Efficacy and Safety of Switching From Anti-C5 Antibody Treatment to Iptacopan Treatment in Study Participants With Atypical Hemolytic Uremic Syndrome (aHUS)

Inclusion Criteria:

1. Male and female participants = 18 years of age at the time of consent.
2. Signed informed consent must be obtained prior to participation in the study.
3. Willing and able to comply with the study visit schedule.
4. Participants with diagnosis of aHUS for whom etiologies of other types of TMA (e.g., Thrombotic Thrombocytopenic Purpura (TTP), Shiga Toxin producing Escherichia Coli (STEC)-TMA, Pneumococcal hemolytic uremic syndrome, TMA secondary to cobalamin C defect, TMA related to Diacylglycerol kinase e (DGKE) nephropathy) and non-aHUS kidney disease have been excluded.
5. Currently on the recommended (as per label) dosage regimen of anti-C5 antibody treatment (e.g., eculizumab or ravulizumab), for at least 3 months prior to entering the screening period.
6. In the opinion of the investigator the participant has responded to anti-C5 antibody treatment prior to screening and has clinical evidence of response (in absence of PE/PI) during the Screening period. Clinical evidence of response to anti-C5 antibody treatment (in absence of PE/PI) confirmed during the Screening period by central laboratory at two visits 12 weeks apart. Clinical evidence of response is defined as:

* Hematological normalization in platelet count =150 x 109/L and LDH below upper limit of normal \[ULN\], and
* Stable kidney function as defined by serum creatinine values within ±15% during the Screening period
7. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required prior to the start of treatment with iptacopan. If the participant has not been previously vaccinated or if a booster is required, the vaccine(s) should be given, according to local regulations, at least 2 weeks prior to first iptacopan dosing. If iptacopan treatment has to start earlier than 2 weeks post-vaccination, prophylactic antibiotic treatment must be initiated at the start of iptacopan study treatment and for at least 2 weeks after vaccination.
8. If not received previously or if a booster is required, vaccination against Haemophilus influenzae infection, should be given, if available and according to local regulations, at least 2 weeks prior to first iptacopan dosing.

Exclusion criteria

1. History of aHUS disease relapse while on anti-C5 antibody treatment.
2. eGFR \< 30 ml/min/1.73m2.
3. Uncontrolled arterial hypertension (systolic blood pressure \>160 mmHg).
4. Active infection or history of recurrent invasive infections caused by encapsulated bacteria, i.e., meningococcus, pneumococcus (e.g., N. meningitidis, S. pneumoniae) or H.

influenzae.
5. Participants with sepsis or active systemic bacterial, viral (including COVID-19) or fungal infection within 14 days prior to study treatment administration..
6. Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV at screening).
7. Kidney, bone marrow transplant (BMT)/hematopoietic stem cell transplant (HSCT), heart, lung, small bowel, pancreas, liver transplantation or any other cell or solid organ transplantation.
8. History of drug or alcohol abuse within the 12 months prior to dosing.
9. Major concurrent comorbidities including but not limited to advanced cardiac disease (e.g., NYHA class IV), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), or hepatic disease (e.g. active hepatitis) that in the opinion of the Investigator precludes participant's participation in the study.
10. Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection defined as hepatitis B virus surface antigen (HBsAg) positive or HCV RNA positive, or liver injury as indicated by abnormal liver function tests at Screening as defined below:

• Any single parameter of alanine amino transferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase must not exceed 3×upper limit of normal (ULN).
11. Any medical condition deemed likely to interfere with the participant's participation in the study.
12. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
13. History of hypersensitivity to iptacopan or any of its excipients or to drugs of similar chemical classes.
14. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer) treated or untreated within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
15. Female participants who are pregnant or nursing (breastfeeding), or intending to conceive during the course of the study.
16. Women of child-bearing potential (WCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using effective methods of contraception during dosing of iptacopan and for 1 week after stopping of iptacopan. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., hormonal profile confirming menopause and/or age-appropriate history of vasomotor symptoms).

Effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods contraception
* Bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment are they not considered to be of childbearing potential.
* Bilateral tubal occlusion, Bilateral tubal ligation (at least six weeks before taking study treatment).
* Male sterilization (vasectomy) at least 6 months prior to screening provided partner(s) has(have) received medical assessment of the surgical success.
* Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal suppository

Use of hormonal contraception methods:
* Combined (estrogen and progesterone), hormonal contraception associated with inhibition of ovulation; oral, intravaginal or transdermal.
* Progestogen-only hormonal contraception (where inhibition of ovulation is not the primary or only mode of action) :oral, injectable or implantable.
* Intrauterine device (IUD) or intrauterine system hormone releasing system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking iptacopan. If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
17. Participants committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
18. Participants dependent on the Sponsor, the study site or the Investigator.