Novel BTK Inhibitor Looks Good for Sjogren’s Syndrome

PHILADELPHIA — Remibrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, appeared effective in reducing signs of Sjogren’s syndrome in a randomized, placebo-controlled trial.

Scores on the EULAR Sjogren’s Syndrome Activity Index (ESSDAI), a comprehensive measure of Sjogren’s severity, fell by 2.86 points with the oral drug relative to placebo during the 24-week trial, according to Thomas Dörner, MD, of Charité Universitätsmedizin Berlin.

Mean ESSDAI scores fell steadily through the study period, by more than 4 points from a baseline of 9.0, Dörner reported at the American College of Rheumatology annual meeting. The placebo group also showed sharp declines during the first 8 weeks, but responses in those patients faltered as treatment continued, ending up with a mean decline from baseline of less than 2 ESSDAI points.

The placebo response was stronger on a parallel, patient-reported outcome measure known as ESSPRI. Scores on this instrument, which asks patients to rate dryness, pain, and fatigue, declined in lockstep in both treatment groups for a mean drop of about 1 point from a baseline average of 6.6. ESSDAI, in contrast, involves physician assessment of 12 organ systems affected by Sjogren’s and is a largely objective measure, Dörner said.

BTK inhibitors have recently become all the rage for autoimmune diseases, after becoming established as treatments for hematologic malignancies. An October 2022 review reported that the first such agent to win approval, ibrutinib (Imbruvica), is now the fourth biggest selling oncology drug worldwide. These drugs help in bringing rogue B cells under control; because B cells are now recognized as important drivers of many autoimmune inflammatory conditions, drugmakers have undertaken trials and created new molecules targeting this market.

Among them is Novartis, remibrutinib’s developer. It has a phase III program underway with the drug in chronic spontaneous urticaria, after positive phase II results were reported earlier this year. Although the drug appears to have failed in an earlier trial in asthma, Novartis is currently running additional studies in multiple sclerosis and peanut allergy. The company hasn’t said yet whether it plans a phase III trial in Sjogren’s syndrome, although Dörner said longer-term studies are expected.

The phase II trial in Sjogren’s presented by Dörner involved a total of 73 patients randomized to one of two oral remibrutinib doses (100 mg once or twice daily) or placebo. Dörner reported most data for the two remibrutinib groups combined (n=49) because outcomes differed little between them, he explained.

Participants were “very representative” of the general Sjogren’s population, he said, with a mean age of about 52, and nearly all women, with disease duration of about 10 years.

Remibrutinib appeared better than placebo on an important secondary outcome, unstimulated salivary flow (Mouth dryness is one of the most common clinical symptoms). Patients in the remibrutinib groups showed increased from baseline of about 0.4 mL/min on average versus virtually no change with placebo. The difference did not reach statistical significance, however, because of substantial interindividual variation within the groups.

Most Sjogren’s biomarkers such as the CXCL13 cytokine and pathological IgG and IgM immunoglobulins also suggested benefit from the BTK inhibitor.

Dörner indicated that safety findings were unremarkable, with little difference between remibrutinib and placebo, including adverse events classified as potentially drug-related while investigators were still blinded. He made a point of saying that no signs of liver toxicity were observed.