A Phase 1 Study of 99mTc-p5+14 in Healthy Volunteers and Patients With AL or ATTR Systemic Amyloidosis

This study will investigate 99mTc-p5+14, an amyloid-reactive synthetic peptide, p5+14, radiolabeled with technetium-99m, as a radiotracer for detecting paamyloid deposits in patients with AL or ATTR-associated systemic amyloidosis, notably with cardiac involvement.

The University of Tennessee Graduate School of Medicine (UTGSM) is investigating 99mTc-p5+14, an amyloid-reactive synthetic peptide, p5+14, radiolabeled with technetium-99m, as a radiotracer for planar gamma scintigraphy (PGS), single photon emission computed tomography (SPECT) or SPECT with x-ray computed tomography (SPECT/CT) for the diagnosis of systemic amyloidosis, notably with cardiac involvement. Based on nonclinical data and clinical data of 124I-p5+14 from Study AMY1001, peptide p5+14 binds many types of human amyloid and is rapidly cleared from the central compartment. When radiolabeled with 99mTc, p5+14 may enable visualization of amyloid laden tissues and organs by SPECT/CT imaging or PGS. Thus, this study has been designed to evaluate the dosimetry and biodistribution of 99mTc-p5+14 in patients with systemic amyloidosis compared with the biodistribution in healthy volunteers.

Eligibility Criteria:
Inclusion Criteria:

PART 1

1. Understand the study procedures and agree to participate in the study by giving written informed consent as described in Section 10.1 - Appendix 1.
2. Be male or female \>18 years of age.
3. Women of child-bearing potential (WOCBP) (those who have not been surgically sterilized, are not postmenopausal \[i.e., last menstrual period \>2 years ago without pharmaceutical intervention\], and women who are fertile) must have a negative pregnancy test prior within 24 h prior to infusion.
4. WOCBP who are not exclusively in same-sex relationships and male participants with female sexual partners who are WOCBP must agree to use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, for at least 2.5 days after injection of 99mTc-p5+14.
5. Have a confirmed diagnosis of systemic AL amyloidosis based on either a histologic confirmation with a biopsy containing deposits of apple-green birefringent, Congophilic material with aberrant organ-specific biomarkers indicating amyloid involvement, physical examination, or imaging study.
6. Have a diagnosis of cardiac amyloidosis within 2 years of screening. PART 2

1) Understand the study procedures and agree to participate in the study by giving written informed consent as described in Section 10.1 - Appendix 1.

2) Be male or female \>18 years of age. 3) WOCBP (those who have not been surgically sterilized, are not postmenopausal \[i.e., last menstrual period \> 2 years ago without pharmaceutical intervention\], and women who are fertile) must have a negative pregnancy test prior within 24 h prior to infusion.

4) WOCBP who are not exclusively in same-sex relationships and male participants with female sexual partners who are WOCBP must agree to use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, for at least 2.5 days after injection of 99mTc-p5+14.

5) Have one of the following:

1. a confirmed diagnosis of systemic AL amyloidosis, based on either a histologic confirmation of a cardiac or extracardiac biopsy containing deposits of apple-green birefringent, Congophilic material AND imaging parameters (ECHO or CMR) indicative of cardiac involvement.
2. a confirmed diagnosis of systemic ATTR amyloidosis, based on either a histologic confirmation of a cardiac biopsy containing deposits of apple-green birefringent, Congophilic material or extracardiac biopsy and imaging parameters (ECHO or CMR or 99mTc-PYP) indicative of cardiac involvement, with no evidence of abnormal serum free light chains.
3. Have a diagnosis of cardiac amyloidosis within 2 years of screening. PART 3

   1. Understand the study procedures and agree to participate in the study by giving written informed consent as described in Section 10.1 - Appendix 1.
   2. Be male or female \>18 years of age.
   3. WOCBP (those who have not been surgically sterilized, are not postmenopausal \[i.e., last menstrual period \> 2 years ago without pharmaceutical intervention\], and women who are fertile) must have a negative pregnancy test prior within 24 h prior to infusion.
   4. WOCBP who are not exclusively in same-sex relationships and male participants with female sexual partners who are WOCBP must agree to use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, for at least 2.5 days after injection of 99mTc-p5+14.
   5. Be in good general health, as determined by no clinically significant findings (including Type 2 diabetes mellitus) in the opinion of the Investigator from review of the medical history.
   6. Does not have a diagnosis of amyloidosis nor has a first- or second-degree relative (parent, sibling, child, aunt, uncle, niece, nephew) with confirmed or suspected familial amyloidosis.

PART 4

1. Understand the study procedures and agree to participate in the study by giving written informed consent as described in Section 10.1 - Appendix 1.
2. Be male or female \>18 years of age.
3. Women of child-bearing potential (those who have not been surgically sterilized, are not postmenopausal \[i.e., last menstrual period \>2 years ago without pharmaceutical intervention\], and women who are fertile) must have a negative pregnancy test prior within 24 h prior to infusion.
4. WOCBP who are not exclusively in same-sex relationships and male participants with female sexual partners who are WOCBP must agree to use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, for at least 2.5 days after injection of 99mTc-p5+14..
5. Has a confirmed diagnosis of systemic ATTR amyloidosis, based on either a histologic confirmation of a cardiac biopsy containing deposits of apple-green birefringent, Congophilic material or extracardiac biopsy and imaging parameters (ECHO or CMR), or abnormal serum biomarkers indicative of cardiac involvement, with no evidence of abnormal serum free light chains.
6. Has a diagnosis of cardiac amyloidosis within 2 years of screening.
7. Has a negative 99mTc-PYP imaging study.

Exclusion Criteria:

PARTS 1-4

1. Due to annual dosimetry limitations, patients who have participated in another nuclear medicine amyloid imaging clinical trial protocol and received tracer injection in the last 6 months.
2. Is pregnant or breast-feeding.
3. Is mentally or legally incapacitated, has significant emotional problems at the time of the study, or has a history of psychosis.
4. Has a known allergy to potassium iodide.
5. Receiving hemodialysis or peritoneal dialysis.
6. Has severe claustrophobia or any medical condition that would prevent completion of the imaging protocol.
7. Has any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject.
8. Has received heparin or heparin analogs (e.g., enoxaparin, dalteparin, fondaparinux) within seven (7) days prior to 99mTc-p5+14 administration.
9. Have previously received any dose of p5+14, in any form.
10. Have a QTc interval, using Bazett's formula (QTcB) of \>480 ms, measured within six months prior to enrollment, or assessed prior to injection.
11. Have a serum AST \>2x the upper limit of normal or 80 IU/L AND total bilirubin \> 1.5x the upper limit of normal or 1.8 mg/dL within the previous six months of enrollment.
12. Have a serum ALT \>2x the upper limit of normal or 64 IU/L AND total bilirubin \> 1.5x the upper limit of normal or 1.8 mg/dL within the previous six months of enrollment.