Atypical Hemolytic Uremic Syndrome (aHUS)

Primary Objective The primary objective of the study is to assess the efficacy of ALXN1210 in complement inhibitor treatment naïve pediatric patients with aHUS to inhibit complement-mediated TMA as characterized by thrombocytopenia, hemolysis, and renal impairment. Secondary Objectives The secondary objectives of the study are to assess the following: 1. To characterize the safety and tolerability of ALXN1210 in this patient population 2. To evaluate the efficacy of ALXN1210 by the following additional measures: a. Dialysis requirement status b. Time to Complete TMA Response c. Complete TMA Response status over time d. Observed value and change from baseline in estimated glomerular filtration rate (eGFR) e. Chronic kidney disease (CKD) stage, as evaluated by eGFR at select target days and classified as improved, stable (no change), or worsened compared to baseline f. Observed value and change from baseline in hematologic parameters (platelets, LDH, hemoglobin) g. Increase in hemoglobin of ≥ 20 g/L from baseline, observed at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between h. Change from baseline in quality of life (QoL), as measured by Pediatric Functional Assessment of Chronic Therapy (FACIT) Fatigue questionnaire 3. To characterize the PK/pharmacodynamics (PD) of ALXN1210 by the following measures: a. Changes in serum ALXN1210 concentration over time b. Changes in free C5 concentration over time 4. To evaluate the long-term safety and efficacy of ALXN1210

ALXN1210

ALXN1210

solution for infusion

10

Primary Efficacy Endpoint
The primary efficacy endpoint of the study is Complete TMA Response during the 26-week
Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet
count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients must meet
all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks
(28 days) apart, and any measurement in between.

Secondary Efficacy Endpoints
The secondary efficacy endpoints of the study are the following and will be measured through
26 weeks and over the entire study period:
1. Dialysis requirement status.
2. Time to Complete TMA Response
3. Complete TMA Response status over time
4. Observed value and change from baseline in eGFR
5. CKD stage, as evaluated by eGFR at select target days and classified as improved, stable
(no change), or worsened compared to baseline
6. Observed value and change from baseline in hematologic parameters (platelets, LDH,
hemoglobin)
7. Increase in hemoglobin of ≥ 20 g/L from baseline, observed at 2 separate assessments
obtained at least 4 weeks (28 days) apart, and any measurement in between
8. Change from baseline in QoL, as measured by Pediatric FACIT Fatigue questionnaire
(patients ≥ 5 years of age)

Pharmacokinetic and Pharmacodynamic Endpoints
The PK and PD endpoints of this study are the following:
1. Changes in serum ALXN1210 concentration over time
2. Changes in free C5 concentration over time

Safety Endpoints
The safety and tolerability of ALXN1210 will be evaluated by physical examinations, vital signs,
physical growth (height, weight, and head circumference) electrocardiograms (ECGs), laboratory
assessments, and incidence of AEs and serious adverse events (SAEs). The proportion of patients
who develop antidrug antibodies (ADA) will also be assessed.

Exploratory Endpoints
Biomarkers
Exploratory biomarkers of PD effect may include, but are not limited to, change from baseline in
levels of markers of complement dysregulation (eg, Factor Ba), vascular inflammation (eg,
soluble tumor necrosis factor receptor 1 [sTNFR1]), endothelial activation/damage (eg, soluble
vascular adhesion molecule 1 [sVCAM-1], thrombomodulin), coagulation (eg, D-dimer), and
renal injury (eg, cystatin C). Additional assessments may include measurements of ALXN1210
excretion in urine, chicken red blood cell (cRBC) hemolysis, total C5, autoantibodies to
complement proteins (eg, anti-factor H).

Genetics Endpoints
Exploratory genetics may be performed to investigate genetic variants in genes known to be
associated with aHUS, as well as to identify novel genetic variants associated with aHUS,
complement dysregulation or metabolism or efficacy of ALXN1210. Patients (or legal guardian)
may decline from providing a sample for exploratory genetics and still participate in the study.

Inclusion Criteria
Patients are eligible for enrollment in the study only if they meet all of the following criteria and
none of the exclusion criteria:
1. Patients from birth up to < 18 years of age and weighing ≥ 5 kg at the time of consent
2. Evidence of TMA, including thrombocytopenia, evidence of hemolysis, and kidney
injury, based on the following Screening Visit laboratory findings:
a. Platelet count < 150,000 per microliter (µL), and
b. LDH ≥ 1.5 × upper limit of normal (ULN), and hemoglobin ≤ lower limit of normal
(LLN) for age and gender, and
c. Serum creatinine level ≥ 97.5th percentile for age (Appendix B) at Screening (patients
who require dialysis for acute kidney injury are also eligible).
3. Among patients with a kidney transplant:
a. Known history of aHUS prior to current kidney transplant, or
b. No known history of aHUS, and persistent evidence of TMA at least 4 days after
modifying the immunosuppressive regimen (eg, suspending or reducing the dose) of
calcineurin inhibitor ([CNI]; eg, cyclosporine, tacrolimus) or mammalian target of
rapamycin inhibitor ([mTORi]; eg, sirolimus, everolimus).
4. Among patients with onset of TMA postpartum, persistent evidence of TMA for > 3 days
after the day of childbirth.
5. To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must
be vaccinated against meningococcal infections within 3 years prior to, or at the time of, initiating study drug. Patients who receive a meningococcal vaccine less than 2 weeks
before initiating ALXN1210 treatment must receive treatment with appropriate
prophylactic antibiotics until 2 weeks after vaccination. Patients who have not been
vaccinated prior to initiating ALXN1210 treatment should receive prophylactic
antibiotics prior to and for at least 2 weeks after meningococcal vaccination. Patients who
cannot be vaccinated must receive antibiotic prophylaxis for the entire treatment period
and for 8 months following last dose.
6. Patients must have been vaccinated against Haemophilus influenzae type b (Hib) and
Streptococcus pneumoniae according to national and local vaccination schedule
guidelines.
7. Female patients of childbearing potential and male patients with female partners of
childbearing potential must follow protocol-specified guidance (Section 9.10) for
avoiding pregnancy while on treatment and for 8 months after last dose of study drug.
8. Patient’s legal guardian must be willing and able to give written informed consent and the
patient must be willing to give written informed assent (if applicable as determined by the
central or local Institutional Review Board [IRB]/ Institutional (or Independent) Ethics
Committee [IEC]) and comply with the study visit schedule.

Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
1. Known familial or acquired ‘a disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13’ (ADAMTS13) deficiency (activity < 5%).
2. Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS) as demonstrated by a
positive test for Shiga toxin or culture of Shiga toxin producing bacteria.
3. Positive direct Coombs test.
4. Known Human Immunodeficiency Virus (HIV) infection.
5. Unresolved meningococcal disease.
6. Patients with a confirmed diagnosis of ongoing sepsis defined as positive blood cultures
within 7 days prior to the start of Screening and untreated with antibiotics.
7. 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.
8. Pregnancy or breastfeeding.
9. Heart, lung, small bowel, pancreas, or liver transplant.
10. Among patients with a kidney transplant, acute kidney dysfunction within 4 weeks of
transplant consistent with the diagnosis of acute antibody-mediated rejection (AMR)
according to Banff 2013 criteria (Appendix C).
11. Among patients without a kidney transplant, history of kidney disease other than aHUS,
such as:
a. Known kidney biopsy finding suggestive of underlying disease other than aHUS
b. Known kidney ultrasound finding consistent with an alternative diagnosis to aHUS
(eg small kidneys for age)
c. Known family history and/or genetic diagnosis of noncomplement mediated genetic
renal disease (eg, focal segmental glomerulosclerosis)
12. Identified drug exposure-related HUS.
13. Receiving plasma exchange/plasma infusion (PE/PI), for 28 days or longer, prior to the
start of Screening for the current TMA.
14. History of malignancy within 5 years of Screening with the exception of a non-melanoma
skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of
recurrence.
15. Bone marrow transplant (BMT)/hematopoietic stem cell transplant (HSCT) within the
last 6 months prior to the start of Screening.
16. HUS related to vitamin B12 deficiency.
17. Known systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), or
antiphospholipid antibody positivity or syndrome.
18. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for
ESKD).
19. Patients receiving chronic intravenous immunoglobulin (IVIg) within 8 weeks prior to
the start of Screening, unless for unrelated medical condition (eg,
hypogammaglobinemia); or chronic rituximab therapy within 12 weeks prior to the start
of Screening.
20. Patients receiving other immunosuppressive therapies such as steroids, mTORi (eg,
sirolimus, everolimus), CNI (eg, cyclosporine or tacrolimus) are excluded unless:
a. part of an established post-transplant antirejection regimen, or
b. patient has confirmed anti-complement factor antibodies requiring
immunosuppressive therapy, or
c. steroids are being used for a condition other than aHUS (eg, asthma).
21. Participation in another interventional treatment study or use of any experimental therapy
within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives
of that investigational product, whichever is greater.
22. Prior use of eculizumab or other complement inhibitors.
23. Hypersensitivity to any ingredient contained in the study drug, including hypersensitivity
to murine proteins.
24. Any medical or psychological condition that, in the opinion of the Investigator, could
increase the risk to the patient by participating in the study or confound the outcome of
the study.
25. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to
the start of Screening.
26. Use of tranexamic acid within 7 days prior to Screening is prohibited.