Study of Efficacy and Safety of NM8074 in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy

Official title

A Phase II, Open-Label Study of NM8074 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Overview

This is a Phase II, open-label study designed to evaluate the safety, efficacy, and immunogenicity of NM8074 administered intravenously to adult patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Detailed description

The proposed study will enroll a planned number of 12 treatment naïve PNH patients with amaximum of 18 PNH patients who have been diagnosed with hemolytic anemia and meet the inclusion criteria. There will be 2 cohorts with 6 to 9 patients each. Patients in Cohort 1 will be administered NM8074 at 20 mg/kg intravenously (IV) every 2 weeks over the treatment period. Cohort 2 patients will be administered a dose of 10 mg/kg NM8074 weekly for 4 weeks followed by a 20 mg/kg dose of NM8074 administered via IV every 2 weeks for the remainder of the treatment period. This study will determine if NM8074 will provide the desired inhibition of the alternative pathway (AP).

Interventions

• Drug NM8074
  NM8074 will be administered as an intravenous infusion. Doses will be administered over a treatment period of 13 weeks.

Primary outcome measures

• Monitoring of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time frame: Up to Study Day 105]
• Number of Participants with Antidrug Antibodies (ADAs) to NM8074 [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Hemoglobin (Hgb) Levels [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Lactate Dehydrogenase (LDH) Levels [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Number of Packed Red Blood Cell (pRBC) Transfusions [Time frame: Up to Study Day 105]
• Percent Change from Baseline in Levels of Membrane Attack Complex (MAC) via Alternative Pathway (AP) of Complement Activity as Compared to Percent Change from Baseline in Levels of MAC via Classical Pathway (CP) of Complement Activity [Time frame: Up to Study Day 105]
• Percent Change from Baseline in Levels of Complement Component C3b via Alternative Pathway (AP) of Complement Activity as Compared to Percent Change from Baseline in Levels of C3b via Classical Pathway (CP) of Complement Activity [Time frame: Up to Study Day 105]

Secondary outcome measures (8)

• Change from Baseline or Percent Change from Baseline in Reticulocyte Count [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Bilirubin Levels [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Survey Assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4. [Time frame: Up to Study Day 105]
• Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Survey 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: Up to Study Day 105]
• Changes in plasma concentration of NM8074 [Time frame: Up to Study Day 105]
• Maximum plasma concentration (Cmax) [Time frame: Up to Study Day 105]
• Time corresponding to Cmax (tmax) [Time frame: Up to Study Day 105]
• Area Under the Drug Concentration-Time Curves (AUC0-t) [Time frame: Up to Study Day 105]

Eligibility criteria

Inclusion criteria

• Patients ≥ 18 years (males and females), weight ≥ 45 kg at the time of consent
• Confirmation of PNH diagnosis by flow cytometry evaluation of white blood cells (WBCs), with neutrophil, granulocyte and/or monocyte clone size of ≥10%
• Evidence of ongoing hemolysis
• ≥1 packed red blood cell (pRBC) transfusion within 12 months prior to screening
• Anemia (Hemoglobin ≤10.5 g/dL)
• 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

Exclusion criteria

• History of bone marrow, hematopoietic stem cell, or solid organ transplantation
• History of splenectomy
• Participation in any other investigational drug trial within 5 elimination half-lives of enrollment, or within 30 days, whichever is longer
• Subjects currently or previously under other complement inhibitor treatments less than 3 months prior to study Day 1
• Participants with known or suspected hereditary or acquired complement deficiency
• 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 known history of meningococcal disease or N. meningitidis infection
• Patients on immunosuppressive agents or systemic corticosteroids less than 8 weeks prior to dosing
• Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator, might interfere with the patient's full participation in the study, pose any additional risk for the patient, or confound the assessment of the patient or outcome of the study
• Severe concurrent co-morbidities not amenable to active treatment, e.g., patients with severe kidney disease (chronic kidney disease (CKD) stage 4, dialysis)
• Subjects currently or previously under other complement inhibitor treatments less than 3 months prior to study Day 1
• Pregnant, planning to become pregnant, or nursing female subjects. 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 week after stopping the investigational drug
• Females who have a positive pregnancy test result at Screening or on Day 1
• 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

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

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT05646524 · NM8074-PNH-105

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗