Last reviewed: December 2018
Last updated: October  2018
26 Oct 2018

Inotersen and patisiran approved in the US for the treatment of polyneuropathy in adults with hereditary TTR amyloidosis

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, [38] and inotersen (available only through a Risk Evaluation and Mitigation Strategy [REMS] program) was approved in October 2018. [39]

Approval of patisiran was based on the results of an 18-month randomized placebo-controlled phase III trial (APOLLO). [40] 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. [41] 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

Original source of update



History and exam

Key diagnostic factors

  • jugular venous distention
  • lower extremity edema
  • periorbital purpura
  • macroglossia

Other diagnostic factors

  • fatigue
  • weight loss
  • dyspnea on exertion
  • paresthesia
  • claudication
  • nausea
  • abdominal cramps
  • alternating bowel habit
  • lightheaded/orthostatic hypotension
  • submandibular salivary gland enlargement
  • hepatomegaly
  • shoulder pad sign
  • diffuse muscular weakness
  • sensory neuropathy
  • Tinel sign
  • Phalen maneuver

Risk factors

  • monoclonal gammopathy of undetermined significance (MGUS)
  • inflammatory polyarthropathy
  • chronic infections
  • inflammatory bowel disease
  • Castleman disease
  • familial periodic fever syndromes

Diagnostic investigations

1st investigations to order

  • serum immunofixation
  • urine immunofixation
  • immunoglobulin free light chain assay
  • bone marrow biopsy
Full details

Investigations to consider

  • tissue biopsy
  • immunohistologic studies of amyloid deposits
  • mass spectrometry
  • immuno-electron microscopy
  • genetic testing
  • CBC
  • comprehensive metabolic profile
  • 24-hour urine collection
  • serum troponin level
  • B-type natriuretic peptide
  • beta-2-microglobulin
  • ECG
  • echocardiogram
  • Doppler echo with strain
  • cardiac MRI
Full details

Treatment algorithm


Authors VIEW ALL

Morie A. Gertz

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.

Peer reviewers VIEW ALL

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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