A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis (CARES)

This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101 combined with standard of care (SoC) plasma cell dyscrasia (PCD) treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. The primary evaluation treatment period (PETP) part of the study will stop when the last patient is randomized in the PETP plus 18 months. Approximately 124 patients will be enrolled using a 2:1 randomization ratio. Stratification will be based on geographic region across investigator sites. The primary endpoint is a composite endpoint of all-cause mortality and frequency of cardiovascular hospitalizations. Patients in both study intervention groups will be followed from randomization until death from any cause, heart transplant, left wall assist device (LVAD) implantation or until the end of study.

Key Inclusion Criteria:

• AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo Clinic Staging (NT-proBNP > 8,500 ng/L) at the time of Screening
• Measurable hematologic disease at Screening as defined by at least one of the following:

• Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL or
• Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio or
• Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL
• Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:

• Immunohistochemistry/Immunofluorescence or
• Mass spectrometry or
• Characteristic electron microscopy appearance/Immunoelectron microscopy
• Cardiac involvement as defined by:

• Documented 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 AND
• At least one of the following:

i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis

• Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC
• Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer
• Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer

Key Exclusion Criteria:

• Have any other form of amyloidosis other than AL amyloidosis
• Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained and prior to randomization is allowed
• Has POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed ≤ 3 months prior to signing the ICF) or biopsy-proven (performed ≤ 3 months prior to signing the ICF) bony or extramedullary plasmacytoma AND one or more of the following CRAB features:

a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder (e.g., multiple myeloma and POEMS syndrome), specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177 mol/L (> 2 mg/dL) OR iii. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed ≤ 3 months prior to signing the ICF): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination OR ii. More than one focal lesion on MRI that is at least 5mm or greater in size

• Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion