medwireNews: Treatment with the selective PI3K-delta inhibitor seletalisib may reduce disease activity in patients with moderate-to-severe primary Sjögren’s syndrome (pSS), suggest data from a phase 2 proof-of-concept study.
Despite recruitment challenges resulting in a loss of statistical power, Francesca Barone (University of Birmingham, UK) and co-investigators believe that their findings support “targeting the PI3K pathway as a novel therapeutic approach in PSS.”
The study enrolled just 27 of the target 58 people with pSS after facing issues such as competition with other studies, requirement for salivary gland biopsies, and a limit on the number of concomitant medications allowed due to safety concerns related to potential interactions.
Nonetheless, the researchers report in Rheumatology that the 13 individuals randomly assigned to receive seletalisib 45 mg/day experienced numerically greater improvements in the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score from baseline to week 12 than the 14 participants who received placebo, at mean reductions of 5.4 versus 2.8 points, and a nonsignificant treatment difference of 2.6 points.
In addition, more patients in the seletalisib compared with the placebo group achieved a minimal clinically important improvement in ESSDAI score (>3-point reduction) at weeks 4 (53.8 vs 21.4%), 8 (80.0 vs 30.8%), and 12 (66.7 vs 54.5%).
Patients who received seletalisib also reported a nonsignificant mean 1.55-point greater reduction in the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score from baseline to week 12 than those who received placebo, with the greatest reduction seen for fatigue, at a significant 2.48 points.
There were no significant changes in saliva and tear flow in either group, but Barone et al observed greater reductions from baseline to week 12 in mean immunoglobulin (Ig) levels among the patients who receive seletalisib relative to those who received placebo, at mean differences of 3.53 g/L for IgG and 0.40 g/L for IgM.
Finally, minor salivary gland biopsies showed greater reductions in size, overall percentage of inflammatory infiltration, and cellular organization of mononuclear inflammatory cell foci with seletalisib compared with placebo treatment.
“This suggests that PI3K-[delta] inhibition affects cell aggregation in the salivary glands, compromising the process of T/B cell activation, as reflected in the observed decrease in immunoglobulins,” Barone and team remark.
They also note that the majority (76.9%) of individuals who received seletalisib experienced a treatment-related adverse event (AE), most commonly diarrhea. There were three serious AEs reported in the seletalisib group and one in the placebo group, while five patients and one patient, respectively, discontinued treatment due to AEs.
Barone and co-authors conclude: “Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS.”
They add: “Larger studies with specific PI3K-[delta] inhibitors and potentially with patient stratification could be considered in the future.”
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