Evuzamitide as SPECT/CT Imaging Agent for Diagnosis of Transthyretin Amyloidosis

Study Overview
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Brief Summary
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This is a single center, prospective cohort study that is evaluating the ability of 124I-evuzamitide PET scanning to: (1) identify extra-cardiac amyloid deposits in patients with ATTRwt-CA and the Val122Ile variant; (2) to detect cardiac TTR amyloidosis in subjects with heart failure, increased wall thickness but only grade 1 Tc99PYP scans who are not currently diagnosed with ATTR-CA; and (3) to detect cardiac ATTR in allele carriers of TTR variants (Phe64Leu, late onset Val30Met) that are associated with cardiac amyloidosis but have PYP scans not diagnostic of ATTR-CM. If 124I-evuzamitide PET scanning is shown to be valuable in any of these three cohorts, it would address critical unmet needs regarding the diagnosis and extent of disease in ATTR-CM. Consented eligible patients will undergo a single 124I-evuzamitide PET scan. Clinically available demographic, clinical and phenotypic data that is collected as part of routine clinical care will be used to characterize the type, severity, and stage of ATTR-CM.

Detailed Description
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Transthyretin cardiac amyloidosis (ATTR-CA) causes progressive heart disease that is often overlooked. It harms the heart muscle because the unstable, unfurled amyloid proteins fold up into large pieces that get caught in between layers of heart tissue, causing amyloid deposits. The earlier it is detected, the better for the patient. There is a need to improve the early diagnosis of this disease because echocardiography (sonograms of the heart) and cardiac MRI are not useful enough for this. There is an X-ray of the heart using a compound called PYP that can detect amyloid deposits earlier than ultrasound images or clinical signs, but it's not clear how early it does so. Also, it can't detect amyloid deposits outside the heart, which causes lots of pain and suffering in people with this disease. A new radiation compound, evuzamitide, has been shown to detect amyloidosis in the heart, liver, spleen, kidney, bone marrow and even in the peripheral nerves. So, the investigators want to use it to detect Transthyretin Amyloidosis: In people who have a type of Amyloidosis which normally deposits in the heart, but in which PYP Scintigraphy didn't find it in there; In people who have a type of Amyloidosis which normally deposits outside the heart, to see if this compound can detect it in the heart; and In people who have proven Amyloid deposits in the heart, to see if this compound can detect them outside the heart.

Official Title
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A Pilot Study Using Amyloid Reactive Peptide AT-01(124I-evuzamitide) in Transthyretin Cardiac Amyloidosis for Early Detection, Assessment of Cardiac Involvement in Rare Variants and Quantification of Extra-Cardiac Amyloidosis

Conditions
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Transthyretin Amyloidosis

Intervention / Treatment
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* Drug: I 124-Evuzamitide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements. New York Heart Association (NYHA) class I-III Able to understand and sign the informed consent document after the nature of the study has been fully explained. Cohort 1: Subjects with grade 1 Tc99-PYP scans who have clinical features suggestive of ATTR-CM or have grade 1 Tc99-PYP scans but endomyocardial biopsy evidence of TTR cardiac amyloidosis. Heart failure with a preserved ejection fraction (EF>40%) Grade 1 Tc99-PYP scan performed for clinical suspicion of ATTR-CM No evidence of monoclonal proteins by assessment of serum kappa and lambda free light chain ratio and immunofixation of serum and urine. Left ventricular septal OR inferolateral wall thickness ≥12 mm. Cohort 2: Subjects with TTR variant such as Phe64Leu, late onset Val30Met, etc.) that are associated with cardiac amyloidosis but have PYP scans not diagnostic of ATTR-CM Tc99-PYP scan performed for clinical suspicion of ATTR-CM that is not diagnostic of ATTR-CM No evidence of monoclonal proteins by assessment of serum kappa and lambda free light chain ratio and immunofixation of serum and urine. Left ventricular septal OR inferolateral wall thickness ≥12 mm with echocardiographic features of ATTR-CM (low tissue doppler velocities, preserved apical strain, elevated E/E') or CMR features of an infiltrative cardiomyopathy (increased wall thickness with delayed enhancement or difficulty nulling of the myocardium) Cohort 3: Subjects with ATTR-CM from either ATTRwt or Val122Ile variant who have biopsy proven evidence of extra-cardiac TTR amyloidosis or clinical suspicion of extracardiac disease, including but not limited to peripheral neuropathy, carpal tunnel syndrome, spinal stenosis. ATTR-CM defined by the following Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining OR technetium scintigraphy with 99m Tc-pyrophosphate with Grade 2 or 3 cardiac uptake in the absence of abnormal light chains ratio, End-diastolic interventricular septum thickness of > 12 mm on previous echocardiogram TTR genotype shown to be either Val122Ile or wild type. Exclusion Criteria: Primary amyloidosis (AL) or secondary amyloidosis (AA). Active malignancy or non-amyloid disease with expected survival of less than 1 year. Heart failure, in the opinion of the investigator, primarily caused by something other than amyloidosis. Ventricular assist device. Impairment from stroke, injury or other medical disorder that precludes participation in the study. Disabling dementia or other mental or behavioral disease. Enrollment in a clinical trial not approved for co-enrollment. Continuous intravenous inotropic therapy. Inability or unwillingness to comply with the study requirements. Chronic kidney disease requiring hemodialysis or peritoneal dialysis. Patients taking heparin, or heparin derivatives (e.g. low molecular weight heparins) for anticoagulation. Other reason that would make the subject inappropriate for entry into this study. Pregnancy or current lactational feeding of infants.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 105 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects with grade 1 Tc99-PYP scans who have clinical features suggestive of ATTR-CM or have grade 1 Tc99-PYP scans but endomyocardial biopsy evidence of TTR cardiac amyloidosis will be administered single dose evuzamitide <1mCi. Heart failure with a preserved ejection fraction (EF>40%) Grade 1 Tc99-PYP scan performed for clinical suspicion of ATTR-CM No evidence of monoclonal proteins by assessment of serum kappa and lambda free light chain ratio and immunofixation of serum and urine. Left ventricular septal OR inferolateral wall thickness ≥12 mm | Drug: I 124-Evuzamitide<br>* Amyloid reactive protein used as imaging agent in whole body SPECT-CT imaging<br>* Other names: Attralus AT-01;|
| Experimental: Cohort 2<br>Subjects with TTR variant such as Phe64Leu, late onset Val30Met, etc.) that are associated with cardiac amyloidosis but have PYP scans not diagnostic of ATTR-CM will be administered single dose evuzamitide <1mCi. Tc99-PYP scan performed for clinical suspicion of ATTR-CM that is not diagnostic of ATTR-CM No evidence of monoclonal proteins by assessment of serum kappa and lambda free light chain ratio and immunofixation of serum and urine. Left ventricular septal OR inferolateral wall thickness ≥12 mm with echocardiographic features of ATTR-CM (low tissue doppler velocities, preserved apical strain, elevated E/E') or CMR features of an infiltrative cardiomyopathy (increased wall thickness with delayed enhancement or difficulty nulling of the myocardium) | Drug: I 124-Evuzamitide<br>* Amyloid reactive protein used as imaging agent in whole body SPECT-CT imaging<br>* Other names: Attralus AT-01;|
| Experimental: Cohort 3<br>Subjects with ATTR-CM from either ATTRwt or Val122Ile variant who have biopsy proven evidence of extra-cardiac TTR amyloidosis or clinical suspicion of extracardiac disease, including but not limited to peripheral neuropathy, carpal tunnel syndrome, spinal stenosis will be administered single dose evuzamitide <1mCi.. ATTR-CM defined by the following Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining OR technetium scintigraphy with 99m Tc-pyrophosphate with Grade 2 or 3 cardiac uptake in the absence of abnormal light chains ratio, End-diastolic interventricular septum thickness of > 12 mm on previous echocardiogram TTR genotype shown to be either Val122Ile or wild type. | Drug: I 124-Evuzamitide<br>* Amyloid reactive protein used as imaging agent in whole body SPECT-CT imaging<br>* Other names: Attralus AT-01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COV in subjects with heart failure and grade 1 PYP scans | Detection of TTR cardiac infiltration. To determine if 124I-evuzamitide PET scanning can detect cardiac TTR amyloidosis in subjects with heart failure, increased wall thickness but only grade 1 Tc99-PYP scans who are either not currently diagnosed with ATTR-CM or have endomyocardial biopsy evidence of ATTR-CM. The organ-specific radioactivity data will be expressed as the mean and standard deviation (SD) of three independent ROIs, unless otherwise noted. The coefficient of variation (COV) will be expressed as (SD/mean)*100. | Up to 1 month after scanning | 
| COV in subjects who are allele carriers with non-diagnostic PYP scans | Detection of TTR cardiac infiltration. To determine if 124I-evuzamitide PET scanning can detect cardiac ATTR in allele carriers of TTR variants (Phe64Leu, late onset Val30Met) that are associated with cardiac amyloidosis but have PYP scans not diagnostic of ATTR-CM. The organ-specific radioactivity data will be expressed as the mean and standard deviation (SD) of three independent ROIs, unless otherwise noted. The coefficient of variation (COV) will be expressed as (SD/mean)*100. | Up to 1 month after scanning | 
| COV in subjects with ATTR-CM | Detection of extra-cardiac TTR amyloidosis. To determine if 124I-evuzamitide PET scanning can identify and quantify extra-cardiac amyloidosis in subjects with ATTR-CM due to either ATTRwt or Val122Ile variant. The organ-specific radioactivity data will be expressed as the mean and standard deviation (SD) of three independent ROIs, unless otherwise noted. The coefficient of variation (COV) will be expressed as (SD/mean)*100. | Up to 1 month after scanning | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATTR-CM, 124I-evuzamitide, Positron Emission Tomography (PET)