Inotersen and patisiran are two novel agents that have been approved by the US Food and Drug Administration (FDA) for treating polyneuropathy in adults caused by hereditary transthyretin (TTR) amyloidosis. They are the first US approvals of a new class of drugs called small interfering ribonucleic acid (siRNA) treatments, which inhibit the production of TTR in the liver by silencing specific genes. Patisiran was approved by the FDA for this indication in August 2018,  and inotersen (available only through a Risk Evaluation and Mitigation Strategy [REMS] program) was approved in October 2018. 
Approval of patisiran was based on the results of an 18-month randomized placebo-controlled phase III trial (APOLLO).  In the trial, patisiran reduced neurologic impairment and improved quality-of-life compared with placebo in patients with TTR amyloidosis with polyneuropathy. The incidence and severity of adverse events were similar in patients receiving patisiran and placebo.
Approval of inotersen was based on the results of a 15-month randomized controlled trial. In the trial, inotersen reduced neurologic impairment and improved quality-of-life compared with placebo in patients with hereditary TTR amyloidosis with polyneuropathy.  Severe thrombocytopenia and glomerulonephritis may occur with inotersen; therefore, regular monitoring of platelets and renal function is required.
TTR amyloidosis is the most common form of inherited amyloidosis. It is a progressively debilitating disease that can lead to death. Liver transplantation is considered standard of care for these patients; however, this is limited to those who are fit enough for transplantation and who have a suitable donor. Inotersen and patisiran provide clinicians with alternative treatment options to liver transplantation in patients with TTR amyloidosis.See Management: approach See Management: treatment algorithm
An amyloid tissue deposition disease that may have a primary cause or be secondary to other diseases.
Usually presents with unexplained weight loss, fatigue, and edema resistant to diuretic therapy.
Immunofixation of the serum and urine confirms the presence of monoclonal light chains in primary systemic amyloidosis. Biopsy verification of amyloid deposits is essential.
Treatment includes appropriate management of resulting clinical syndromes, such as nephrotic syndrome, neuropathy, cardiomyopathy, and conduction disorders.
Definitive treatment of primary systemic amyloidosis (AL amyloidosis) includes myeloablative high-dose chemotherapy with stem cell reconstitution in selected patients, or chemotherapy.
Any histologic tissue specimen that binds the cotton wool dye, Congo red, and demonstrates green birefringence when viewed under polarized light is, by definition, an amyloid deposit. The patient with this deposit has amyloidosis. Deposits of amyloid may be localized in tissue or part of a systemic process. Progressive deposition of amyloid is disruptive to tissue and organ function and manifests its clinical sequelae by the dysfunction of those organs in which it deposits.  
Seidler Jr. Professor of Medicine
Consultant in Hematology
Chair Emeritus of the Department of Medicine
Mayo Distinguished Clinician
Mayo Clinic College of Medicine
MAG declares that he has received honoraria from Celgene Corporation, Prothena Corporation Plc, Onyx Pharmaceuticals, Alnylam, and Ionis Pharmaceuticals. MAG is also an author of several references cited in this monograph.
Associate Professor of Medicine
Program for Multiple Myeloma and Related Diseases
Princess Margaret Hospital
DR has been reimbursed by Millennium Pharmaceuticals, Inc and Johnson and Johnson, the manufacturers of bortezomib, for attending several conferences, for speaking at educational meetings, and for consulting work. She has also been reimbursed by Celgene, the manufacturer of lenalidomide and thalidomide, for attending several symposia and serving as a speaker.
Assistant Professor of Medicine and Oncology
Division of Hematology/Oncology
Wayne State University School of Medicine
Barbara Ann Karmanos Cancer Institute
JZ declares that he has no competing interests.
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