The Effect of an Antisense Oligonucleotide to Lower Transthyretin (TTR) Levels on the Progression of -Wild-type TTR Involving the Heart

An 18 Month Open Label Study Of The Tolerability And Efficacy Of An Antisense Oligonucleotide In Patients With Wild-Type Transthyretin Amyloid Cardiomyopathy (Senile Systemic Amyloidosis)

ATTRwt (also known as senile systemic, or senile cardiac amyloidosis) is a progressive heart disease, causing congestive heart failure. It is caused by amyloid protein deposits in the heart, that are derived from a normal protein, TTR, made in the liver. The aim of the study is to determine whether lowering the blood levels of TTR, by a weekly injection of a compound designed specifically to do this, will slow the progression of the disease when treated patients are compared to previously-followed patients who were not receiving this drug. The study also aims to determine how well this drug is tolerated and the existence and severity of any drug side-effects.

All patients with documented SSA will be considered for inclusion. SSA is defined as an echocardiographic appearance of left ventricular wall thickness of 13 mm or more, in the absence of uncontrolled hypertension, and with a positive biopsy for amyloid, which also stains positive for TTR by immunochemistry or mass spectrometry. For the definition of SSA, genetic testing should be negative for a mutation. Identification of amyloid type is standard of care for all patients seen at the Cardiac Amyloidosis Program and the presence of a clinically -obtained positive biopsy will be a requirement for study inclusion. The positive biopsy can be from any organ, providing that the echocardiographic appearance is typical of amyloidosis.

Inclusion Criteria:

1. Patients should, in the opinion of the Investigator, be in a stable state in terms of NYHA class. Class I-III patients will be recruited.
2. Age 50-90 years
3. Male or non-pregnant, non-lactating females. If a woman is premenopausal, or a male partners with a premenopausal woman, she/he must be willing to use the following methods of contraception: condoms, oral/hormonal contraception, Intrauterine Device, diaphragm, or abstinence
4. Written informed consent to be obtained prior to study treatment
5. Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens
6. Molecular definition of the absence of a TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody and negative genetic testing for a TTR mutation.
7. Willingness to return to the treating center for follow-up.
8. Willingness and ability to self-administer, or to have spouse administer weekly subcutaneous injections of study drug.

Exclusion Criteria:

1. Patients who, in the opinion of the Investigator, require further adjustment of diuretics at the time of screening to achieve optimal treatment of heart failure. Once stable for 2 weeks, patients in Class I-III will become eligible for inclusion.
2. Patients with NYHA class 4 congestive heart failure.
3. Concomitant non-amyloid heart disease that might, in the opinion of the investigator, cause changes in strain imaging on serial follow-up (e.g. aortic stenosis of greater than mild severity, unstable coronary artery disease).
4. Prior liver transplantation or liver transplantation anticipated in less than 6 months;
5. ALT and/or AST ³ 2 x ULN and/or Alkaline phosphatase ³ 2 x UNL;
6. Estimated glomerular filtration rate (EGFR) < 50 ml/min;
7. Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
8. History of poor compliance with medications or medical treatment, based on a review of medical records.
9. History of hypersensitivity to any of the ingredients of the study therapy;
10. Use of any investigational drug for amyloidosis within 4 weeks prior to study entry or during the study.
11. Current use of tafamidis, diflunisal, doxycycline or TUDCA for therapy of amyloidosis.