Study of NM8074 in Patients with AHUS with Evidence of Ongoing Thrombotic Microangiopathy

Phase 2

Not yet recruiting

• Conditions: AHUS - Atypical Hemolytic Uremic Syndrome
• Interventions: Drug: NM8074

• Registration Number: NCT05684159
• Lead Sponsor: NovelMed Therapeutics

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2023-01-04
• Study First Submitted QC: 2023-01-12
• Study First Posted: 2023-01-13
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-14
• Last Update Posted: 2024-11-18
• Study Start: 2025-07
• Primary Completion: 2025-12
• Study Completion: 2027-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 12

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1	NM8074	6 subjects will receive an intravenous (IV) infusion of NM8074 at every two weeks for a total of 7 doses
Cohort 2	NM8074	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

Primary Outcome Measures

Name	Time	Method
Change from Baseline or Percent Change from Baseline in Haptoglobin	Up to Study Day 120
Normalization of platelet count (≥150 x 10^9/L)	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.
Normalization of LDH levels to below ULN	Up to Study Day 120
Change from Baseline or Percent Change from Baseline in proteinuria/creatininuria	Up to Study Day 120
Change from Baseline or Percent Change from Baseline in Hemoglobin	Up to Study Day 120

Secondary Outcome Measures

Name	Time	Method
Time to achieve complete TMA response	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	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.
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 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
Time to achieve higher hemoglobin from baseline	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.