In Sjögren’s disease, the immune system attacks the cells in glands responsible for producing tears and saliva — causing dry eyes, dry mouth, fatigue, and, in a few cases, life-threatening complications. Despite being the second most common systemic autoimmune disease after rheumatoid arthritis, Sjögren’s disease lacks approved therapies targeting its underlying immune disruption. Treatment remains limited to managing symptoms, for example, by using eye drops. Now, scientists have reported Phase 2b trial results on the safety and efficacy of the monoclonal antibody iscalimab, which targets an inflammatory pathway that contributes to the disease. The drug led to improvements in clinician-reported disease activity and patient-reported dryness and fatigue, offering hope after many prior drug failures (1).
Women in middle age are the most affected by Sjögren’s disease, with a female-to-male ratio of about nine to one. Clinical scientist Sue Lester from The Queen Elizabeth Hospital (TQEH), who was not involved in the new study, stressed the challenging daily lives these women face. “The impact of having severely dry eyes and dry mouth really affects your quality of life, but also the fatigue, which is like a bone-crushing fatigue,” she said. “These people deserve treatment, something to alleviate their symptoms and make them feel better.” Lester found the trial’s results particularly promising in terms of patient-reported improvements in fatigue and dryness, but she stressed that more research is necessary.
In the randomized, double-blind trial, researchers studied two distinct cohorts of individuals with Sjögren’s disease from 23 countries. The first cohort consisted of 173 patients with moderate to severe systemic activity — meaning that the disease manifested across various organs as assessed by physicians — and high symptom burden, as reported by patients. The second cohort included 100 participants who also had a high symptom burden but lower systemic involvement, a Sjögren’s subgroup often excluded from clinical trials despite being a large proportion of those with the disease. Including them in this trial was, therefore, a good decision, said Maureen Rischmueller, a physician scientist at TQEH who was not involved in this work but has collaborated with some of the authors in other projects.
In this Novartis-funded trial, researchers assessed the efficacy and safety of iscalimab, an anti-CD40 antibody from Novartis that is also being tested for treating other autoimmune disorders in separate Phase 2 trials. The antibody targets a pathway that participates in the proinflammatory processes in the tissues of patients with Sjögren’s disease.
In this study’s first cohort, researchers tested three drug doses (150 mg, 300 mg, and 600 mg). While patients treated with any dose for over 24 weeks showed a trend toward improvement in disease activity compared to placebo, the researchers only observed significant results with the 150 mg and 600 mg doses. Symptom improvement, as reported by patients, occurred across all three dosage groups in the first cohort, but it was not statistically significant. The researchers administered the 600 mg dose or a placebo to the patients in the second cohort with lower systemic activity but a high symptom burden. In this group, there was an overall trend toward symptom relief in those treated with iscalimab, particularly for dryness and fatigue, though these changes were also nonsignificant.
The results are exciting, said coauthor Benjamin Fisher, a rheumatologist at the University of Birmingham. “There are strong trends to symptom improvements; that’s encouraging for the field.”
There are strong trends to symptom improvements; that’s encouraging for the field.
– Benjamin Fisher, University of Birmingham
Rischmueller noted that although the study was not specifically powered to assess the statistical significance of patient-reported outcomes, symptoms improved in both treatment cohorts compared to those on the placebo. She added, “This is really important because most clinical trials to date … have shown improvement — or not — in systemic disease activity, but not improvement in the patient-reported outcomes.” She cautioned that a few previous clinical trials for Sjögren’s disease have met their endpoints in Phase 2 trials but failed in Phase 3 trials, so she looks forward to seeing how the drug will perform in future tests.
University of Florida immunologist Cuong Nguyen, who was not involved in this trial, agreed that these results are encouraging, especially in light of past clinical trial disappointments. He noted that some previous failures stemmed from variable responses between populations in different locations. Thus, he praised the decision to include participants from a wide range of countries in this trial. Yet, he stressed that larger, equally diverse trials are necessary to confirm the drug’s efficacy.
During the 24 weeks of treatment, 13 participants, including three on the placebo, experienced serious adverse events. Some were potentially unrelated to the treatment. None of the patients died during this period. However, the trial continued for a second 24-week period (not yet reported in the paper), in which participants originally treated with the placebo switched to iscalimab treatment. During this second stage, two patients died. One death was due to a Pneumocystis jiroveci pneumonia infection and was suspected to be related to the treatment. “It’s quite a large study. That’s only one case,” said Fisher. “There’ll be a case for studying it further,” he said, adding that Novartis is likely pausing and looking at safety data in more detail before moving into the next phase.
Currently, other potential drugs for Sjögren’s disease are in the pipeline, produced by Novartis and other pharmaceutical companies (2). For instance, Amgen’s dazodalibep, which targets the CD40 ligand — the same pathway as iscalimab — has also shown encouraging results in improving patient-reported symptoms (3). “There are clearly several promising drugs, and it will be really nice to get one of them coming through that we can treat our patients with,” said Fisher.
This article was updated on January 10, 2025 to correct Sue Lester and Maureen Rischmueller's descriptors. Sue Lester is a clinical scientist, not a clinician scientist. Maureen Rischmueller is a physician scientist, not a translational scientist.
References
- Fisher, B.A. et al. Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. Lancet 404, 540-553 (2024).
- Colafrancesco, S. and Priori, R. Sjögren’s disease: a new era for clinical trials? Lancet 404, 498-499 (2024).
- St. Clair, E.W. et al. CD40 ligand antagonist dazodalibep in Sjögren’s disease: a randomized, double-blinded, placebo-controlled, phase 2 trial. Nat Med 30, 1583-1592 (2024).
