Interim analysis:Open-label extension study of leniolisib for patients with APDS

Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Objective: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Methods: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Results: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P =.004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Conclusions: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. ClinicalTrials.gov identifier: NCT02859727.</p

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was −0.25 (−0.38, −0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm 3], −186; 95% CI, −297 to −76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173

Influence of interspecific competition and landscape structure on spatial homogenization of avian assemblages

Human-induced biotic homogenization resulting from landscape change and increased competition from widespread generalists or ` winners', is widely recognized as a global threat to biodiversity. However, it remains unclear what aspects of landscape structure influence homogenization. This paper tests the importance of interspecific competition and landscape structure, for the spatial homogeneity of avian assemblages within a fragmented agricultural landscape of eastern Australia. We used field observations of the density of 128 diurnal bird species to calculate taxonomic and functional similarity among assemblages. We then examined whether taxonomic and functional similarity varied with patch type, the extent of woodland habitat, land-use intensity, habitat subdivision, and the presence of Manorina colonies (a competitive genus of honeyeaters). We found the presence of a Manorina colony was the most significant factor positively influencing both taxonomic and functional similarity of bird assemblages. Competition from members of this widespread genus of native honeyeater, rather than landscape structure, was the main cause of both taxonomic and functional homogenization. These species have not recently expanded their range, but rather have increased in density in response to agricultural landscape change. The negative impacts of Manorina honeyeaters on assemblage similarity were most pronounced in landscapes of moderate land-use intensity. We conclude that in these human-modified landscapes, increased competition from dominant native species, or 'winners', can result in homogeneous avian assemblages and the loss of specialist species. These interacting processes make biotic homogenization resulting from land-use change a global threat to biodiversity in modified agro-ecosystems

Incidence of competitors and landscape structure as predictors of woodland-dependent birds

Globally, modification of landscapes for agriculture has had a strong influence on the distribution and abundance of biota. In particular, woodland-dependent birds are under threat across agricultural landscapes in Britain, North America and Australia, with their decline and extirpation attributed to the loss and fragmentation of habitat. Other native species have become over-abundant in response to anthropogenic landscape change and have strong interactive effects on avian assemblage structure. In eastern Australia, the hyper-aggressive noisy miner (Manorina melanocephala) often dominates woodlands in agricultural landscapes through interspecific competition, resulting in declines of species richness of woodland-dependent birds. We aimed to determine the relative influence and importance of interspecific competition, in situ habitat structure and landscape structure for woodland-dependent bird species at the landscape level. We recorded species-specific landscape incidence of woodland-dependent birds in 24 agricultural-woodland mosaics (25 km(2)) in southern Queensland, Australia. We selected extensively cleared landscapes (10-23 % woodland cover) where fragmentation effects are expected to be greatest. We applied generalised linear models and hierarchical partitioning to quantify the relative importance of the landscape-level incidence of the noisy miner, mistletoe abundance, shrub cover, woodland extent, woodland subdivision and land-use intensity for the incidence of 46 species of woodland birds at the landscape-scale. The landscape-level incidence of the noisy miner was the most important explanatory variable across the assemblage. Both in situ habitat structure and landscape structure were of secondary importance to interspecific aggression, although previous research suggests that the increasing incidence of the noisy miner in fragmented agricultural landscapes is itself a consequence of anthropogenic changes to landscape structure. Species' responses to fragmentation varied from positive to negative, but complex habitat structure had a consistently positive effect, suggesting in situ restoration of degraded habitats could be a conservation priority. Landscape wide conservation of woodland-dependent bird populations in agricultural landscapes may be more effective if direct management of noisy miner populations is employed, given the strong negative influence of this species on the incidence of woodland-dependent birds among landscapes