Researchers have for the first time shown efficacy of a single biologic in patients with primary Sjögren’s syndrome, paving the way for future studies and raising hopes for the first disease-modifying treatment for the condition.
A research team led by rheumatologists at University Hospitals Birmingham NHS Foundation undertook a Phase 2b dose-finding study of the drug in patients with primary Sjögren’s syndrome with moderate to severe disease activity.
To be eligible for the trial, patients (18-75 years old) had to have a disease activity score of 6 or more (as per the EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI]), a symptom severity score of at least 5 (as per EULAR Sjögren’s Syndrome Patient Reported Index [ESSPRI]), anti-SSA antibodies and a stimulated salivary flow rate of more than 0·1 mL/min.
Participants (n=190) were randomly assigned to receive either subcutaneous placebo (n=49), ianalumab 5mg (n=47), ianalumab 50mg (n=47) or ianalumab 300mg (n=47) every four weeks for 24 weeks.
The study met its primary objective, demonstrating a dose-related decrease in disease activity as measured by ESSDAI at week 24, with the maximum score change from baseline recorded in the ianalumab 300mg (mean ESSDAI change [minus placebo effects] from baseline at week 24 was –1·92 points; p=0·092).
Statistically significant improvements were also observed for the PhGA score (-8.4mm; p=0·022) and for the stimulated salivary flow rate at week 24 (mean change 0·20 mL/min; p=0·037). While tear flow did not change significantly over time, there was a numerically greater improvement at week 24 than at baseline in the 300mg group.
Patient-reported outcomes, such as the ESSPRI score, did not show any improvement at week 24 in the 300mg group, however, the authors noted that “some improvements could have been missed due to large placebo effects, low endpoint sensitivity, or small responses in severely affected patients”.
Ianalumab has two modes of action – direct lysis of B cells by antibody-dependent cellular cytotoxicity, and BAFF receptor blockade ultimately interrupting signalling for B-cell maturation, proliferation and survival.
According to the researchers, their study published in The Lancet is the first randomised, controlled, double-blind trial to show the ability of a new anti-B-cell drug (ianalumab) “to dose-dependently reduce disease activity and also increase saliva flow in patients with Sjögren’s syndrome within a 24-week treatment period”.
Having identified a safe and active dose of ianalumab for future testing, the trial has also provided “a template for patient selection, efficacy parameters, and endpoints, which might inform the design of future trials,” they noted.
In an accompanying editorial, Professor Alain Saraux, Prof. of Rheumatology at the Brest University Medical School and Dr Valérie Devauchelle-Pensec, a Consultant Rheumatologist at Cavale Blanche Hospital, France, said the findings “provide an enhanced understanding” of previous non-conclusive trials in primary Sjögren’s syndrome.
The first observation is that both ESSDAI and physician global assessment scores were improved with the highest dose of ianalumab, whereas ESSPRI and patients global assessment scores were not. They suggested that visual analogue scales and overall symptom severity could fluctuate daily and might not be as sensitive as expected, and that “a post-hoc analysis of this study and a better evaluation of symptoms (eg, using a daily measure of symptoms or more objective evaluation using connected tools or web application) should help clinicians in the future”.
Also of particular note was the study’s eligibility criteria, which included a very specific subgroup of patients. “The proportion of patients with primary Sjögren’s syndrome fulfilling these criteria in other cohorts and previous randomised controlled trials is likely to be small, but needs to be evaluated further. Exploratory post-hoc evaluation should help to better choose the selection criteria,” they concluded.
The study was supported by funding from Novartis.