Eculizumab to Cemdisiran Switch in aHUS
Eculizumab to Cemdisiran Switch in aHUS
Atypical Hemolytic Uremic Syndrome (aHUS) is a rare, lifethreatening, chronic disease of
 complement-mediated thrombotic microangiopathy (TMA) characterized by acute onset of renal
 impairment, thrombocytopenia, and microangiopathic hemolytic anemia. The estimated incidence
 of aHUS is approximately 0.5 per million per year. aHUS affects both adults and children, but
 is observed primarily in children and young adults.

 Atypical HUS commonly develops due to dysregulation of the alternative complement pathway and
 can be sporadic (80%) or familial(20%).

 The clinical course of aHUS is often unpredictable and can be dependent upon the specific
 genetic abnormality present within the complement system, if any, and/or triggering events
 associated with complement activation or inflammation, including autoimmune disease,
 transplant, pregnancy, infection, metabolic conditions, and drug use. In patients with
 dysregulated complement activity, such as those with complement mutations commonly observed
 in aHUS, the kidney vasculature is often the site of thrombosis stemming from endothelial
 injury.

 Cemdisiran has been designed to reduce the level of C5 mRNA in the liver, thereby reducing
 levels of circulating C5 protein, inhibiting terminal complement pathway activity, and
 preventing formation and deposition of the MAC (C5-b9) on endothelial cells in the kidney. As
 a result, complement-mediated endothelial cell damage in patients with aHUS and subsequent
 progression to End Stage Renal Disease (ESRD) may be reduced.
Inclusion Criteria:

 1. 12 years and older at the time of consent;

 2. Written informed consent (of parents or the guardian in case of underage participants)
 to enter the study;

 3. Consent to stop eculizumab therapy during the whole study period and to resume
 eculizumab therapy in case of disease recurrence

 4. >40 kg body weight;

 5. On stable disease status with eculizumab continuous therapy for aHUS for ≥ 12
 consecutive months (stability assessed on the basis of hematological/biochemical
 parameters by the Investigator)

 6. Hematological remission at screening and inclusion;

 7. Estimated GFR (by the simplified MDRD equation) > 30/ml/min 1.73 m2;

 8. Known high risk of aHUS recurrence due to at least one of the following criteria;

 1. History of aHUS recurrence after interruption of eculizumab therapy;

 2. Plasma dependent and/or recurrent disease before the introduction of eculizumab
 therapy;

 3. Documented mutations in complement factors that are associated with a high risk
 of disease recurrence such as mutations in Factor H, I or B;

 9. Females childbearing potential and non-sterile males must agree to use a method of
 contraception;

 10. Documented previous immunisation against Neisseria meningitidis (serotypes A, C, Y,
 W135 e B) by anti A, C, W and Y vaccine and anti B vaccine (Bexsero®) and antibiotic
 prophylaxis in accordance with the KDIGO guidelines and local standard of care of the
 PI at the trial Center, OR de-novo immunisation against Neisseria meningitidis and
 antibiotic prophylaxis in accordance with the KDIGO guidelines and local standard of
 care of the PI at the trial Center, if necessary. Documented previous immunization
 against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Study
 participants who do not have a sufficient history for some or all of these vaccines
 should be vaccinated.

 Exclusion Criteria:

 1. Solid organ or bone marrow/stem cell transplantation;

 2. Alanine transaminase (ALT) >3×ULN, INR >2 (or >3.5 if on anticoagulants), or total
 bilirubin >3×ULN (unless bilirubin elevation is due to Gilbert's syndrome);

 3. Clinical or biochemical evidence of active thrombotic; microangiopathy or flare of
 aHUS at the time of enrolment

 4. Evidence of Shigatoxin associated HUS;

 5. Patients who required intensified eculizumab therapy because of uncontrolled disease
 (these patients could be at very high risk of relapse after the shift, even in the
 cemdisiran treatment arm and their inclusion could be unsafe);

 6. Patients who did not relapse despite prolonged (>3 months) interruption of eculizumab
 therapy (these would probably be low risk patients that are expected to be event-free
 throughout the whole study period independent of treatment allocation and could have a
 dilution effect for event analyses);

 7. Patients with a confirmed diagnosis of sepsis, defined as positive blood cultures
 within 7 days of the screening visit and not treated with antibiotics to which the
 organism is sensitive;

 8. Presence or suspicion of active and untreated systemic bacterial infection that, in
 the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the
 ability to manage the aHUS disease;

 9. Evidence of human immunodeficiency virus (HIV) (positive serology for HIV antibody
 [HIV Ab]), hepatitis B infection (positive hepatitis B surface antigen [HbsAg]), or
 hepatitis C infection (positive anti-HCV antibody [HCV Ab]) at Screening or
 historically

 10. Unresolved meningococcal disease;

 11. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or
 syndrome;

 12. Exposure to any other investigational drug acting directly on the complement system
 (except for eculizumab) within 5 half-lives of screening is prohibited;

 13. Chemotherapeutic agents within 3 months of enrolment in the study are prohibited;

 14. History of malignancy within 5 years of screening;

 15. Participation in other clinical trials within 4 weeks of signing the consent form;

 16. Active systemic autoimmune diseases other than the target condition. Dermatologic
 diseases such as atopic dermatitis or psoriasis will not be a reason for exclusion
 unless there are associated systemic symptoms such as arthritis;

 17. Any severe systemic disorder that could interfere with the evaluation of the study
 treatment (e.g. hepatic disease) that in the opinion of the Investigator would affect
 the outcome of the study or interfere with interpretation of results;

 18. Failure to satisfy the Investigator of fitness to participate for any other reason or
 any condition (e.g. severe depression or psychiatric disorder) that, in the opinion of
 the Investigator, could increase the subject's risk by participating in the study or
 confound the outcome of the study;

 19. If female, the subject is pregnant or lactating or intending to become pregnant
 before, during, or within 90 days after last dose; or intending to donate ova during
 such time period;

 20. If male, the subject intends to donate sperm while on the study or for 90 days after
 last study drug administration;

 21. The subject has a history of drug abuse (defined as any illicit drug use) or a history
 of alcohol abuse within one year prior to screening. Alcohol abuse is defined as
 regular weekly intake of >14 units (unit: 1 glass of wine [125 mL] =1 measure of
 spirits=1/2 pint [0.25 mL] of beer). Alcohol is limited to no more than 2 units per
 day for the duration of the study;

 22. Patients with a poor prognosis that is expected to limit their life expectancy to less
 than 3 months, in the opinion of the Investigator;

 23. History of multiple drug allergies or history of allergic reaction to an
 oligonucleotide or GalNAc;

 24. History of intolerance to subcutaneous (SC) injection(s) or significant abdominal
 scarring that could potentially hinder cemdisiran administration or evaluation of
 local tolerability.