Seletalisib Shows Trend Toward Easing Primary Sjögren’s in Phase 2 Trial

Using the PI3K-delta inhibitor seletalisib as an add-on to standard treatment showed a trend toward easing disease activity and  dryness, and significantly lowered patient-reported fatigue in people with primary Sjögren’s syndrome (pSS), according to data from a Phase 2 trial.

Findings from this proof-of-concept study (NCT02610543) — which was stopped early due to enrollment challenges that left the study underpowered — suggest that seletalisib or other PI3K-delta blockers may effectively treat Sjögren’s syndrome. Side effects reported with treatment, however, may be a concern.

The study, “A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome,” was published in the journal Rheumatology.

PI3K-delta is a protein that has attracted interest as a target for pSS due to its activity in immune B-cells; a similar inhibitor of this protein (idelalisib) is approved to treat some blood cancers. B-cells can affect a person’s ability to produce fluids like tears and saliva by wrongly attack secretory glands. These attacks can also result in joint pain, a persistent cough, and chronic fatigue.

Following promising preclinical results in mice, researchers at UCB Pharma designed the study to assess seletalisib’s safety, tolerability, and early efficacy in adults with moderate-to-severe pSS.

Conducted across 16 sites in France, Italy, Spain, Sweden, and the U.K., the trial enrolled a total of 27 patients out of 51 screened. Those enrolled were randomly assigned to oral seletalisib or a placebo once daily for 12 weeks, in addition to their current Sjögren’s treatment.

Do to difficulties in enrolling participants — reasons cited included other studies of interest, required biopsies, and number of study visits — that trial had a significant loss of statistical power. In other words, rather than having a confidence of 80% that results were not due to chance, this confidence was 36%.

Eight patients on seletalisib and 12 of those on placebo completed the study; about 38% of the seletalisib group left due to treatment side effects. Most of those finishing were women, with an average age of 56.4, and they had been diagnosed a median of 6.1 years earlier.

The trial’s main efficacy goal was to determine if patients on seletalisib had greater reductions in disease activity — assessed as changes in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) from baseline (study’s start) to week 12 — than those assigned to placebo.

Secondary measures included changes in ESSDAI at weeks four and eight, changes in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) — a measure of patient-reported symptoms — and saliva and tear production. Safety, tolerability, and changes in salivary glands were also assessed.

Results showed a trend toward lower disease activity in those given seletalisib for 12 weeks compared with a placebo: a 2.59-point difference in ESSDAI scores.

A greater proportion of patients on seletalisib than placebo (66.7% vs. 54.5%) also attained at least a three-point reduction in these scores — the minimum necessary for a clinically important improvement — over the 12-week period.

Seletalisib also lowered scores of patient-reported symptoms more than placebo, although only changes in scores related to fatigue were considered statistically significant. Visual analog scale and Profile of Fatigue and Discomfort–Sicca Symptoms Inventory (PROFAD-SSI) scores — two patient-reported scales — also showed improvements in feelings of fatigue.

The investigators did not observe significant changes in saliva or tear production between the two groups, but blood concentrations of IgG and IgM — two antibodies that can be produced at high levels in Sjögren’s patients — showed greater reductions in patients taking seletalisib.

People in this group also reported less overall dryness, dryness of the mouth, pain in general, and pain during sexual intercourse. However, seletalisib was no better than placebo at reducing vaginal dryness, the production of the anti-SSA and anti-SSB Sjögren’s antibodies, or the levels of complement system proteins — a part of the immune system often active in autoimmune disorders.

Of the 13 patients assigned to seletalisib, 10 reported undesirable side effects and five left the trial. Three of 14 placebo-group patients also reported drug-related side effects, with one leaving the trial.

The most common was diarrhea, reported by five patients taking seletalisib. Side effects causing patients on seletalisib to discontinue the study were diarrhea, increased hepatic (liver) enzyme, tissue swelling, hives, and skin reactions; in the case of the placebo patient, it was impaired kidney function.

“The most common AE [adverse event] in the seletalisib group was diarrhoea, previously described as a very common AE in patients receiving the PI3Kd inhibitor idelalisib for chronic lymphocytic leukaemia and follicular lymphoma,” the researchers wrote. “In our study, the gastrointestinal side effects were of moderate severity in most patients.”

Investigators examined salivary gland biopsies to see if seletalisib lowered the amount of immune cells infiltrating these glands. Both infiltration and the sizes of patients’ glands diminished among patients on seletalisib, as compared with those on placebo. Most of these patients were also those who reached the minimal clinically important change in ESSDAI scores.

The researchers conducting the study felt the results warrant further investigation.

“While not meeting all efficacy end points due to enrolment challenges, this study supports targeting the PI3K pathway as a novel therapeutic approach in pSS,” the investigators wrote.