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

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.

• NM8074 (Drug): 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.

Primary outcomes

• 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 [Up to Study Day 120]: Assessed via the change from baseline or percent change from baseline in serum creatinine level.
• 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 outcomes

• 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. [Baseline through Study Day 120]: 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.
• 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 [Baseline through Study Day 120]: 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.

Other outcomes

• Change from Baseline or Percent Change from Baseline in CP modulation [Baseline through Study Day 120]
• Change from Baseline or Percent Change from Baseline in Factor B levels [Baseline through Study Day 120]
• Change from Baseline or Percent Change from Baseline in plasma concentration of NM8074 [Baseline through Study Day 120]
• Maximum plasma concentration (Cmax) [Baseline through Study Day 120]
• Time corresponding to Cmax (tmax) [Baseline through Study Day 120]
• Area under the drug concentration-time curves (AUC0-t) [Baseline through Study Day 120]

Sex: All, ages: 18 Years to 65 Years

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.

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