Leniolisib for Immune Dysregulation in PIDs

A Study to Assess Safety and Tolerability, and Explore Efficacy of Leniolisib for Immune Dysregulation in Primary Immunodeficiency Disorders

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Primary Immunodeficiency Disorders (PIDs)
• Intervention / Treatment: Drug: Leniolisib

Detailed Description

Patients ages 12-75 diagnosed with genetically defined PID disorders linked to PI3K signaling. This includes disorders caused by pathogenic variants in SOCS1, PTEN, CTLA4, NFKB1 (variants leading to NFKB pathway activation), FAS (germline or somatic), or RAS-associated leukoproliferative disorder caused by somatic variants in NRAS or KRAS (not juvenile myelomonocytic leukemia [JMML]). All subjects participating will receive leniolisib film-coated tablets (FCTs) with a planned dose regimen consisting of a starting dose of 10 mg twice daily (BID) for 4 weeks, followed by 30 mg BID for 4 weeks, and then 70 mg BID for 12 weeks. Leniolisib dose increase at the individual subject level will occur if no safety or tolerability issues have been identified by the Investigator that precludes the planned dose escalation.

Subjects not continuing leniolisib treatment outside of the current protocol will be followed up, with the EOS visit planned to occur approximately 28 days after last dose of leniolisib.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute of Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects 12 to 75 years of age.
2. Diagnosed with a PID due to disease-causing pathogenic or likely pathogenic variant(s) in the following genes: SOCS1, PTEN, CTLA4, NFKB1 (only those variants leading to NFKB pathway activation), or FAS (germline or somatic), or diagnosed with RAS associated leukoproliferative disorder (and not juvenile myelomonocytic leukemia [JMML]) due to somatic variants in NRAS or KRAS.

3. Subjects must have 1 or more of the following:

   • One or more blood cytopenias related to the underlying PID defined as hemoglobin <10 g/dL, platelet count <100,000/µL, or neutrophil count <1000/µL
   • Splenomegaly evident by CT imaging with craniocaudal spleen measurement >10 cm
   • Lymphadenopathy evident by CT imaging with at least 1 measurable index lymph node (long axis >1.5 cm) as per Cheson methodology
   • GLILD or other PID-related ILD with quantifiable CT chest imaging findings evident on baseline CT scan

4. At screening, vital signs.

   • Systolic blood pressure 80-139 mm Hg
   • Diastolic blood pressure 50-89 mm Hg
   • Pulse rate 50-110 bpm
   • Oxygen saturation 93-100%
5. Subjects or their legal representatives (for subjects under the age of 18 years) must be able to provide written informed consent.

Exclusion Criteria:

1. Subject has had a successful hematopoietic stem-cell transplant (HSCT).

2. Previous or concurrent use of immunosuppressive medication, such as:

   • Use of an mTOR inhibitor or a PI3Kδ inhibitor within 3 weeks prior to first dosing .
   • Rituximab or other B-cell depleting antibodies, belimumab, cyclophosphamide, or alemtuzumab within 6 months prior to first dosing.
   • Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine, methotrexate, tacrolimus, ruxolitinib, or other JAK inhibitors within 3 weeks prior to first dosing.
   • Corticosteroids above 25 mg prednisone or equivalent per day within 2 weeks prior to first dosing.
   • Other immunosuppressive agents expected to have a significant impact on immune cell number or function.
   • Abatacept is allowed during study if the subject has been receiving a stable dosing regimen for more than 3 months prior to first dosing.
3. Subject is receiving concurrent treatment with another investigational therapy or use of another investigational therapy less than 4 weeks or 5 half-lives (whichever is longer) prior to first dosing.
4. History of hypersensitivity to the study drug or to drugs of similar chemical classes.
5. Current use of medication known to be a strong inhibitor, or moderate or strong inducer, of isoenzyme P450 CYP3A.
6. Current use of medications that act as BCRP, OATP1B1, and OATP1B3 substrates.
7. Subject has a history or current electrocardiogram (ECG) abnormalities indicating a significant risk of safety for subjects participating in the study
8. History of acquired immunodeficiency diseases, including a positive HIV test result at screening.
9. Uncontrolled chronic or recurrent infectious disease (except those considered to be characteristic of a PID) or evidence of tuberculosis infection
10. Any surgical or medical condition which may jeopardize the subject in case of participation in the study, or might significantly alter the absorption, distribution, metabolism, or excretion of drugs.
11. A positive hepatitis B surface antigen, positive hepatitis B PCR, positive hepatitis C PCR, or positive hepatitis C antibody result at screening.
12. Administration of live vaccines starting from 6 weeks before first dose of study medication.
13. Subject has a previous diagnosis of lymphoma within 1 year of the first dose of study medication.
14. Subject has a history of malignancy (except lymphoma) within 3 years before the first dose of study medication, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
15. Subject has uncontrolled post-transplant lymphoproliferative disease (PTLD)-like EBV related lymphoproliferative disease.
16. Donation or loss of 400 mL or more of blood within 8 weeks before the first dose.
17. Subject has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first dose or has a planned or expected major surgical procedure during the study period.
18. Pregnant or nursing (lactating) individuals,.
19. Individuals of child-bearing potential, unless they are using highly effective methods of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leniolisib; 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.	Drug: Leniolisib; The doses selected will range from 10 to 70 mg twice daily (BID) (resulting in total daily doses ranging from 20 to 140 mg per day).; Other Names: Joenja

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Treatment-emergent adverse events (TEAEs), Serious Adverse Events (SAEs) , and Adverse Events (AEs)	• To assess the number of AEs/SAEs and number of participants with AEs/SAEs	From Baseline to the end of 20 weeks of Treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the impact of leniolisib on hemoglobin counts in PID disorders linked to PI3K	• Hemoglobin over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on platelet counts in PID disorders linked to PI3K	• Platelet count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on absolute neutrophil counts in PID disorders linked to PI3K	• Absolute neutrophil count over time	From Baseline to the end of 20 weeks of Treatment
To assess the PK of leniolisib in PID disorders linked to PI3K	• PK parameters for leniolisib defined by Cmax	From Baseline to the end of 20 weeks of Treatment
To assess the PK of leniolisib in PID disorders linked to PI3K	• PK parameters for leniolisib defined by Tmax	From Baseline to the end of 20 weeks of Treatment
To assess the PK of leniolisib in PID disorders linked to PI3K	• PK parameters for leniolisib defined by t1/2	From Baseline to the end of 20 weeks of Treatment
To assess the PK of leniolisib in PID disorders linked to PI3K	• PK parameters for leniolisib defined by AUC (0-t)	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on lymphocyte PI3K/AKT/mTOR pathway activity in PID disorders linked to PI3K	• Percent change in pAKT and/or pS6 in B cells and/or T cells, under resting and stimulated conditions, at different dose levels of leniolisib relative to baseline pAKT/pS6 levels, as feasible	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on PID-related ILD in PID disorders linked to PI3K	• Change in CT evidence of GLILD or other PID-related ILD evaluated using Hartmann scoring methodology	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on PFTs in PID disorders linked to PI3K	• Change in forced expiratory volume 1 (FEV1)	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on PFTs in PID disorders linked to PI3K	• Change in forced vital capacity (FVC)	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on PFTs in PID disorders linked to PI3K	• Change in total lung capacity (TLC)	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on PFTs in PID disorders linked to PI3K	• Change in diffusing capacity (DLCO)	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on lymphoproliferation in PID disorders linked to PI3K	Percent change from baseline in lymphadenopathy measured as the sum of product of diameters (SPD) in the index lesions selected per the Cheson methodology; Percent change from baseline in lymphadenopathy measured as SPD of measurable non-index lesions selected as per the Cheson methodology	From Baseline to the end of 20 weeks of Treatment
To assess the clinical efficacy of leniolisib on splenomegaly in PID disorders linked to PI3K	• Percent change from baseline in splenomegaly measured by three-dimensional (3D) volume and bi-dimensional (2D) size of spleen	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• White blood cell count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• Absolute monocyte count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• Absolute lymphocyte count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• Absolute eosinophil count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• Absolute basophil count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• CD4+ T cell count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• CD8+ T cell count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• Natural killer (NK) cell count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on white blood cell counts in PID disorders linked to PI3K	• B cell count over time	From Baseline to the end of 20 weeks of Treatment
To assess the impact of leniolisib on B cell and T cell phenotypic populations of interest in PID disorders linked to PI3K	• Percentages of naïve B cells, CD21lo B cells and T regulatory cells over time	From Baseline to the end of 20 weeks of Treatment
To examine levels of CXCL13 and soluble IL-2Rα and assess the impact of leniolisib in PID disorders linked to PI3K	Levels of CXCL13 over time; Levels of soluble IL-2Rα over time	From Baseline to the end of 20 weeks of Treatment

Collaborators and Investigators

• Sponsor: Pharming Technologies B.V.
• Collaborators: Aixial Group
• Investigators: Principal Investigator: Gulbu Uzel, M.D., National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Hassan C, Ponstein Y, Hanssen R, Thorneloe KS, Marsh RA, Rao VK. Leniolisib reduced lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome. J Hum Immun. 2025 Nov 17;2(1):e20250125. doi: 10.70962/jhi.20250125. eCollection 2026 Jan 5.

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: July 17, 2024
• First Submitted That Met QC Criteria: August 8, 2024
• First Posted (Actual): August 12, 2024

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Immune System Diseases; Immunologic Deficiency Syndromes; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Primary Immunodeficiency Diseases; leniolisib
• Other Study ID Numbers: LE 7201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No