A long-term study of leniolisib in people with APDS found that modeled infection rates were 25% lower for every additional year of treatment. The pattern covered both overall infections and respiratory infections, but it is an association within a treated group, not proof that leniolisib caused infections to fall.
The single-arm, open-label extension followed 37 people with genetically confirmed APDS who were at least 12 years old. They received leniolisib at 70 mg twice daily and entered from earlier dose-finding or randomized trials, or from studies of other PI3Kδ inhibitors. The latest OLE visit was on January 30, 2025. Twenty-six participants had previously received leniolisib.
The signal appeared over years
Median leniolisib exposure was 4.3 years, ranging from 1.2 to 7.0 years, and 22 patients had at least four years of exposure. Three completed the extension as planned, six discontinued, and 31 continued leniolisib after the OLE. Later outcomes after the extension were not available within this study, and there was no concurrent comparison group.
Infection trends and treatment burden
By the end of the extension, the study had recorded 181 infections in 31 patients, or 84% of the group. There were 120 respiratory infections in 28 patients, or 76%. The analysis used follow-up time to model annual trends and estimated a 25% lower rate for both overall and respiratory infections with each additional treatment year. Confidence intervals were not reported, and patient-level variation was not characterized.
Treatment-related support also appeared to decline. At the start of the extension, 27 patients, or 73%, were receiving immunoglobulin replacement therapy, known as IRT. Ten stopped it, and two achieved at least a 25% reduction. Among patients followed for at least one year, IRT consumption fell 11% per treatment year. In a five-year subgroup of 10 patients, annual use fell from 331.8 grams in year one to 173.2 grams in year five, a 48% reduction. Antibiotic use declined 2% per year and 20% between years one and five, but the annual antibiotic trend was statistically uncertain.
Quality of life and biological measures
Quality-of-life measures moved in the same direction. Before treatment in the extension, 23 of 32 patients, or 72%, reported low general health. Their SF-36 general-health score, a measure used to assess quality of life, increased by 8.5 points. Among nine patients with low vitality scores, seven reached at least 45. Eight of 13 patients with below-normal physical component scores and eight of 13 with below-normal mental component scores also reached at least 45. Patient and physician global disease-activity assessments fell 37% and 81%, respectively.
Immune measurements showed several B-cell measures reaching reference ranges, while elevated IgM levels normalized. Among the 24 patients whose naïve B-cell levels were below 48% at baseline, 20 met the study's responder threshold of at least a 25% increase. Naïve T-cell levels remained below the reference range. These are laboratory markers, not direct measures of clinical events.
Imaging-based measures of lymph-node and spleen enlargement also decreased. The study's mean lymph-node size measure fell 50% from baseline among 30 patients, with mean size decreasing by 8.13 square centimetres. Spleen three-dimensional volume fell 36% among 31 patients. Among those with enlarged nodes, 24 of 30, or 80%, met the study's responder threshold; among those with enlarged spleens, 16 of 24, or 67%, did so. Imaging was optional, and missing scans limited this analysis.
What the study can and cannot show
The safety results were based on prolonged exposure but varied follow-up. Adverse events were reported in 34 patients, or 92%, and the paper reported that 86.5% were grade 1. Serious adverse events occurred in 10 patients, or 27%, and none was judged related to leniolisib. The discussion also reported that two patients stopped treatment because of adverse events, five patients, or 14%, had treatment-related events, none of them serious, and fewer than 30% had grade 3 or greater events.
The extension was single-arm, and most outcomes were analyzed descriptively, so it cannot establish that leniolisib caused the observed changes. Participants came from prior trials or other PI3Kδ-inhibitor studies, and that selection may limit how broadly the findings apply. Follow-up after patients continued treatment outside the extension was unavailable, optional or missing imaging limited the lymphoproliferation results, and patients younger than 12 were not studied.
Novartis designed, oversaw and analyzed the study. Pharming acquired leniolisib rights in 2019 and took over full trial management in December 2022. The funding section named Novartis Pharmaceuticals. Disclosures reported Pharming-related relationships, including a sponsor employee with a pending patent and an author's ongoing leniolisib trials; no other disclosures were reported.
Paper data and sources
Original title: Open-label extension study of leniolisib in activated PI3Kδ syndrome: Long-term efficacy and safety
Authors: Rao V, Šedivá A, Dalm V et al.
Journal/Repository: Journal of human immunity
Status: Peer-reviewed
First online: 2026-10-14
DOI: Not available
Original paper · Full text