johnson’s first-in-class FcRn blocker, significantly reduces disease activity in moderate-to-severe Sjögren’s disease. The DAHLIAS phase 2 shows Nipocalimab 15 mg/kg achieved a statistically significant reduction in ClinESSDAI at 24 weeks versus placebo, providing the strongest clinical evidence to date that targeted IgG reduction can improve disease activity in seropositive, moderate-to-severe Sjögren’s disease. Confirmation in the ongoing phase 3 DAFFODIL programs is required before Nipocalimab can be considered a disease-modifying therapy.
About Nipocalimab
Nipocalimab is a fully human monoclonal antibody that selectively blocks the neonatal Fc receptor (FcRn), preventing the recycling of immunoglobulin G (IgG) and reducing circulating autoantibody levels without impairing protective immunity. The drug, developed by Johnson & Johnson Innovative Medicine, is marketed as Imaavy for its first approved indication in generalized myasthenia gravis (gMG). Its modular efficacy across antibody-mediated diseases has positioned Nipocalimab as a potential paradigm-shifting therapeutic in systemic autoimmune disorders.
Nipocalimab received its first U.S. FDA approval in April 2025 for gMG in adults and adolescents aged ≥12 years who are anti-AChR or anti-MuSK antibody positive. The same year, the European Medicines Agency issued a positive opinion recommending approval. Beyond gMG, the antibody is under active clinical development for hemolytic disease of the fetus and newborn (HDFN), autoimmune thrombocytopenia, warm autoimmune hemolytic anemia, and now Sjögren’s disease, under both Breakthrough and Fast Track designations.
By binding with high affinity to FcRn, Nipocalimab accelerates catabolism of IgG, including autoreactive antibodies such as anti-Ro/SSA and anti-La/SSB, which are central to Sjögren’s disease pathogenesis. This reduction alleviates downstream inflammation, immune-complex deposition, and tissue injury. Importantly, FcRn inhibition does not suppress global immune function, distinguishing it from traditional immunosuppressants.
DAHLIAS Phase 2 Trial: Design and Endpoints
The multicenter, randomized, double-blind, placebo-controlled DAHLIAS trial (NCT04968912) enrolled 163 patients across 69 centers in Europe, Asia; and the U.S. Participants had moderate-to-severe, active Sjögren’s disease, defined as a Clinical European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ClinESSDAI) ≥6 and seropositivity for anti-Ro60 and/or anti-Ro52 IgG antibodies. Subjects were randomized 1:1:1 to receive:
Nipocalimab 5 mg/kg IV every 2 weeks
Nipocalimab 15 mg/kg IV every 2 weeks
Placebo IV every 2 weeks
The primary endpoint was the change from baseline in the Clinical ESSDAI (ClinESSDAI) at week 24. Key secondary endpoints included ESSDAI, ESSPRI, physician and patient global assessments, composite response tools (CRESS, STAR), and salivary flow improvement.
Clinical Efficacy Results
The 15 mg/kg Nipocalimab group achieved a statistically significant reduction in ClinESSDAI versus placebo with least squares mean score –6.40 as compared to –3.74 for placebo; least squares mean difference versus placebo –2.65
The 5 mg/kg cohort exhibited a non‑significant trend (least squares mean difference versus placebo –0.34).
15 mg/kg recipients also showed clinically meaningful gains across secondary endpoints notably in ESSDAI, ESSDAI‑4, STAR, and CRESS scores, establishing disease-modifying potential.
Median reductions of 60.9% in total IgG and up to 53–60% in anti‑Ro and anti‑La autoantibodies were recorded at week 24.
Biomarker analyses revealed dose‑dependent declines in rheumatoid factor, ESR, and immune complexes all correlating with clinical improvement.
Patients treated with 15 mg/kg Nipocalimab also reported improved dryness, pain, and fatigue, with a twofold higher proportion achieving ≥50% increase in salivary flow compared with placebo.
Safety Profile
Nipocalimab safety was comparable to placebo, with no major new signals:
Adverse events (AEs): Occurred in ~80% of participants in all arms.
Serious AEs: 7 % overall, similar to placebo.
No deaths or opportunistic infections were observed.
Hypogammaglobinemia was observed more frequently with Nipocalimab (reported lab declines in total IgG and 50% meeting the trial’s hypogammaglobinemia threshold in the 15 mg/kg arm). These reductions were mostly asymptomatic over 24 weeks and were reversible after treatment stopped; infection rates were not higher in the active arm during the trial period. Longer follow-up is needed to define clinical risk.
A single anaphylaxis event (5 mg/kg) resolved with standard care.
These data reinforce FcRn blockade as safe and reversible, with IgG returning to baseline within 8 weeks post‑treatment.
Key Expert Opinions
Prof. Jacques‑Eric Gottenberg, lead academic investigator (Strasbourg University Hospital), commented that “these results confirm the pathogenic role of autoantibodies in Sjögren’s disease and demonstrate that selective IgG reduction can translate into real clinical benefit.”
Dr. Ghaith Noaiseh, Associate Professor of Allergy, Clinical Immunology, and Rheumatology at The University of Kansas Medical Center, emphasized that the DAHLIAS Phase 2 trial demonstrates a major step forward in FcRn inhibition as a treatment pathway for Sjögren’s disease. He highlighted that Nipocalimab produced clinically meaningful improvements in disease activity and key biological markers, offering a promising approach to address autoantibody-mediated pathology through rapid, reversible IgG reduction achieved without broad immune suppression.
Dr. Leonard L. Dragone, Disease Area Leader for Rheumatology and Autoantibody at Johnson & Johnson Innovative Medicine, noted that a significant unmet need persists for patients with Sjögren’s, most of whom are women living with debilitating chronic symptoms and no approved therapies. He added that the Lancet–published data strengthen confidence in Nipocalimab therapeutic potential and reflect Johnson & Johnson’s commitment to advancing treatments for autoantibody‑driven diseases.
What It Means for Patients
The DAHLIAS results represent the strongest clinical evidence to date supporting IgG autoantibody reduction as a viable disease‑modifying approach in Sjögren’s disease. If confirmed in phase 3, Nipocalimab could become the first targeted therapy for a condition that has relied solely on symptomatic care for decades.
Future Outlook: DAFFODIL Phase 3 Program
Following the success of DAHLIAS, Johnson & Johnson has launched the DAFFODIL Phase 3 study, aiming to evaluate Nipocalimab long‑term efficacy, safety, and quality‑of‑life benefits in a larger global cohort of seropositive patients. The study is expected to inform potential filing for regulatory approval as the first disease‑modifying therapy for Sjögren’s disease.
References
Noaiseh G, Sivils KL, Campbell K, et al. Efficacy and safety of nipocalimab in patients with moderate-to-severe Sjögren’s disease (DAHLIAS): a randomized, phase 2, placebo-controlled, double-blind trial. The Lancet, Published online October 24, 2025, https://doi.org/10.1016/S0140-6736(25)01430-8
Mariette X, Criswell LA, Primary Sjögren’s syndrome, New England Journal of Medicine, 2018; 378:931–939
Qin B, Wang J, Yang Z, et al, Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis, Annals of the Rheumatic Diseases, 2015;74:1983–1989
Seth NP, Xu R, DuPrie M, et al. Nipocalimab, an immunoselective FcRn blocker that lowers IgG and has unique molecular properties. mAbs 2025;17:2461191
Antozzi C, Vu T, Ramchandren S, et al. Safety and efficacy of nipocalimab in adults with generalized myasthenia gravis (Vivacity-MG3): a phase 3, randomized, double-blind, placebo-controlled study. Lancet Neurology. 2025;24:105–116
A Study of Nipocalimab in Adults with Primary Sjogren’s Syndrome (pSS), ClinicalTrials.gov ID NCT04968912, https://clinicaltrials.gov/study/NCT04968912
Published in The Lancet: Nipocalimab significantly decreased Sjögren’s disease (SjD) activity and severity through substantial reduction in Sjögren’s-related autoantibodies, 24 Oct 2025, Johnson and Johnson, https://www.investor.jnj.com/investor-news/news-details/2025/Published-in-The-Lancet-Nipocalimab-significantly-decreased-Sjgrens-disease-SjD-activity-and-severity-through-substantial-reduction-in-Sjgrens-related-autoantibodies/default.aspx