24 Month Open Label Study of the Tolerability and Efficacy of an Antisense Oligonucleotide (Inotersen) in Patients With Transthyretin (TTR) Amyloid Cardiomyopathy
Transthyretin is a protein produced in the liver that transports thyroid hormone and vitamin A. A single substitution of an amino acid in the structure of TTR can result in a relatively unstable protein, the breakdown products of which (predominantly monomers) aggregate abnormally and produce proteinaceous deposits in nerves and the heart. These deposits are known as amyloid and produce progressive nerve and heart damage. Amyloidosis due to a mutant TTR is usually an autosomal dominant and hence is a familial condition. Wild-type TTR is also capable of producing amyloid deposits which predominantly involves the heart (rather than the nervous system) resulting in a progressive decrease in cardiac function with increasing signs of heart failure. This study aims to determine whether subcutaneous injection of an antisense oligonucleotide drug, known as inotersen, that has been specifically designed to reduce production of the protein transthyretin by the liver, can slow or stop the progression of TTR amyloid cardiomyopathy as compared to historical controls, using advanced echocardiography and cardiac MRI. The study also aims to determine the tolerability and safety of this drug when administered over a 24-month period to patients with TTR amyloid cardiomyopathy.
• Patients must have ATTR amyloidosis, defined as is defined as an echocardiographic appearance of left ventricular wall thickness of 13 mm or more, in the absence of uncontrolled hypertension, and with EITHER a positive biopsy for amyloid, which also stains positive for TTR by immunochemistry or mass spectrometry OR a positive cardiac technetium pyrophosphate scan with isotope uptake in the heart equal or greater to rib uptake and with no evidence of a plasma cell dyscrasia.
• For patients meeting the above criteria, wild-type TTR amyloidosis (ATTRwt)will be defined as having transthyretin genetic sequencing negative for a mutation. Mutant/hereditary TTR (ATTRh) will be defined as TTR amyloid cardiomyopathy with TTR sequencing showing an amyloidogenic mutation. A positive biopsy can be from any organ, providing that the echocardiographic appearance is typical of amyloidosis.
• 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.
• Age 18-85 years
• Male, or non-pregnant, non-lactating females. If a woman is premenopausal, or 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
• Written informed consent to be obtained prior to study treatment
• If diagnosis is made by tissue biopsy histochemical diagnosis (positive stains for TTR in absence of staining for light chains, or AA amyloid) in the presence of green birefringent material in Congo red-stained tissue specimens or sulfated Alcian blue stain typical for amyloid deposition. NB. All patients will have had a definitive diagnosis of TTR amyloidosis made prior to study entry, either by tissue biopsy or positive PYP scan, and all will have been genotyped. No further diagnostic testing will need to be done at or after study entry.
• If diagnosis is made by nuclear imaging, a positive technetium pyrophosphate scan, characterized by isotope uptake in the heart of an intensity equal to or greater than, rib uptake.
• Willingness to return to the treating center for follow-up.
• Willingness and ability to self-administer, or to have spouse administer weekly subcutaneous injections of study drug.
• Willingness to take daily oral Vitamin A supplementation throughout the study and for 3 months thereafter.