Leniolisib for Immune Dysregulation in CVID

Inclusion Criteria:

1. Subject is 12 to 75 years of age (inclusive). a. Specifically at sites located in the United Kingdom subjects must be 18 to 75years of age (inclusive)

2. Subject must have a minimum body weight of 45 kg

3. Subject has a clinical diagnosis of CVID supported by all of the following (a thruc):

4. A low IgG level compared to age-adjusted reference range [OR if this cannot bedocumented, subject must have one of the following: i) absent isohemagglutininsand/or poor response to vaccines; or ii) Low class-switched memory B cells lessthan 2%]

5. Low IgA and/or IgM compared to age-adjusted reference range

6. No identified secondary causes of hypogammaglobulinemia

7. Inborn Errors of Immunity/ PID Panel testing:

8. Lacks an identified pathogenic/likely pathogenic genetic driver for their CVIDprimary immunodeficiency OR

9. Subject has an identified pathogenic/likely pathogenic genetic driver(s) fortheir CVID limited to the following genes: TNFRSF13B (TACI), TNFRSF13C (BAFFR),CD19, CD20, CD81, CR2 (CD21), LRBA, CTLA4, NFKB1, NFKB2, IKZF1 (excludingvariants associated with combined immune deficiency), CARD11 (gain offunction), SH3KBP1, SEC61A1 IRF2BP2, CTNNBL1, TWEAK or PTEN.

10. Subject has lymphoproliferation, as evidenced by CT imaging: splenomegaly withcraniocaudal spleen measurement >10 cm and/or lymphadenopathy with at least 1measurable index lymph node (long axis >1.5 cm) as per Cheson methodology.

11. Subject has at least ONE of the following CVID clinical manifestations of immunedysregulation:

12. Clinical symptoms related to splenomegaly or lymphadenopathy which interferewith activities of daily living or are associated with chronic pain, dyspnea,functional impairment, or limitations in usual activities

13. One or more blood cytopenias related to CVID (and not due to other medicalconditions such as iron-deficiency or lead exposure) defined as hemoglobin <10g/dL, platelet count <100,000/µL, and/or neutrophil count <1,000/µL

14. Previous pathologic confirmation of ILD and attributed to CVID by theInvestigator with quantifiable CT chest imaging findings evident on baseline CTscan

15. Clinical diagnosis of CVID enteropathy or other GI tract diagnosis attributableto CVID by the Investigator which involves the small intestine and meets thefollowing enteropathy criteria: i. Clinical symptoms of GI disease including at least 1 of: abdominal pain ordiarrhea at least 3 days of the week for at least 4 weeks or longer, or dependenceon supplemental enteral or parenteral nutrition ii. Lacks a clinical diagnosis ofCeliac Disease, and negative human leukocyte antigen (HLA)-DQ2 and -DQ8 testing atscreening iii. Presence of small bowel villous shortening/atrophy/blunting with orwithout intraepithelial lymphocytosis noted in a pathology report pertaining to asmall bowel biopsy performed within 5 years of enrollment iv. Negative stool PCRGastrointestinal Profile at screening

16. At screening, vital signs. Ranges: Systolic blood pressure 80-159 mm Hg Diastolic blood pressure 50-109 mm Hg Pulserate 50-110 beats per minute (bpm) Oxygen saturation 93-100%

17. 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 therequirements of the study, including an ability to provide written informed consent.

Exclusion Criteria:

1. Laboratory evidence of significant T cell deficiency including CD4+ T cells <200/uL.

2. Laboratory evidence of significant NK cell deficiency including NK cells <1% ofperipheral blood lymphocytes or less than 50/mcL.

3. Clinical history of infections suggestive of clinically significant T cell or NKcell deficiency such as Pneumocystis jirovecii, atypical mycobacteria, severe warts,or unusually severe (as determined by the PI) infections with herpesviruses.

4. Presence of uncontrolled chronic/recurrent infectious disease (except thoseconsidered to be characteristic of antibody deficiency).

5. Positive blood polymerase chain reaction (PCR) for cytomegalovirus.

6. Evidence of tuberculosis infection

7. Positive blood cryptococcal antigen

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

• Use of an mTOR inhibitor or a PI3K inhibitor within 3 weeks.

• Rituximab or other B cell depleting antibodies, belimumab, cyclophosphamide, oralemtuzumab within 6 months.

• Cyclosporine A, mycophenolate mofetil, 6-mercaptopurine, azathioprine,methotrexate, tacrolimus, ruxolitinib, or other Janus kinase (JAK) inhibitorswithin 3 weeks.

• Glucocorticoids above 25 mg prednisone or equivalent per day within 2 weeks

• Immunosuppressive monoclonal or polyclonal antibody therapeutics such asdirected against TNF-alpha, α₄β₇ integrin, IL-6, IL-12/IL-23 and others within 5 half-lives

• 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 .

• Enteral budesonide is allowed during study if the subject has been receiving astable dosing regimen for more than 3 months.

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

10. HIstory of hypersensitivity to the study drug or to drugs of similar chemicalclasses.

11. Current use of medication known to be a strong inhibitor, or moderate or stronginducer, of isoenzyme cytochrome P450 CYP3A.

12. Current use of medications that, to a larger extent, are BCRP, OATP1B1, and/orOATP1B3 substrates.

13. History of HIV or positive test result at screening.

14. Any surgical or medical condition which may jeopardize the subject in case ofparticipation in the study.

• Chronic need for supplemental oxygen or invasive or non-invasive respiratorysupport.

• Liver failure or clinically significant liver disease or dysfunction asindicated by alanine transaminase (ALT) or aspartate transaminase (AST) greaterthan 2.5 times the upper limit of normal, bilirubin greater than 1.5 times theupper limit of normal, international normalized ratio (INR) greater than 1.5 inthe 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 ifelevation is determined to be a consequence of immune dysregulation by the sitePrincipal Investigator and if the elevation has been stable for 3 months priorto enrollment.

• History of significant renal injury/renal disease severely affecting renalfunction or presence of impaired renal function as indicated by estimatedglomerular filtration rate of less than 30 mL/min/1.73 m2.

15. A positive hepatitis B surface antigen (HBsAg), positive hepatitis B PCR, positivehepatitis C PCR, or positive hepatitis C antibody result at screening.

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

17. Subject has a history of malignancy (except lymphoma) within 3 years before thefirst dose of study medication or has evidence of residual disease from a previouslydiagnosed malignancy, except for adequately treated cancers of the skin (basal orsquamous cell) or carcinoma in situ of the uterine cervix.

18. Subject has a previous diagnosis of lymphoma that has been treated withchemotherapy, radiotherapy, or transplant within 1 year of the first dose of studymedication or is anticipated to require lymphoma treatment within 6 months of thefirst dose of study medication.

19. Subject has uncontrolled post-transplant lymphoproliferative disease-likeEpstein-Barr virus related lymphoproliferative disease.

20. Donation or loss of 400mL or more of blood within 8 weeks before the first dose ofstudy medication

21. Subject has had major surgery requiring hospitalization or radiotherapy within 4weeks prior to the first dose of study medication or has a planned or expected majorsurgical procedure during the study period.

22. Pregnant or nursing (lactating) women.

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