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AMSTERDAM -- Leniolisib, an oral inhibitor of the lipid kinase PI3Kδ, failed to provide symptomatic improvements among patients with Sjogren's syndrome in a small placebo-controlled trial reported here.

In a study that included 30 patients, the response curves for disease activity in patients randomized to leniolisib, 70 mg twice daily, and those receiving placebo did not differentiate at week 12 and the confidence intervals were overlapping, reported Thomas Dörner, MD, of Charité University Hospital in Berlin, at the annual European Congress of Rheumatology here, which is sponsored by the European League Against Rheumatism (EULAR).

Moreover, more than half of patients receiving the active treatment developed skin rashes, and in one, the rash was sufficiently severe to require hospitalization.

Current thinking about the pathogenesis of Sjogren's syndrome suggests a substantial role for the intracellular kinase PI3Kδ for the formulation and maintenance of germinal centers in the inflamed glandular tissues. This kinase also is important in B-cell activation and antigen presentation as well as in the production of autoantibodies, T-cell activation, and toll-like receptor signaling. It also has critical downstream effects such as inhibiting the phosphorylation of AkT, which is required for the survival of immune cells, Dörner explained.

In an earlier study of healthy volunteers, leniolisib showed good pharmacokinetic properties and demonstrated effects on phosphorylated AkT in ex vivo-stimulated B cells.

The patients included in the current study were mostly women; mean age was 48. They had clinically active disease, with EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) scores at baseline of at least 6 and EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) scores of at least 5. The mean ESSDAI scores at baseline ranged from 9.1 to 10.3, and all participants had some residual salivary flow.

They were randomized in a 2:1 ratio to receive the active treatment or placebo for 3 months, at which time the response curves for both ESSDAI and ESSPRI did not clearly differentiate. There were slight improvements, albeit not statistically significant, in dryness, pain, and fatigue, on the mental and physical components of the Short Form-36 Health Assessment Questionnaire, and in lachrimal function.

However, analysis of the biologic effects of the compound confirmed target engagement, with decreases in phosphorylation of AkT in B cells only in the active treatment group. There also was a significant decrease in serum levels of the chemokine CXCL13, which plays a key role in germinal center maintenance, and in circulating levels of follicular T-helper cells.

"These results seem a little disappointing," said the session moderator David Isenberg, MD, of University College London, who was not involved in the study.

"A lot of patients with Sjogren's present several years after they had had dryness of their eyes and mouth, saying they thought it was old age," Isenberg said. "Do you think part of the problem with Sjogren's trials is that by the time they present, many patients had damage so it's impossible to change anything?" he asked.

Dörner said that can't be ruled out, but there could also be functional abnormalities involved that have not been shown to be amenable to therapeutics. "And in terms of glandular function, we have not seen improvements even with high doses of corticosteroids, which I consider a reference intervention," he said.

"In addition, we probably are not patient enough, and need longer treatment," he concluded.