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

Official title

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

Overview

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.

Interventions

• Drug NM8074
  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 outcome measures

• Normalization of platelet count (≥150 x 10^9/L) [Time frame: Up to Study Day 120]
• Normalization of LDH levels to below ULN [Time frame: Up to Study Day 120]
• Normalization of Schistocyte levels (<1%) [Time frame: Up to Study Day 120]
• Change from Baseline or Percent Change from Baseline in renal function [Time frame: Up to Study Day 120]
• Change from Baseline or Percent Change from Baseline in Haptoglobin [Time frame: Up to Study Day 120]
• Change from Baseline or Percent Change from Baseline in Hemoglobin [Time frame: Up to Study Day 120]
• Change from Baseline or Percent Change from Baseline in proteinuria/creatininuria [Time frame: Up to Study Day 120]

Secondary outcome measures (8)

• Time to achieve complete TMA response [Time frame: Baseline through Study Day 120]
• Time to achieve higher hemoglobin from baseline [Time frame: Baseline through Study Day 120]
• Change from Baseline or Percent Change from Baseline in blood clots [Time frame: Up to Study Day 120]
• Change from Baseline or Percent Change from Baseline in the total number of plasma infusions or exchanges [Time frame: Baseline through Study Day 120]
• Change from Baseline or Percent Change from Baseline in eGFR (estimated glomerular filtration rate) [Time frame: Baseline through Study Day 120]
• Change from Baseline or Percent Change from Baseline in dialysis requirement [Time frame: 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. [Time frame: 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 [Time frame: Baseline through Study Day 120]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Barbour T, Scully M, Ariceta G, Cataland S, Garlo K, Heyne N, Luque Y, Menne J, Miyakawa Y, Yoon SS, Kavanagh D; 311 Study Group Members. Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults. Kidney Int Rep. 2021 Mar 24;6(6):1603-1613. doi: 10.1016/j.ekir.2021.03.884. eCollection 2021 Jun. PMID 34169200
• Cammett TJ, Garlo K, Millman EE, Rice K, Toste CM, Faas SJ. Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab. Mol Diagn Ther. 2023 Jan;27(1):61-74. doi: 10.1007/s40291-022-00620-3. Epub 2022 Nov 4. PMID 36329366
• Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, Bedrosian CL, Faas SJ. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015 May 21;125(21):3253-62. doi: 10.1182/blood-2014-09-600411. Epub 2015 Apr 1. PMID 25833956
• 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

Identifiers

NCT: NCT05684159 · NM8074-aHUS-401

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗