Leniolisib for Immune Dysregulation in PIDs

Inclusion Criteria:

1. Subjects 12 to 75 years of age.

2. Diagnosed with a PID due to disease-causing pathogenic or likely pathogenicvariant(s) in the following genes: SOCS1, PTEN, CTLA4, NFKB1 (only those variantsleading to NFKB pathway activation), or FAS (germline or somatic), or diagnosed withRAS 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 ashemoglobin <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 lymphnode (long axis >1.5 cm) as per Cheson methodology

• GLILD or other PID-related ILD with quantifiable CT chest imaging findingsevident 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 firstdosing .

• Rituximab or other B-cell depleting antibodies, belimumab, cyclophosphamide, oralemtuzumab within 6 months prior to first dosing.

• Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine,methotrexate, tacrolimus, ruxolitinib, or other JAK inhibitors within 3 weeksprior to first dosing.

• Corticosteroids above 25 mg prednisone or equivalent per day within 2 weeksprior to first dosing.

• Other immunosuppressive agents expected to have a significant impact on immunecell number or function.

• Abatacept is allowed during study if the subject has been receiving a stabledosing regimen for more than 3 months prior to first dosing.

3. Subject is receiving concurrent treatment with another investigational therapy oruse of another investigational therapy less than 4 weeks or 5 half-lives (whicheveris longer) prior to first dosing.

4. History of hypersensitivity to the study drug or to drugs of similar chemicalclasses.

5. Current use of medication known to be a strong inhibitor, or moderate or stronginducer, 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 asignificant risk of safety for subjects participating in the study

8. History of acquired immunodeficiency diseases, including a positive HIV test resultat screening.

9. Uncontrolled chronic or recurrent infectious disease (except those considered to becharacteristic of a PID) or evidence of tuberculosis infection

10. Any surgical or medical condition which may jeopardize the subject in case ofparticipation 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 hepatitisC PCR, or positive hepatitis C antibody result at screening.

12. Administration of live vaccines starting from 6 weeks before first dose of studymedication.

13. Subject has a previous diagnosis of lymphoma within 1 year of the first dose ofstudy medication.

14. Subject has a history of malignancy (except lymphoma) within 3 years before thefirst 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 EBVrelated 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 4weeks prior to the first dose or has a planned or expected major surgical procedureduring the study period.

18. Pregnant or nursing (lactating) individuals,.

19. Individuals of child-bearing potential, unless they are using highly effectivemethods of contraception.