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Title A Phase 2, uncontrolled, three-stage, dose-escalation cohort study to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of OMS721 in adults with thrombotic microangiopathies

IRB OMRS1Z14

CC 15-426

Hospital Main Campus

Phase Phase 2

Disease Thrombotic Microangiopathies

Drug OMS721

Description

• Assess the safety and tolerability of multiple-dose administration of OMS721 in subjects with thrombotic microangiopathies (TMA)
• Evaluate the clinical activity of multiple-dose administration of OMS721 in subjects with TMA
• Determine the pharmacokinetics of multiple-dose administration of OMS721 in subjects with TMA
• Determine the pharmacodynamics of multiple-dose administration of OMS721 in subjects with TMA
• Determine the anti-drug antibody response of multiple-dose administration of OMS721 in subjects with TMA

Inclusion Criteria

1. Competent to provide informed consent.
2. Voluntarily provide informed consent 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. Are age ≥18 at screening (Visit 1).
4. Have a diagnosis of one of the following TMAs:
   • Primary aHUS, diagnosed clinically and having ADAMTS13 activity > 10% 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: 1) screening platelet count < 150,000/μL despite at least four plasma therapy treatments prior to screening; 2) evidence of microangiopathic hemolysis (presence of schistocytes, serum lactate dehydrogenase (LDH) > upper limit of normal (ULN), haptoglobin < LLN); and 3) serum creatinine > ULN.
     • Chronic plasma therapy-responsive aHUS patients (plasma therapysensitive) must require at least once-per-week plasma therapy for four weeks before first dose of OMS721 with serum creatinine > ULN.
   • TTP defined as having all of the following:
     • Platelet count < 150,000/μL
     • Evidence of microangiopathic hemolysis (presence of schistocytes, serum LDH > ULN, or haptoglobin < LLN)
     • ADAMTS13 activity ≤ 10% during the current episode of TTP or historically
   • Persistent HSCT-associated TMA defined as having all of the following at least two weeks following modification or discontinuation of calcineurin inhibitor treatment or at least 30 days after the transplant:
     • Platelet count < 150,000/μL
     • Evidence of microangiopathic hemolysis (presence of schistocytes, serum LDH > ULN, or haptoglobin < LLN)
     • Renal dysfunction (doubling of serum creatinine from pretransplant).
5. No clinically apparent alternative explanation for thrombocytopenia and anemia.
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 which 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.

Exclusion Criteria

1. Had eculizumab therapy within three months prior to screening.
2. Have STEC-HUS.
3. Have a positive direct Coombs test.
4. Have an active systemic bacterial or fungal infection requiring antimicrobial therapy (prophylactic antimicrobial therapy administered as standard of care is allowed).
5. Baseline resting heart rate < 45 beats per minute or > 115 beats per minute.
6. Baseline QTcF > 470 milliseconds.
7. Have malignant hypertension (diastolic blood pressure > 120 mm Hg with bilateral hemorrhages or "cotton-wool" exudates on funduscopic examination).
8. Have a poor prognosis with a life expectancy of less than three months in the opinion of the investigator.
9. Are pregnant or lactating.
10. Have received treatment with an investigational drug or device within four weeks prior to screening.
11. Have abnormal liver function tests defined as ALT or AST > five times ULN.
12. Have a positive test for human immunodeficiency virus (HIV) antibodies.
13. Are an employee of Omeros, an investigator, a study staff member, or their immediate family member.
14. Have a known hypersensitivity to any constituent of the product.
15. Presence of any condition that the Investigator believes would put the subject at risk.