Leniolisib for immune dysregulation in CVID

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharming Technologies B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

14 Jul 2025 → ongoing

Decision date (initial)

2025-05-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

To assess safety and tolerability of leniolisib in patients with CVID

Secondary objectives 5

1. To assess the clinical efficacy of leniolisib for lymphoproliferative, autoimmune, and end-organ infiltrative/inflammatory manifestations of immune dysregulation in patients with CVID
2. To assess the impact of leniolisib on leukocyte populations in patients with CVID
3. To assess the impact of leniolisib on B and T cell phenotypic populations of interest in patients with CVID
4. To examine levels of CXCL13 and soluble interleukin-2 receptor (IL-2R)α and assess the impact of leniolisib in patients with CVID
5. To assess the PK of leniolisib in patients with CVID

Conditions and MedDRA coding

Common variable immunodeficiency

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Subject is 12 to 75 years of age (inclusive). a. Specifically at sites located in the United Kingdom subjects must be 18 to 75 years of age (inclusive)
2. 3. Subject has a clinical diagnosis of CVID supported by: a. A low IgG level compared to age-adjusted reference range on 2 or more measurements separated by at least 3 weeks, unless only 1 result was obtained before initiation of IRT. OR If this cannot be documented, subject must have at least ONE of the following: a. Absent isohemagglutinins and/or poor response to vaccines as determined by the Investigator and supported by criteria in Orange, 2012 b. Low class-switched memory B cells less than 2% AND c. Low IgA and/or IgM compared to age-adjusted reference range AND d. No identified secondary causes of hypogammaglobulinemia
3. 4. Patient has completed Inborn Error of Immunity/ PID genetic testing panel at the Screening Visit and a. Lacks an identified pathogenic/likely pathogenic genetic driver for their CVID primary immunodeficiency OR b. Subject has an identified pathogenic/likely pathogenic genetic driver(s) for their CVID limited to the following genes: TNFRSF13B (TACI), TNFRSF13C (BAFFR), CD19, CD20, CD81, CR2 (CD21), LRBA, CTLA4, NFKB1, NFKB2, IKZF1 (excluding variants associated with combined immune deficiency), CARD11 (gain of function), SH3KBP1, SEC61A1 IRF2BP2, CTNNBL1, TWEAK or PTEN. (This inclusion criterion also includes consideration of any other previous clinically obtained sequencing test.)
4. 5. Subject has lymphoproliferation, as evidenced by CT imaging: splenomegaly with craniocaudal spleen measurement >10 cm and/or lymphadenopathy with at least 1 measurable index lymph node (long axis >1.5 cm) as per Cheson methodology.
5. 6. Subject has at least ONE of the following CVID clinical manifestations of immune dysregulation: a. Clinical symptoms related to splenomegaly or lymphadenopathy which interfere with activities of daily living or are associated with chronic pain, dyspnea, functional impairment, or limitations in usual activities b. One or more blood cytopenias related to CVID (and not due to other medical conditions such as iron-deficiency or lead exposure) defined as hemoglobin <10 g/dL, platelet count <100,000/μL, and/or neutrophil count <1,000/μL c. Previous pathologic confirmation of ILD and attributed to CVID by the Investigator with quantifiable CT chest imaging findings evident on baseline CT scan d. Clinical diagnosis of CVID enteropathy or other GI tract diagnosis attributable to CVID by the Investigator which involves the small intestine and meets the following enteropathy criteria: i. Clinical symptoms of GI disease including at least 1 of: abdominal pain or diarrhea at least 3 days of the week for at least 4 weeks or longer, or dependence on supplemental enteral or parenteral nutrition ii. Lacks a clinical diagnosis of Celiac Disease, and negative human leukocyte antigen (HLA)-DQ2 and -DQ8 testing at screening iii. Presence of small bowel villous shortening/atrophy/blunting with or without intraepithelial lymphocytosis noted in a pathology report pertaining to a small bowel biopsy performed within 5 years of enrollment iv. Negative stool PCR Gastrointestinal Profile at screening (If a patient has CVID enteropathy but does not meet items i through iv above, they may still enroll in the study if they meet at least ONE the other CVID clinical manifestations of immune dysregulation; however, they will not be eligible for the optional enteropathy endoscopic evaluation.)
6. 7. At screening, vital signs (systolic and diastolic blood pressure, pulse rate, and oxygen saturation in the absence of any supplemental oxygen) will be assessed in the sitting position after the subject has rested for at least 3 minutes. If the initial assessment yields vital sign parameters outside the defined ranges, a subsequent 2 assessments may be completed. If the average of all 3 repeated vital sign assessments are found within range, the subject is considered to have met this inclusion criterion. Ranges: − Systolic blood pressure 80-159 mm Hg − Diastolic blood pressure 50-109 mm Hg − Pulse rate 50-110 beats per minute (bpm) − Oxygen saturation 93-100%
7. 8. Subjects or their legal representatives (for subjects under the age of 18 years) must be able to communicate with the Investigator and understand and comply with the requirements of the study, including an ability to provide written informed consent before any assessment is performed (through an interpreter if non-English speaking).
8. 2. Subject must have a minimum body weight of 45 kg.

Exclusion criteria 23

1. 1. Laboratory evidence of significant T cell deficiency including CD4+ T cells <200/μL at screening (Spee-Meyer 2019; Malphettes 2009; Seidel 2019).
2. 2. Laboratory evidence of significant NK cell deficiency including NK cells <1% of peripheral blood lymphocytes or less than 50/mcL (Mace 2016; Ebbo 2016).
3. 3. Clinical history of infections suggestive of clinically significant T cell or NK cell deficiency such as Pneumocystis jirovecii, atypical mycobacteria, severe warts, or unusually severe (as determined by the PI) infections with herpesviruses.
4. 4. Presence of uncontrolled chronic/recurrent infectious disease (except those considered to be characteristic of antibody deficiency).
5. 5. Positive blood polymerase chain reaction (PCR) for cytomegalovirus.
6. 6. Evidence of tuberculosis infection as defined by a positive QuantiFERON® TB-Gold test or other IFN-ɣ release assay such as T-SPOT®.TB test at Screening. If the presence of latent tuberculosis is established, treatment should be completed following local guidelines, and based on best clinical care practice.
7. 7. Positive blood cryptococcal antigen
8. 8. Previous or concurrent use of immunosuppressive medication, such as: – Use of an mTOR inhibitor (e.g., sirolimus, everolimus) or a PI3K inhibitor (selective or non-selective PI3K inhibitors) within 3 weeks prior to pre-dose CT scan. − Rituximab or other B cell depleting antibodies, belimumab, cyclophosphamide, or alemtuzumab within 6 months prior to first dosing of study medication. − Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine, methotrexate, tacrolimus, ruxolitinib, or other Janus kinase (JAK) inhibitors within 3 weeks prior to pre-dose CT scan. − Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks prior to pre-dose CT scan. − Immunosuppressive monoclonal or polyclonal antibody therapeutics such as directed against TNF-α, α₄β₇ integrin, IL-6, IL-12/IL-23 and others within 5 half-lives prior to first dosing of study medication − 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 of study medication.  Enteral budesonide is allowed during study if the subject has been receiving a stable dosing regimen for more than 3 months prior to first dosing of study medication.
9. 9. 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 of study medication.
10. 10. History of hypersensitivity to the study drug or to drugs of similar chemical classes.
11. 11. Current use of medication known to be a strong inhibitor, or moderate or strong inducer, of isoenzyme cytochrome P450 CYP3A. Treatment can be discontinued or switched to a different medication prior to starting study treatment.
12. 12. Current use of medications that, to a larger extent, are BCRP, OATP1B1, and/or OATP1B3 substrates.
13. 13. History of HIV or positive test result at screening.
14. 14. 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. The Investigator should make this determination in consideration of the subject’s medical history. Examples of reasons for exclusion include but should not be limited to the following: − Uncontrolled hypertension − Congestive heart failure (New York Heart Association status of class III or IV) − Diagnosis of electrocardiogram (ECG) abnormalities indicating a significant risk of safety − Chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage 3-4) − Chronic need for supplemental oxygen or invasive or non-invasive respiratory support − Major GI tract surgery that may affect drug absorption (such as gastric bypass surgery, gastroenterostomy) − Acute pancreatitis − Liver failure or clinically significant liver disease or dysfunction as indicated by alanine transaminase (ALT) or aspartate transaminase (AST) greater than 2.5 times the upper limit of normal, bilirubin greater than 1.5 times the upper limit of normal, international normalized ratio (INR) greater than 1.5 in the absence of anticoagulation, or presence of diuretic refractory ascites. ▪ Elevation of ALT or AST up to 6 times the upper limit of normal is allowed if elevation is determined to be a consequence of immune dysregulation by the site Principal Investigator and if the elevation has been stable for 3 months prior to enrollment. − History of significant renal injury/renal disease severely affecting renal function or presence of impaired renal function as indicated by estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 estimated using creatinine results.
15. 15. A positive hepatitis B surface antigen (HBsAg), positive hepatitis B PCR, positive hepatitis C PCR, or positive hepatitis C antibody result at screening. − Subjects who are positive for hepatitis B core antibody (HBcAb) but negative for HBsAg and negative for hepatitis B PCR should receive tenofovir or other appropriate therapy while on study if the testing is judged by the Investigator to reflect past infection. It is recommended to have monthly HBsAg and hepatitis B PCR monitoring. Anti-HBcAb positivity may also be observed following immunoglobulin administration and represent passive transfer in which case tenofovir therapy is not indicated, but laboratory monitoring may be considered per the discretion of the Investigator. Patients should end study participation if HBsAg or hepatitis B PCR become positive.
16. 16. Administration of live vaccines (this includes any attenuated live vaccines) starting from 6 weeks before first dose of study medication, during the study, and up to 7 days after the last dose of leniolisib.
17. 17. Subject has a history of malignancy (except lymphoma) within 3 years before the first dose of study medication or has evidence of residual disease from a previously diagnosed malignancy, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
18. 18. Subject has a previous diagnosis of lymphoma that has been treated with chemotherapy, radiotherapy, or transplant within 1 year of the first dose of study medication or is anticipated to require lymphoma treatment within 6 months of the first dose of study medication.
19. 19. Subject has uncontrolled post-transplant lymphoproliferative disease-like Epstein-Barr virus related lymphoproliferative disease.
20. 20. Donation or loss of 400 mL or more of blood within 8 weeks before the first dose of study medication.
21. 21. Subject has had major surgery requiring hospitalization or radiotherapy within 4 weeks prior to the first dose of study medication or has a planned or expected major surgical procedure during the study period.
22. 22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG serum laboratory test.
23. 23. Individuals of child-bearing potential who are physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study medication and for 7 days after stopping study treatment (see Section 5.6.1 for contraception requirements).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Adverse events (AEs; via assessment of vital signs, safety labs, physical exams and overall trial safety monitoring)

Secondary endpoints 14

1. Percent change from baseline in splenomegaly measured by 3D volume and 2D size of spleen
2. Percent change from baseline in lymphoproliferation measured as the SPD in the index lesions selected per the Cheson methodology
3. Percent change from baseline in lymphoproliferation measured as SPD of measurable non-index lesions selected as per the Cheson methodology
4. Hemoglobin over time
5. Platelet count over time
6. Absolute neutrophil count over time
7. Change in CT evidence of ILD evaluated using Hartmann scoring methodology
8. Change in pulmonary function testing, including forced expiratory volume 1 (FEV1), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), diffusion capacity for carbon monoxide (DLCO)
9. Absolute numbers and percentages of leukocyte populations (including lymphocyte subsets) over time
10. Percentages of naïve B cells and CD21low B cells over time
11. Percentage of T regulatory cells over time
12. Levels of CXCL13 over time
13. Levels of soluble IL-2Rα over time
14. Define the PK parameters for leniolisib in patients with CVID

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharming Technologies B.V.

Sponsor organisation

Pharming Technologies B.V.

Address

Darwinweg 24

City

Leiden

Postcode

2333 CR

Country

Netherlands

Scientific contact point

Organisation

Pharming Technologies B.V.

Contact name

Clinical Research Department

Public contact point

Organisation

Pharming Technologies B.V.

Contact name

Clinical Research Department

Third parties 11

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 21 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications