Trial Summary
What is the purpose of this trial?This study is an exploratory, non-randomized, open-label, within-patient dose escalation study. The primary objective is to assess safety and tolerability of leniolisib. Secondary objectives include assessments of PK/PD, and to explore clinical efficacy measures with administration of three different dose levels of leniolisib.
What safety data is available for leniolisib in treating primary immunodeficiency?Leniolisib, also known as Joenja or CDZ173, has been evaluated for safety in a phase 3 trial for activated PI3Kδ syndrome (APDS). In this trial, leniolisib was well tolerated, with fewer treatment-related adverse events reported compared to placebo. Most adverse events were mild (grades 1-2). Unlike other PI3Kδ inhibitors, leniolisib did not cause severe immune-mediated adverse events such as colitis, neutropenia, or hepatotoxicity, which have been observed with other treatments. This suggests leniolisib has a favorable safety profile for treating APDS.35678
What data supports the idea that Leniolisib for Primary Immunodeficiency (also known as: Leniolisib, Joenja, CDZ173) is an effective treatment?The available research shows that Leniolisib is effective for treating Primary Immunodeficiency, specifically activated PI3Kδ syndrome (APDS). In a study with 31 patients, those who took Leniolisib had a significant reduction in the size of their lymph nodes and an increase in certain immune cells compared to those who took a placebo. Another study with 6 patients showed that Leniolisib reduced the size of lymph nodes and spleen by about 39% and 40%, respectively, and improved other immune system markers. These results suggest that Leniolisib helps manage symptoms and improves immune function in people with APDS.24567
Is the drug Leniolisib a promising treatment for primary immunodeficiency?Yes, Leniolisib is a promising drug for primary immunodeficiency, specifically for a condition called activated PI3Kδ syndrome (APDS). It has been shown to improve immune function by reducing lymph node size and increasing important immune cells. It is well tolerated and has been approved for use in patients aged 12 and older.15678
Do I need to stop my current medications to join the trial?The trial requires stopping certain medications before joining. You must stop using mTOR inhibitors, PI3Kδ inhibitors, and other specified immunosuppressive drugs within 3 weeks before the first dose. Rituximab and similar drugs must be stopped 6 months prior. Corticosteroids above 25 mg per day should be stopped 2 weeks before. Abatacept is allowed if you've been on a stable dose for over 3 months. Check with the trial team for other specific medications.
Eligibility Criteria
This trial is for people aged 12-75 with Primary Immunodeficiency (PID) who have certain blood issues, enlarged spleen or lymph nodes, specific blood pressure and heart rate ranges, lung disease related to PID, and genetic mutations linked to PID. It's not suitable for those with conditions that could explain their symptoms like iron-deficiency.Inclusion Criteria
I am between 12 and 75 years old.
I have a genetic disorder affecting my immune system or a specific type of blood disorder not including juvenile myelomonocytic leukemia.
Exclusion Criteria
I have successfully undergone a stem-cell transplant.
I have used certain medications that suppress my immune system.
I am not pregnant, nursing, or I use effective birth control if of child-bearing age.
I am taking medication that affects the CYP3A enzyme.
I am currently taking medication that affects specific body processes.
I have a long-term infection that isn't under control.
I have an uncontrolled EBV-related condition after a transplant.
Treatment Details
The study tests Leniolisib at three different doses in patients with immune dysregulation due to PIDs. It's an open-label trial where everyone knows what treatment they're getting. The main goal is safety; other goals include how the body processes the drug and its effectiveness.
1Treatment groups
Experimental Treatment
Group I: LeniolisibExperimental Treatment1 Intervention
All subjects participating will receive Leniolisib film-coated tablets (FCTs) at a starting dose of 10 mg BID for 4 weeks, followed by 30 mg BID for 4 weeks, and then 70 mg BID for 12 weeks.
Leniolisib is already approved in United States for the following indications:
🇺🇸 Approved in United States as Joenja for:
- Activated phosphoinositide 3-kinase delta syndrome (APDS)
Find a clinic near you
Research locations nearbySelect from list below to view details:
National Institute of HealthBethesda, MD
Loading ...
Who is running the clinical trial?
Pharming Technologies B.V.Lead Sponsor
Aixial GroupCollaborator
Aixial GroupIndustry Sponsor
References
Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. [2021]Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics.
Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. [2021]Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.
Duvelisib for the treatment of chronic lymphocytic leukemia. [2022]Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III 'DUO' trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab.
Shorter Diagnostic Delay in Polish Adult Patients With Common Variable Immunodeficiency and Symptom Onset After 1999. [2021]Common variable immunodeficiency (CVID) is the most clinically significant primary antibody immunodeficiency recognized in adulthood. Previously published data have shown an average diagnostic delay of 10 years for Polish adult patients with CVID. In the current study, we aimed to analyze the current diagnostic delay of adult patients with CVID in Poland. To this end, we identified patients from four immunological centers specialized in the care of adult patients with primary immunodeficiencies (PID). Demographic and clinical data of patients were collected using an internet database. We identified 103 adult patients (F:M 44.7%:55.3%) in Poland with CVID. The median age at onset of symptoms was 24 (0-66), 33 (4-70) at diagnosis, and 37 (18-73) years at the time of analysis. The median diagnostic delay for the entire study population was 6 (0-57) years. However, this delay was higher in patients with symptom onset before the year 2000 than after the year 1999 [15 (0-57) vs. 3 (0-19) years; p < 0.001]. Comparing patients (median ≤ 6 years, N = 53) with short diagnostic delay (SDD) and those (median > 6 years, N = 50) with long diagnostic delay (LDD), the LDD group had a statistically significant higher incidence of infections of the lower respiratory tract before diagnosis (90.0 vs. 71.70%). During the entire observation period, cytopenias (44.00 vs. 22.64%), granulomatous lesions (28.00 vs. 11.32%), and solid tumors (14.00 vs. 1.89%) were significantly more frequent in the LDD group. In conclusion, we found a significant reduction in the median diagnostic delay in Polish CVID patients with disease onset in the last two decades.
Primary immunodeficiency-related genes in neonatal intensive care unit patients with various genetic immune abnormalities: a multicentre study in China. [2022]The present phenotype-based disease classification causes ambiguity in diagnosing and determining timely, effective treatment options for primary immunodeficiency (PID). In this study, we aimed to examine the characteristics of early-onset PID and proposed a JAK-STATopathy subgroup based on their molecular defects.
A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. [2023]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.
Leniolisib: First Approval. [2023]Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kδ syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren's syndrome has been discontinued. This article summarizes the milestones in the development of leniolisib leading to this first approval for APDS.
PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond. [2023]The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.