Study to Evaluate the Impact of Iptacopan on Top of SOC on Biopsy Changes in Kidneys of Adult Patients With IgAN

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study;participants should be able to communicate well with the investigator, understandand comply with the requirements of the study.

2. Male and female participants ≥18 years of age with biopsy-confirmed IgA nephropathyand an eGFR ≥ 30 mL/min/1.73m2. eGFR will be calculated using the CKD-EPI 2009formula.

3. Proteinuria as assessed at screening by UPCR ≥ 0.8g/g or 1g/d sampled from FMV.

4. Biopsy at baseline should confirm IgAN with < 50% tubulointerstitial fibrosis.

5. Participants must be on ACEi or ARB treatment at either the locally approved maximaldaily dose or the maximally tolerated dose (per investigators' judgment) forapproximately 90 days prior to baseline visit and continue on a stable dosethroughout the study. Participants with allergies or intolerance to ACEi and ARB areeligible for the study, but the investigator should clearly document the reasons fornot being on maximal ACEi/ARB dose in the source documents. In addition, ifparticipants are taking diuretics, other antihypertensive medication orSodium-Glucose Co-Transporter 2 inhibitors (SGLT2i), the doses should be stabilizedfor at least 90 days prior to baseline.

6. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infectionsrequired to be completed at least 2 weeks prior to the start of study treatment. Ifthe participants have not been previously vaccinated, or if a booster is required,vaccine should be given according to local regulations at least 2 weeks prior tofirst study drug administration. If study treatment must start earlier than 2 weekspost-vaccination, prophylactic antibiotic treatment should be initiated.

7. Vaccination against Haemophilus influenzae infection should be given, if availableand according to local regulations, at least 2 weeks prior to first study drugadministration.

Exclusion Criteria:

1. Any secondary IgAN (at historic or baseline biopsies) as defined by the investigatorand IgA vasculitis Henoch-Scholein Purpura (HSP). Secondary IgAN can be associatedwith cirrhosis, celiac disease, Human Immunodeficiency Virus (HIV) infection,dermatitis herpetiformis, seronegative arthritis, small-cell carcinoma, lymphoma,disseminated tuberculosis, bronchiolitis obliterans, and inflammatory bowel disease,familial Mediterranean fever, etc.

2. Any secondary diagnosis at baseline biopsy (other than IgA nephropathy).

3. Evidence of significant urinary obstruction or difficulty in voiding; any urinarytract disorder other than IgAN at screening and before first study drugadministration.

4. Current or planned usage of any homeopathic and/or herbal medications for IgANdisease progression, such as but not limited to Lei Gong Teng.

5. Current acute kidney injury (AKI) defined by Acute Kidney Injury Network (AKIN)criteria within 4 weeks of screening.

6. Presence of rapidly progressive glomerulonephritis (RPGN) as defined by 50% declinein eGFR within 3 months prior to screening, or presence of nephrotic syndrome.

7. Sitting office SBP >140 mmHg or DBP >90 mmHg at the screening visit.

8. Participants treated with immunosuppressive or other immunomodulatory agents such asbut not limited to cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab,mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus,sirolimus, everolimus, systemic corticosteroids exposure (>7.5 mg/dprednisone/prednisolone equivalent) or targeted release formulation (TRF) ofbudesonide within 90 days (or 180 days for rituximab) prior to first study drugadministration. Participants using other medication such us hydroxychloroquine orEndothelin receptor antagonists (ERAs).

9. Use of other investigational drugs within 5 half-lives or within 30 days ofenrollment, whichever is longer.

10. Prior use of iptacopan or prior enrollment in any other iptacopan clinical trialwhere study drug was taken, including matching placebo.

11. All transplanted participants (any solid organ transplantation, including bonemarrow transplantation).

12. History of recurrent invasive infections caused by encapsulated organisms, such asmeningococcus and pneumococcus.

13. Major concurrent comorbidities including but not limited to advanced cardiac disease (e.g., New York Heart Association (NYHA) class IV), severe pulmonary disease (e.g.,severe pulmonary hypertension (World Health Organization (WHO) class IV)), orhepatic disease (e.g., active hepatitis) that in the opinion of the investigatorprecludes participant's participation in the study.

14. Any medical condition deemed likely to interfere with the participant'sparticipation in the study or that will require the use of prohibited medications.

15. Active systemic bacterial, viral (including COVID-19) or fungal infection within 14days prior to study drug administration.

16. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration.

17. Human immunodeficiency virus (HIV) infection (known history of HIV or test positivefor HIV antibody at Screening).

18. History of hypersensitivity to any of the study drugs or its excipients or to drugsof similar chemical classes.

19. Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV)infection defined as positive HBsAg in conjunction with core antibody (anti-HBc), orHCV-RNA positive at screening, or liver injury as indicated by abnormal liverfunction tests at screening as defined below:

• Any single parameter of ALT, AST, GGT, alkaline phosphatase must not exceed 3 ×upper limit of normal (ULN)

• Serum bilirubin must not exceed 2 × ULN

20. History of malignancy of any organ system (other than localized basal cell carcinomaof the skin or in situ cervical cancer treated with curative intent), treated oruntreated, within the past 5 years, regardless of whether there is evidence of localrecurrence or metastases.

21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive human chorionic gonadotropin (HCG) laboratory test.

22. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they agree to use effective methods of contraceptionduring dosing of investigational drug and for 1 week after stopping ofinvestigational drug.

Effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of theparticipant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy or bilateral tubal ligation at least six weeksbefore taking investigational drug. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment.

• Male sterilization (at least 6 months prior to screening) of male partner of thefemale participant.

• Barrier methods of contraception: condom or occlusive cap (diaphragm orcervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginalsuppository.

• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods ofcontraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormonecontraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).

• In case of use of oral contraception women should have been stable on the same pillfor a minimum of 3 months before taking investigational drug.

• If local regulations are more stringent than the contraception methods listed above,local regulations apply and will be described in the ICF.

• Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., ageappropriate, history of vasomotor symptoms). Women are considered not ofchildbearing potential if they are post-menopausal or have had surgical bilateraloophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation atleast six weeks ago. In the case of oophorectomy alone, only when the reproductivestatus of the woman has been confirmed by follow up hormone level assessment is sheconsidered not of childbearing potential.

• If local regulations deviate from the contraception methods listed above to preventpregnancy, local regulations apply and will be described in the ICF.