Study of NM8074 in Patients With aHUS With Evidence of Ongoing Thrombotic Microangiopathy

Study Overview
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Brief Summary
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This is a Phase II, open-label study designed to determine if intravenously administered NM8074 results in remission from TMA in treatment-naïve aHUS patients.

Detailed Description
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The proposed study, NM8074-aHUS-401,will initially assign six (6) patients per cohort in a 2-cohort trial. In the first cohort, we will evaluate a biweekly dosing regimen whereas in the second cohort, we will evaluate a weekly dose (10 mg/kg) followed by the biweekly dose (20 mg/kg) over a 3-month period. These studies will determine if NM8074 results in remission from TMA in aHUS patients. If the study shows efficacy in aHUS, additional patients may be added per cohort.

Official Title
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A Phase II, Open-Label Study of NM8074 in Patients With Atypical Hemolytic Uremic Syndrome (aHUS)

Conditions
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aHUS - Atypical Hemolytic Uremic Syndrome

Intervention / Treatment
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* Drug: NM8074


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years at the time of consent Patients with evidence of resistant or relapsed complement-mediated aHUS with symptoms of Thrombocytopenia, hemolysis, ongoing Thrombotic Microangiopathy and acute kidney injury. Evidence of ongoing Thrombotic Microangiopathy which includes Haptoglobin <LLN or undetectable and/or presence of schistocytes Acute kidney injury (proteinuria/creatinuria > ULN and/or reduced eGFR) Platelets less than 150,000 per microliter (Thrombocytopenia) Anemia (Hemoglobin ≤10 g/dL) due to hemolysis Lactate dehydrogenase (LDH) level ≥ 1.5 times the upper limit of normal (xULN) during Screening All patients must be vaccinated prior to dosing with MenACWY Menactra® polysaccharide diphtheria toxoid conjugate vaccination against Neisseria meningitidis serogroups A, C, Y, and W-135 and MenB meningococcal serogroup B vaccine (Bexsero®). If the window of vaccination is short, then patients will be prophylactically treated with appropriate antibiotics Willing and able to understand and complete informed consent procedures, including signing and dating the informed consent form (ICF), and comply with the study visit schedule. Male patients and partners of child-bearing potential must agree to use contraceptives and male patients must agree to refrain from donating sperm for the duration of the study. Female partners of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative pregnancy test at screening and must agree to use highly effective methods of contraception during dosing and for 1 month after stopping the investigational drug. Exclusion Criteria: History of bone marrow, hematopoietic stem cell, or solid organ transplantation Treatment with complement blockers Patients with infections HUS due to ADAMTS-13 deficiency (<5%) Kidney disease other than aHUS Chronic dialysis (hemo or peritoneal) Liver disease or other major autoimmune diseases Typical HUS (Shiga toxin +) Known Systemic Lupus Erythematosus (SLE), Systemic Sclerosis, or antiphospholipid antibody positivity or syndrome History of currently active primary or secondary immunodeficiency Currently active systemic infection or suspicion of active bacterial, viral, or fungal infection within 2 weeks prior to first dose, or history of unexplained, recurrent bacterial infections Has a currently active or known history of meningococcal disease or N. meningitidis infection Severe concurrent co-morbidities not amenable to active treatment, e.g., patients with severe kidney disease (CKD stage 4, chronic dialysis) Females who have a positive pregnancy test result at Screening or on Day 1. Pregnant, planning to become pregnant, or nursing female subjects.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will enroll a planned total of 12 patients as subjects for the trial, with extra enrollment if needed, at the discretion of the Investigator. All subjects will be assigned to either Cohort 1 or Cohort 2. Enrollment in Cohort 2 will occur after at least three patients in Cohort 1 have been evaluated for safety for 3 days after the first dose. No more than three patients will be dosed in a day. Safety data will be assessed and reviewed by the Sponsor and Study Investigators for dosed subjects prior to dosing of the rest of the study subjects. In Cohort 1, all 6 subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses. All 6 patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses followed by biweekly doses at 20 mg/kg for a total of 5 doses.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>6 subjects will receive an intravenous (IV) infusion of NM8074 at every two weeks for a total of 7 doses | Drug: NM8074<br>* NM8074 will be administered as an intravenous infusion. In Cohort 1, all subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses from Day 1 to Day 85 of the Treatment Period. Patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses from Day 1 to Day 22 followed by biweekly doses at 20 mg/kg for a total of 5 doses from Day 29 to Day 85.<br>|
| Experimental: Cohort 2<br>6 subjects will receive weekly doses of 10 mg/kg for a total of 4 doses followed by biweekly doses at 20 mg/kg for a total of 5 doses | Drug: NM8074<br>* NM8074 will be administered as an intravenous infusion. In Cohort 1, all subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses from Day 1 to Day 85 of the Treatment Period. Patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses from Day 1 to Day 22 followed by biweekly doses at 20 mg/kg for a total of 5 doses from Day 29 to Day 85.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of platelet count (≥150 x 10^9/L) |  | Up to Study Day 120 | 
| Normalization of LDH levels to below ULN |  | Up to Study Day 120 | 
| Normalization of Schistocyte levels (<1%) |  | Up to Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in renal function | Assessed via the change from baseline or percent change from baseline in serum creatinine level. | Up to Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in Haptoglobin |  | Up to Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in Hemoglobin |  | Up to Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in proteinuria/creatininuria |  | Up to Study Day 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to achieve complete TMA response |  | Baseline through Study Day 120 | 
| Time to achieve higher hemoglobin from baseline |  | Baseline through Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in blood clots |  | Up to Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in the total number of plasma infusions or exchanges |  | Baseline through Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in eGFR (estimated glomerular filtration rate) |  | Baseline through Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in dialysis requirement |  | Baseline through Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in quality of life (QoL) Assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4. | The FACIT-fatigue scale is a 13-item patient-reported measure of fatigue with a 7-day recall period. Items are scored on a 0 - 4 response scale ranging from Not at all to Very much so. All items are summed to create a single fatigue score with a range from 0 to 52 with a better quality of life indicated by a higher score. | Baseline through Study Day 120 | 
| Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Assessed via the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale (QLQ- C30), Version 3.0 | All EORTC QLQ-C30 scales and single-item measures range from 0 to 100. This includes 3 symptom scales (fatigue, pain, nausea and vomiting), 5 functional scales (physical, role, cognitive, emotional, and social), single-item questions addressing symptoms like insomnia, dyspnea, loss of appetite, and others that are commonly reported by cancer patients, and the perceived financial impact of the disease. A higher score is associated with a greater quality of life for global health status. | Baseline through Study Day 120 |