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Title A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of NEOD001 in Previously Treated Subjects with Light Chain (AL) Amyloidosis who have Persistent Cardiac Dysfunction

IRB PROT1A16

CC 16-283

Hospital Main Campus

Phase Phase 2

Disease Amyloidosis

Drug NEOD001

Description

The objective of this study is to determine the efficacy and safety of NEOD001 versus placebo in subjects with AL amyloidosis who have persistent cardiac dysfunction.

Inclusion Criteria

1. Age ≥18 years
2. Confirmed diagnosis of systemic AL amyloidosis by the following:
   • Histochemical diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens OR characteristic electron microscopy appearance AND
   • Confirmatory electron microscopy immunohistochemistry OR mass spectroscopy of AL amyloidosis
3. Confirmed diagnosis of AL amyloidosis by mass spectrometry of tissue biopsy (if archival tissue is not available, a biopsy is required) if the subject meets any of the following:
   • Is black or African American
   • Is over 75 years of age with concurrent monoclonal gammopathy
   • Has a history of familial amyloidosis and has concurrent monoclonal gammopathy
4. Cardiac involvement as defined by ALL of the following:
   • Past documented or presently noted clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
   • Either an endomyocardial biopsy consistent with AL amyloidosis OR an echocardiogram demonstrating a mean left ventricular wall thickness in diastole >12 mm in the absence of other causes (e.g., severe hypertension, aortic stenosis) which would adequately explain the degree of wall thickening
   • NT-proBNP ≥650 pg/mL in the absence of renal failure defined by an eGFR <30 mL/min/1.73 m² or atrial fibrillation with an uncontrolled ventricular rate, as defined by >110 beats per minute
5. NT-proBNP <5000 pg/mL
6. Received at least one prior systemic chemotherapeutic regimen, which may include stem cell transplant, for AL amyloidosis
7. Achieved at least a partial hematologic response (per Appendix 1) to a previous therapy resulting in a stable hematologic condition not currently requiring additional active treatment against the PCD component of their AL disease
8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by:
   • Absolute neutrophil count (ANC) ≥1.0 x10⁹/L
   • Platelet count ≥75 x 10⁹/L
   • Hemoglobin ≥9 g/dL
   • Total bilirubin ≤2 x upper limit of normal (ULN)
   • Aspartate aminotransferase (AST) ≤3 x ULN
   • Alanine aminotransferase (ALT) ≤3 x ULN
   • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
9. Systolic blood pressure (BP) 90-180 mmHg
10. Distance walked during 6MWT is >100 meters and <600 meters
11. Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug and must agree to use highly effective physician-approved contraception (Appendix 2) from Screening to 90 days following the last study drug administration
12. Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception (Appendix 2) from Screening to 90 days following the last study drug administration
13. Ability to understand and willingness to sign an ICF prior to initiation of any study procedures

Exclusion Criteria

1. Diagnosis of non-AL amyloidosis
2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma (Appendix 3)
3. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject's ability to safely receive treatment or complete study assessments
4. Myocardial infarction, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit
5. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm²) or severe congenital heart disease
6. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
   • First degree atrioventricular (AV) block
   • Second degree AV block Type 1 (Mobitz Type 1/Wenckebach type)
   • Right or left bundle branch block
   • Atrial fibrillation with a controlled ventricular rate
7. Note: Prior to randomization, any ECG screening abnormalities must be reviewed and designated as either "clinically significant" or "not clinically significant" by the Investigator
8. Has not recovered (i.e., equivalent to a CTCAE Grade 1 [mild] or better) from the clinically significant toxic effects of prior anticancer therapy. Exception: subjects with prior bortezomib treatment may have CTCAE Grade 2 neuropathy.
9. Received any of the following within the specified time frame prior to the Month 1-Day 1 Visit:
   • Oral or intravenous antibiotics, antifungals, or antivirals within 1 week, with the exception of prophylactic oral agents
   • Hematopoietic growth factors, transfusions of blood or blood products within 1 week
   • Chemotherapy, radiotherapy, or other plasma cell directed therapy within 6 months
   • ASCT within 12 months
   • Major surgery within 4 weeks or planned major surgery during the study
   • Any other investigational agent within 4 weeks
   • Prior treatment with NEOD001, 11-1F4, anti-serum amyloid P antibody, or other investigational treatment directed at amyloid
10. Active malignancy with the exception of any of the following:
    • Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
    • Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years
    • Stage I prostate cancer that does not require treatment
    • Any other cancer from which the subject has been disease-free for ≥2 years
11. History of Grade ≥3 infusion-related AEs or hypersensitivity to another monoclonal antibody
12. Known prior allergic or infusion reaction to any of the study drug excipients
13. Uncontrolled bacterial, viral, fungal, HIV, hepatitis B, or hepatitis C infection
14. Women who are breastfeeding
15. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator, unacceptably increase the subject's risk by participating in the study
16. Unable or unwilling to adhere to the study-specified procedures and restrictions
17. Subject is under legal custodianship