Seletalisib shows therapeutic potential in primary Sjögren’s syndrome

The selective PI3Kδ inhibitor seletalisib demonstrates clinical activity in patients with primary Sjögren’s syndrome (PSS) despite enrolment-related underpowering, as shown in phase II trial data.

In total, 27 patients with moderate-to-severe PSS were randomized to treatment with either seletalisib 45 mg/day (n=13; mean age, 52.2 years; 12 women) or placebo (n=14; mean age, 60.2 years; 13 women); 20 of them completed the study. The trial was terminated prematurely due to enrolment challenges with loss of statistical power (36 percent vs 80 percent planned).

At week 12, both arms showed a change in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score, but the reduction was greater with the study drug (difference, –2.59, 95 percent confidence interval [CI], –7.30 to 2.11; p=0.266). The change seen in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score was also greater with seletalisib (difference, –1.55, 95 percent CI, –3.39 to 0.28).

There were no significant changes in saliva and tear flow.

In terms of safety, serious adverse events (AEs) developed in 3/13 of patients on seletalisib vs 1/14 of those on placebo. AEs led to treatment discontinuation in five and one patients, respectively. The most common event was diarrhoea.

Serum IgM and IgG concentrations markedly dropped in the seletalisib arm. The study drug produced an improvement in size and organization of salivary gland inflammatory foci and in target engagement, which therefore reduced PI3K-mTOR signaling compared with placebo.

Larger studies with specific PI3Kδ inhibitors and, potentially, with patient stratification are needed.