A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis

1. Age ≥18 years
2. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures
3. Diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo Red-stained tissue specimens; and confirmed diagnosis of ATTR amyloidosis by immunohistochemistry, mass spectrometry, documentation of an ATTR mutation by gene sequencing, or 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans and/or technetium pyrophosphate (PYP) SPECT cardiac imaging. If scintigraphy is used for diagnosis then the grade must be 2 or greater, indicative of transthyretin amyloidosis-cardiomyopathy (ATTR-CM) (Gillmore, 2016)
4. Known TTR mutation
5. [Inclusion Criterion 5 removed in Amendment 2]
6. Patients receiving concomitant tafamidis or diflunisal may enroll in the study, providing the dose has been stable for the last 6 months
7. Karnofsky Performance Status (KPS) ≥60%

8. Adequate organ function, including all of the following:

   1. Adequate bone marrow reserve, defined as the following: absolute neutrophil count ≥1.0 × 109/L; platelet count ≥100 × 109/L; hemoglobin ≥10 g/dL
   2. Hepatic: total bilirubin ≤ 2 times the upper limit of normal (× ULN), transaminases (aspartate aminotransferase and/or alanine aminotransferase) ≤3 × ULN; alkaline phosphatase ≤5 × ULN
   3. Renal: estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2
9. If currently receiving a diuretic, must have been on a stable dose for at least 4 weeks prior to the first dose of study drug
10. Systolic blood pressure ≥90 mmHg and ≤180 mmHg
11. Subjects with cardiomyopathy must have an NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (ie, ≥76.9 pmol/L and ≤591 pmol/L) or evidence of septal wall thickening >1.2 cm on echocardiogram
12. Must have a biopsy unless data are available from a previous one. The biopsy may be taken from any tissue or organ affected by ATTR amyloidosis (eg, skin, lip, abdominal fat pad, salivary gland), at the Investigator's discretion. Nerve biopsies are not required.
13. Women of childbearing potential 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 from Screening to 90 days following the last study drug administration
14. Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration
15. Polyneuropathy Disability (PND) Score ≤IIIB
16. Neuropathy Impairment Score (NIS) ≥5 and ≤130

Exclusion Criteria:

1. Amyloid light chain or other non-ATTR amyloidosis
2. Any past history of or present abuse of alcohol, diabetes, B12 or folate deficiencies, autoimmune diseases, hereditary disorders other than transthyretin (eg, Charcot-Marie-Tooth), uncontrolled hypothyroidism, or other etiologies for the peripheral neuropathy
3. Received prior liver transplant
4. Planned liver transplant during the study
5. Modified body mass index (mBMI) ≤600 kg/m2 × g/L
6. New York Heart Association (NYHA) Functional Class III-IV (Appendix 2)
7. LVEF ≤45%
8. Uncontrolled symptomatic orthostatic hypotension
9. Myocardial infarction, unstable or uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the first dose of study drug
10. Any history of clinically significant sinus pauses on ECG
11. Sinus pauses >3 seconds in the day or sinus pauses >5 seconds at night during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug)
12. Arrhythmia requiring treatment diagnosed during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug). Note: subject could be reconsidered for entry into the study if appropriate treatment is obtained
13. Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug

14. Uncontrolled infection, or active malignancy with the exception of the following:

    • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer
    • Low risk prostate cancer with Gleason score \<7 and prostate specific antigen \<10 mg/mL
    • Any other cancer from which the subject has been disease-free for ≥2 years
15. Clinically significant pleural effusion per Investigator (e.g., presence of pleural effusion ≥30% in either hemithorax)
16. History of Grade ≥3 hypersensitivity-associated AEs or hypersensitivities to other monoclonal antibodies or the excipients found in the PRX004 formulation
17. Known HIV infection or known hepatitis B or C virus carrier
18. Women who are pregnant or breastfeeding
19. Treatment with an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to Month 1-Day 1
20. 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 Medical Monitor or Investigator unacceptably increase the subject's risk by participating in the study
21. Treatment with patisiran or inotersen within 90 days or 5 halflives (whichever is longer) prior to Month 1-Day 1