Leniolisib 70mg tablets

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 [cm3], -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.

Abstract licence: CC BY-NC-ND 4.0

Abstract Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: –1.09 g/L; 95% CI: –1.78, –0.39, P = 0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden.

Abstract licence: CC BY 4.0

Purpose Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare inborn error of immunity, characterised by immune deficiency and dysregulation. In a randomised controlled trial (RCT; NCT02435173) and open-label extension (OLE; NCT02859727), leniolisib, a selective PI3Kδ inhibitor, was efficacious and well-tolerated in individuals with APDS. These trials suggested some improvements with leniolisib in health-related quality of life (HRQoL) using generic instruments, with other anecdotal evidence also describing improvements in specific domains. Here, all available qualitative data relating to treatment experience were systematically assessed to evaluate any perceived impacts of leniolisib on patients’ lives. Methods Changes in APDS-related symptoms and patient HRQoL were assessed using unsolicited qualitative data captured from 36 leniolisib-treated individuals: RCT and OLE clinician-recorded, open-text patient narratives (n=31); case reports (n=4); standalone qualitative study conducted with APDS patient/caregiver interviews/narratives (n=1). Results Improvements in APDS-related symptoms and HRQoL were reported following treatment with leniolisib: 86.1% (31/36) of individuals mentioned improvements in ≥1 symptom/HRQoL impact. Of these, 87.1% (27/31) explicitly attributed ≥1 improvement to leniolisib. One-third (12/36) of individuals explicitly attributed improvements in fatigue/energy to leniolisib. This was associated with reported HRQoL improvements explicitly attributed to leniolisib: physical activity (33.3% [12/36]), work/school performance/attendance (13.9% [5/36]) and travel ability (8.3% [3/36]). Moreover, 36.1% (13/36) of participants explicitly attributed improvements in their overall wellbeing to leniolisib. Conclusion As data were unsolicited and baseline symptoms/HRQoL were not available, results may not represent all changes experienced, and is not possible to determine the amount of change in symptoms/HRQoL associated with leniolisib. Nevertheless, these analyses indicate that participants with APDS experienced improvements in symptoms and overall wellbeing following treatment with leniolisib.

Abstract licence: CC BY 4.0

Phosphoinositide 3-kinases (PI3Ks) are ubiquitous enzymes, that regulate different cellular functions, most involved in pathogenesis and progression of several oncological diseases. Indeed, some PI3K inhibitors have been approved for blood cancers, such as lymphoma. Interestingly, leniolisib, a selective PI3Kδ kinase inhibitor, has been approved for the rare disease Activated Phosphoinositide 3-kinase Delta Syndrome (APDS). Activation of PI3K/AKT signaling is downstream to VEGF-A pro-angiogenic signaling, detrimental in diabetic retinopathy progression, a microvascular complication of diabetes mellitus. Recently, a report evidenced that inhibition of class IA PI3K (PI3Kδ) delivered beneficial effects in an in-vivo model of diabetic retinopathy. We hereby explored the implication of PI3K signaling in diabetic retinopathy. Moreover, we reviewed the current literature to highlight molecular features of class I PI3K selective inhibitors, to further guide the design of novel selective and safe drugs targeting PI3Kδ, for management of diabetic retinopathy or other retinal proliferative diseases.

Abstract licence: CC BY