Safety and Efficacy Study of OMS721 in Patients With Atypical Hemolytic Uremic Syndrome

This is a Phase 3, uncontrolled, open-label study to evaluate the effect of OMS721 in subjects with aHUS. The primary outcome to be measured is platelet count change from baseline. The secondary outcomes to be measured are other efficacy measures, safety, PK, PD, and immunogenicity (i.e., presence of anti-drug antibody \[ADA\] response. Subjects with plasma therapy-resistant aHUS and plasma therapy-responsive aHUS will be eligible. The efficacy endpoints, including the primary efficacy endpoint, may not be relevant for plasma therapy-responsive subjects because these subjects may enter the study with normal markers of aHUS activity due to successful treatment with plasma therapy. Therefore, efficacy analyses will be performed separately in the plasma therapy-resistant and plasma therapy responsive subjects. The principal efficacy analyses will be the analyses in the plasma therapy resistant cohort and efficacy analyses of the plasma therapy-responsive cohort will be supportive. Safety analyses will be conducted in all subjects.

• OMS721 (narsoplimab) (Biological), also known as narsoplimab: Intravenous loading dose followed by daily subcutaneous injections

Primary outcomes

• Platelet Count (10^9 Platelets/L) Change From Baseline at Week 26 [Week 26]: The primary outcome to be measured is platelet count change from baseline.

Secondary outcomes

• Safety as Measured by Incidences of Adverse Events, Vital Signs, ECG, and Clinical Laboratory Tests [Pre-dose and up to 771 days post-dose]: Assessment of safety of OMS721 (narsoplimab) in participants with aHUS by incidence of Adverse Events, clinically significant vital sign abnormalities, ECG abnormalities, and clinical laboratory test abnormalities
• Thrombotic Microangiopathies (TMA) Response [26 weeks]: Complete TMA response defined as normalization of platelet count, normalization of serum lactate dehydrogenase (LDH), and > 25% decrease in serum creatinine by at least 2 consecutive measures over at least 4 consecutive weeks, within the initial 26-week period
• TMA Event-free Status [26 weeks]: No decrease in platelet count of > 25% from baseline, no plasma exchange or plasma infusion, and no initiation of new dialysis over at least 12 consecutive weeks, within the initial 26-week period
• Increase in Estimated Glomerular Filtration Rate (eGFR) [26 weeks]: Increase of greater than 15 ml/min/1.73 m2 in eGFR calculated by the modification of diet in renal disease (MDRD) Equation
• Hematological Normalization [26 weeks]: Normalization of platelet count and normalization of serum LDH by 2 consecutive measurements over at least 4 weeks, within the initial 26-week period
• TMA Remission [26 weeks]: Platelet count greater than or equal to 150,000/μL on at least 2 consecutive measures over at least 2 consecutive weeks, within the initial 26-week period
• Incidence of Antidrug Antibodies (ADA) [771 days post-dose]: Incidences of ADA in participants with aHUS, administered OMS721 (narsoplimab)
• Change From Baseline in Serum Creatinine (mg/dL) [26 weeks]: Assessment of subject's change from baseline in serum creatinine.
• Change From Baseline in Serum LDH (U/L) [26 weeks]: Assessment of subject's change from baseline in serum LDH
• Change From Baseline in Haptoglobin (mg/dL) [26 weeks]: Assessment of subject's change from baseline in haptoglobin
• Pharmacokinetics (PK): Trough Plasma Concentration, Lower Limit of Quantification (LLOQ) [Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (RT) (if occurs): RT Days 1-4; Follow-Up at Day 771]: Pharmacokinetics (PK): Trough plasma concentration, lower limit of quantification (LLOQ)
• Pharmacokinetics (PK): Maximum Plasma Concentrations (Cmax) [Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771]: Pharmacokinetics (PK): Maximum plasma concentrations (Cmax)
• Pharmacokinetics (PK): Area Under Time-concentration Curve (AUC) [Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771]: Pharmacokinetics (PK): Area under time-concentration curve (AUC)
• Pharmacodynamics (PD): Inhibition of C3 Activity (%) [Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771]: Pharmacodynamics (PD): Inhibition of C3 activity
• Pharmacodynamics (PD): Inhibition of C4 Activity (%) [Days 1-4; Treatment Maintenance (103 weeks): 17 visits; Rescue Therapy (if occurs): RT Days 1-4; Follow-Up at Day 771]: Pharmacodynamics (PD): Inhibition of C4 activity

Sex: All, ages: 12 Years to any

Inclusion Criteria:

1. Are age >= 12 years old at screening (Visit 1).
2. Have a primary aHUS, diagnosed clinically, and have ADAMTS13 activity > 5% in plasma. Participants are eligible with or without a documented complement mutation or anti-CFH antibody. Participants are categorized according to their response to plasma therapy (plasma exchange or plasma infusion):

   * Plasma therapy-resistant aHUS participants 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 participants 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
3. 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.
4. Do not have access to eculizumab treatment, have not derived therapeutic benefit from eculizumab treatment, or have not been able to tolerate eculizumab treatment.

Exclusion Criteria:

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.

Participant flow

Outcome results

• Platelet Count (10^9 Platelets/L) Change From Baseline at Week 26 (Primary), Median, 10^9 platelets/L: OMS721 (Narsoplimab) 42 (-21 to 115.5)
• Safety as Measured by Incidences of Adverse Events, Vital Signs, ECG, and Clinical Laboratory Tests (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 6
• Thrombotic Microangiopathies (TMA) Response (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 0
• TMA Event-free Status (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 2
• Increase in Estimated Glomerular Filtration Rate (eGFR) (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 0
• Hematological Normalization (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 1
• TMA Remission (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 2
• Incidence of Antidrug Antibodies (ADA) (Secondary), Count of participants, Participants: OMS721 (Narsoplimab) 1
• Change From Baseline in Serum Creatinine (mg/dL) (Secondary), Median, mg/dL: OMS721 (Narsoplimab) 1.53 (-0.98 to 3.16)
• Change From Baseline in Serum LDH (U/L) (Secondary), Median, U/L: OMS721 (Narsoplimab) -12 (-112 to 389)
• Change From Baseline in Haptoglobin (mg/dL) (Secondary), Median, mg/dL: OMS721 (Narsoplimab) 30 (4 to 56)
• Pharmacokinetics (PK): Trough Plasma Concentration, Lower Limit of Quantification (LLOQ) (Secondary), Mean, ng/mL: OMS721 (Narsoplimab) 15477.2 +/- 6471.62
• Pharmacokinetics (PK): Maximum Plasma Concentrations (Cmax) (Secondary), Median, ng/mL: OMS721 (Narsoplimab) 48350 (25100 to 86300)
• Pharmacokinetics (PK): Area Under Time-concentration Curve (AUC) (Secondary)
• Pharmacodynamics (PD): Inhibition of C3 Activity (%) (Secondary), Median, Inhibition of C3 activity (%): OMS721 (Narsoplimab) 84.4 (1.7 to 101.4)
• Pharmacodynamics (PD): Inhibition of C4 Activity (%) (Secondary), Median, Inhibition of C4 activity (%): OMS721 (Narsoplimab) 91.9 (11.9 to 99.9)

Adverse events

Time frame: From Day 1 to Final Study Visit (up to Day 771)

Serious adverse events by term

Other adverse events by term

• Results publication: Pugh D, O'Sullivan ED, Duthie FA, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Mar 23;3(3):CD012862. doi: 10.1002/14651858.CD012862.pub2. PMID 33783815

• Study Protocol (PDF, 2017-05-31)
• Statistical Analysis Plan (PDF, 2024-04-07)