Study of NM8074 in Adult PNH Patients With Inadequate Response to Soliris

Study Overview
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Brief Summary
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This is a Phase II, open-label study designed to evaluate the safety, efficacy, and immunogenicity of NM8074 in PNH patients undergoing complement-inhibitor therapy with Soliris.

Detailed Description
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The proposed study, NM8074-PNH-106, will enroll a planned number of 12 Soliris-treated PNH patients who have been diagnosed with hemolytic anemia and meet the defined inclusion criteria. This study will evaluate the safety, efficacy, and immunogenicity of NM8074 as both a mono- and combination therapy with complement component C5 blocker Soliris. Patients will be evenly divided into two cohorts.

Official Title
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A Phase II, Open-Label Study of NM8074 in Soliris®-Treated Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Drug: NM8074
* Drug: Soliris


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years (males and females), weight ≥ 45 kg at the time of consent. Confirmation of PNH diagnosis by flow cytometry evaluation white blood cells (WBCs), with neutrophil, granulocyte and/or monocyte clone size of ≥10%. Evidence of ongoing hemolysis. ≥1 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. Treatment with Soliris 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: Subjects currently or previously under other complement inhibitor treatments other than Soliris less than 3 months prior to study Day 1 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 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 (CKD stage 4, dialysis) 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 not donate sperm for the duration of the study.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Interventional Model Description: Patients will be divided evenly into two cohorts that will be evaluated in parallel. Both cohorts will evaluate NM8074 as a combination therapy with Soliris and Cohort 1 will also evaluate NM8074 as a monotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>6 Soliris-treated patients will receive an intravenous (IV) dose of NM8074 at 10 mg/kg weekly for 4 weeks. Patients will then discontinue Soliris treatment and be administered NM8074 at 20 mg/kg IV every 2 weeks for the remainder of the treatment period (8 weeks). At the end of the treatment period, patients will resume Soliris monotherapy as prescribed. | Drug: NM8074<br>* NM8074 is an anti-Factor Bb humanized monoclonal antibody that will be administered as an intravenous infusion. Doses will be administered over a treatment period of 13 weeks.<br>Drug: Soliris<br>* Complement C5 blocker administered intravenously<br>* Other names: Eculizumab;|
| Experimental: Cohort 2<br>6 Soliris-treated patients will receive an intravenous (IV) dose of NM8074 at 10 mg/kg for 4 weeks. Patients will then continue receiving Soliris while being administered NM8074 as a combination therapy at 20 mg/kg IV every 2 weeks for the remainder of the treatment period (8 weeks). At the end of the treatment period, patients will resume Soliris monotherapy as prescribed. | Drug: NM8074<br>* NM8074 is an anti-Factor Bb humanized monoclonal antibody that will be administered as an intravenous infusion. Doses will be administered over a treatment period of 13 weeks.<br>Drug: Soliris<br>* Complement C5 blocker administered intravenously<br>* Other names: Eculizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monitoring of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events will be graded according to the CTCAE v4.03. If the AE term is not described in the grading scales, the AE severity shall be reported according to the following: Grade I: Mild (awareness of sign or symptom, but easily tolerated) Grade II: Moderate (discomfort sufficient to cause interference with normal activities) Grade III: Severe (incapacitating, with inability to perform normal activities) Grade IV: Life threatening Grade V: Fatal | Up to Study Day 105 | 
| Number of Participants with Antidrug Antibodies (ADAs) to NM8074 |  | Up to Study Day 105 | 
| Change from Baseline or Percent Change from Baseline in Hemoglobin (Hgb) Levels |  | Up to Study Day 105 | 
| Change from Baseline or Percent Change from Baseline in Lactate Dehydrogenase (LDH) Levels |  | Up to Study Day 105 | 
| Change from Baseline or Percent Change from Baseline in Number of Packed Red Blood Cell (pRBC) Transfusions |  | 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 |  | 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 |  | Up to Study Day 105 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline or Percent Change from Baseline in Reticulocyte Count |  | Up to Study Day 105 | 
| Change from Baseline or Percent Change from Baseline in Bilirubin Levels |  | 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. | 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. | 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. | 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. | Up to Study Day 105 | 
| Changes in plasma concentration of NM8074 |  | Up to Study Day 105 | 
| Maximum plasma concentration (Cmax) |  | Up to Study Day 105 | 
| Time corresponding to Cmax (tmax) |  | Up to Study Day 105 | 
| Area Under the Drug Concentration-Time Curves (AUC0-t) |  | Up to Study Day 105 |