Atypical Hemolytic Uremic Syndrome (aHUS)

Objectives : The primary objective of this study is to evaluate the effect of OMS721 in subjects with aHUS on: • Platelet count change from baseline The secondary objectives of this study are to evaluate the effect of OMS721 in subjects with aHUS on: • Safety and tolerability measured by adverse events (AEs), serious AEs (SAEs),vital signs, laboratory measures, electrocardiograms (ECGs), and physical examination • The proportion of subjects who achieve complete thrombotic microangiopathy (TMA) response defined as normalization of platelet count, normalization of serum lactate dehydrogenase (LDH), and > 25% decrease in the baseline serum creatinine on at least 2 consecutive measurements over at least 4 weeks • The duration of complete TMA response measured from the time of the first measurement of complete TMA response to the end of the complete TMA response • The time to complete TMA response measured by the time to reach the first measurement of complete TMA response • The proportion of subjects who achieve TMA event-free status during treatment defined as no decrease in platelet count of > 25% from baseline, no plasma exchange or plasma infusion, and no initiation of new dialysis for ≥ 12 consecutive weeks • The time to TMA event-free status measured by the time to reach the first documented TMA event-free status from the first dose of OMS72 • The proportion of subjects who achieve an increase of > 15 ml/min/1.73 m2 in the estimated glomerular filtration rate (eGFR) calculated by either the Modification of Diet in Renal Disease Study (MDRD) Equation for subjects aged ≥ 18 years and the Schwartz equation for subjects < 18 years • The time to eGFR increase of > 15 ml/min/1.73 m2 measured by the time to reach the first measurement increase in eGFR of > 15 ml/min/1.73 m2 from the first dose of OMS721 • The proportion of subjects who achieve hematological normalization defined as normalization of platelet count and normalization of serum LDH on at least 2 consecutive measurements over at least 4 weeks • The time to hematological normalization measured by the time to reach the first measurement of hematological normalization from the first dose of OMS721 • The proportion of subjects who achieve TMA remission defined as platelet count ≥150,000/μL on at least 2 consecutive measures over at least 2 weeks • Quality of life as measured by EQ-5D-5L • Serum creatinine change from baseline • Serum LDH change from baseline • Serum haptoglobin change from baseline • Rate of TMA interventions defined as the number of dialysis events, plasma infusion events and plasma exchange events per subject per day • Determine the pharmacokinetics (PK) of OMS721 • Determine the pharmacodynamics (PD) of OMS721 • Determine the immunogenicity of OMS721 [Proportion of subjects who develop anti-drug antibody (ADA)]

OMS721

OMS721 (MASP-2 monoclonal antibody)

Solution

185 mg/mL, 2 mL/vial

Primary Endpoint
• Platelet count change from baseline to week 26
Secondary Endpoints
• Safety as assessed by AEs, SAEs, vital signs, ECGs, physical examinations, and
laboratory measures
• Complete TMA response defined as normalization of platelet count, normalization of
serum LDH, and > 25% decrease in serum creatinine on at least 2 consecutive
measures over at least 4 weeks
• Duration of complete TMA response measured from the time of the first measurement
of complete TMA response to the last consecutive measurement of complete TMA
response
• Time to complete TMA response measured by the time to reach the first measurement
of complete TMA response
• TMA event-free status during treatment defined as no decrease in platelet count of >
25% from baseline, no plasma exchange or plasma infusion, and no initiation of new
dialysis for at least 12 consecutive weeks
• Time to TMA event-free status measured by the time to reach the first documented
TMA event-free status from the first dose of OMS721
• Increase of > 15 ml/min/1.73 m2 in the estimated glomerular filtration rate (eGFR)
calculated by the Modification of Diet in Renal Disease Study (MDRD) Equation for
subjects aged ≥ 18 years and the Schwartz equation for subjects < 18 years
• Time to eGFR increase of > 15 ml/min/1.73 m2 measured by the time to reach the first
measurement increase in eGFR of > 15 ml/min/1.73 m2 from the first dose of OMS721
Protocol No. OMS721-HUS-002 (A01)
CONFIDENTIAL
No use, disclosure or reproduction outside of Omeros without prior written authorization
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• Hematological normalization defined as normalization of platelet count and
normalization of serum LDH on at least 2 consecutive measurements over at least 4
weeks
• Time to hematological normalization measured by the time to reach the first
measurement of hematological normalization from the first dose of OMS721
• TMA remission defined as platelet count ≥ 150,000/μL on at least 2 consecutive
measures over at least 2 weeks
• Quality of life as measured by EQ-5D-5L
• Serum creatinine change from baseline
• Serum LDH change from baseline
• Serum haptoglobin change from baseline
• Rate of TMA interventions defined as the number of dialysis events, plasma infusion
events and plasma exchange events per subject per day over the treatment period
• PK of OMS721
• PD of OMS721
• ADA

Subjects may be included in the study only if they meet all of the following criteria:
1. Competent to provide informed consent or, if a minor, have at least one parent or legal guardian to provide informed consent with written assent from the subject.
2. If an adult, voluntarily provide informed consent in accordance with regulations and governing ethics committee requirements prior to any procedures or evaluations performed specifically for the sole purpose of the study. If a minor, at least one parent or legal guardian must provide informed consent and the subject must provide assent in accordance with local regulations and governing ethics committee requirements prior to any procedures or evaluations performed specifically for the sole purpose of the study.
3. Willing and able to comply with study procedures.
4. Are age ≥12 at screening (Visit 1).
5. Have a primary aHUS, diagnosed clinically, and have ADAMTS13 activity > 5% in plasma. Patients are eligible with or without a documented complement mutation or anti-CFH antibody. Patients are categorized according to their response to plasma therapy (plasma exchange or plasma infusion):
• Plasma therapy-resistant aHUS patients must have all of the following:
 ■ Screening platelet count < 150,000/μL despite at least four plasma therapy treatments in a 7-day period prior to screening
 ■ Evidence of microangiopathic hemolysis (at least one of: (1) presence of schistocytes, (2) serum LDH > 1.5 times upper limit of normal (ULN), and (3) haptoglobin < LLN)
 ■ Serum creatinine > ULN
• Plasma therapy-responsive aHUS patients must have all of the following:
 ■ Have a documented history of requiring plasma therapy to prevent aHUS exacerbation defined as all of the following:
− decrease in platelet count > 25% when plasma therapy frequency has been decreased (including discontinuation of plasma therapy)
− LDH > 1.5 times ULN when plasma therapy frequency has been decreased (including discontinuation of plasma therapy)
 ■ Have received plasma therapy at least once every 2 weeks at an unchanged frequency for at least 8 weeks before first dose of OMS721
6. If sexually active and of childbearing potential, must agree to practice a highly effective method of birth control until the end of the study, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner.
7. Do not have access to eculizumab treatment, have not derived therapeutic benefit from eculizumab treatment, or have not been able to tolerate eculizumab treatment.

Subjects will be excluded from the study for any of the following reasons:
1. Have STEC-HUS.
2. Have a positive direct Coombs test.
3. Have a history of hematopoietic stem cell transplant.
4. Have HUS from an identified drug.
5. History of vitamin B12 deficiency-related HUS.
6. History of Systemic Lupus Erythematosus.
7. History of antiphospholipid syndrome.
8. Active cancer or history of cancer (except non-melanoma skin cancers) within 5 years of screening.
9. Have been on hemodialysis or peritoneal dialysis for  12 weeks.
10. Have an active systemic bacterial or fungal infection requiring systemic antimicrobial therapy (prophylactic antimicrobial therapy administered as standard of care is allowed).
11. Baseline resting heart rate < 45 beats per minute or > 115 beats per minute.
12. Baseline QTcF > 470 milliseconds.
13. Have malignant hypertension (diastolic blood pressure [BP] > 120 mm Hg with bilateral hemorrhages or “cotton-wool” exudates on funduscopic examination).
14. Have a poor prognosis with a life expectancy of less than three months in the opinion of the Investigator.
15. Are pregnant or lactating.
16. Have received treatment with an investigational drug or device within four weeks of the screening visit.
17. Have abnormal liver function tests defined as ALT or AST > five times ULN.
18. Have HIV infection.
19. History of cirrhosis of the liver.
20. Are an employee of Omeros, an Investigator, a study staff member, or their immediate family member.
21. Have a known hypersensitivity to any constituent of the product.
22. Presence of any condition that the Investigator believes would put the subject at risk or confound the interpretation of the data.
23. Have previously completed treatment in an OMS721study.
24. Have received intravenous immunoglobulin (IVIG) treatment within 8 weeks of screening visit.
25. Have received rituximab within 24 weeks of screening visit.