Hereditary Transthyretin Amyloidosis (hATTR)

Tegsedi® (inotersen) is an antisense oligonucleotide (ASO) inhibitor indicated for the treatment of polyneuropathy associated with hereditary transthyretin amyloidosis (hATTR) in adults.1,2 Hereditary transthyretin amyloidosis derives from a mutation in the TTR gene that promotes the accumulation of TTR protein fragments as amyloid fibers, mainly in the nerves and the heart. In addition to the typical polyneuropathy and cardiomyopathy observed in hATTR, patients may experience symptoms affecting the kidneys, eyes, thyroid, and gastrointestinal tract.2 

Tegsedi has been developed by Ionis Pharmaceuticals and Akcea Therapeutics for use in patients with hATTR who present with stage 1 or stage 2 polyneuropathy, and it was granted approval in the European Union in July 2018 and by the US Food and Drug Administration (FDA) in October 2018.1-3 

Mechanism of Action and Usage of Tegsedi

The active ingredient of Tegsedi is inotersen, an ASO inhibitor of mutant and wild-type human TTR. Hereditary transthyretin amyloidosis is an autosomal dominant condition in which most of the amyloid deposits found in tissues and organs correspond to mutant and wild-type TTR protein resulting from the expression of mutated TTR and wild-type genes.2 Through a Watson-Crick hybridization mechanism, inotersen is able to bind selectively to the messenger RNA (mRNA) that encodes the TTR protein and promote the degradation of both mutant and wild-type TTR mRNA, preventing TTR protein synthesis in the liver.1-3 The reduction in the levels of circulating TTR results in lower amyloid deposition.1,2

Tegsedi is administered by subcutaneous injection once a week, and the recommended dose is 284 mg. Subcutaneous administration of inotersen has significantly reduced neurological progression and improved quality of life in patients with polyneuropathy and hATTR. This medication is contraindicated in patients with low platelet counts (<100×109/L) and in patients with hypersensitivity to the drug or who have developed acute glomerulonephritis following administration.1,2 

Read more about hATTR therapies

Warnings and precautions include stroke, thrombocytopenia, glomerulonephritis, neurologic adverse reactions, liver effects, and vitamin A deficiency.1,2 Close monitoring of patients before and during treatment is required due to the increased risk of thrombocytopenia and glomerulonephritis.3 Nausea, headache, fatigue, thrombocytopenia, fever, and reactions at the injection site are common adverse events.1,2

Inotersen in Clinical Studies

A phase 1 trial involving 65 healthy volunteers receiving inotersen or a placebo in single or multiple doses has been conducted to determine the pharmacodynamics, pharmacokinetics, safety, and tolerability of the drug. In this study, the levels of TTR protein decreased in the multiple-dose cohorts, and these levels were maintained for about 3 to 4 weeks following the last administered dose.4 

The NEURO-TTR (NCT01737398) trial was a randomized, double-blind, placebo-controlled phase 2/3 trial that evaluated the efficacy of Tegsedi over 15 months.5 Patients with stage 1 or stage 2 hATTR polyneuropathy were enrolled and randomized to receive inotersen at 300 mg or a placebo. In total, 173 patients were randomized and 172 received at least 1 dose. Data show that treatment with 300 mg of inotersen significantly improved symptoms related to neuropathy as well as health-related quality of life. The discontinuation of treatment in patients receiving inotersen resulted mainly from the adverse events experienced, such as nausea, fatigue, diarrhea, headache, pyrexia, thrombocytopenia, and low platelet count.6 

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Patients who completed the 15-month study were eligible to enroll in an open-label extension study focused on assessing the long-term safety and efficacy of inotersen (NCT02175004).7 In this study, 135 patients received inotersen for 5 years. A recent publication reports that long-term treatment with inotersen preserved health-related quality of life in these patients for up to 3 years.8

A 24-month, open-label, phase 2, investigator-initiated trial is studying inotersen in hereditary or wild-type ATTR patients presenting with cardiomyopathy who have a diagnosis confirmed by biopsy (NCT03702829).9 This is a single-center study that has enrolled 50 patients with cardiac amyloidosis to receive 300 mg of inotersen each week. The progression of the disease will be followed through cardiac biomarkers, 6-minute walk test, cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary stress tests.9 Preliminary results from 15 patients with moderate to severe cardiomyopathy show that inotersen promoted improvements in cardiac structural parameters and stabilization of functional cardiac parameters. By month 12, no patients showed signs of disease progression. Inotersen was well tolerated by these patients, and adverse events reported included injection site reactions, pruritus, and fatigue.10

An expanded access program was also developed in the United States (NCT03400098) to provide inotersen access to about 100 hATTR patients with limited or no treatment options.11


1. Tegsedi. Prescribing Information. Ionis Pharmaceuticals, Inc; 2018. Accessed July 12, 2022.

2. Keam SJ. Inotersen: first global approval. Drugs. 2018;78(13):1371-1376. doi:10.1007/s40265-018-0968-5

3. Gertz MA, Scheinberg M, Waddington-Cruz M, et al. Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Expert Rev Clin Pharmacol. 2019;12(8):701-711. doi:10.1080/17512433.2019.1635008

4. Ackermann EJ, Guo S, Benson MD, et al. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid. 2016;23(3):148-157. doi:10.1080/13506129.2016.1191458

5. Efficacy and safety of inotersen in familial amyloid polyneuropathy. November 29, 2012. Updated July 17, 2019. Accessed July 12, 2022.

6. Benson MD, Waddington-Cruz M, Berk JL,et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793

7. Open-label extension assessing long term safety and efficacy of IONIS-TTR Rx in familial amyloid polyneuropathy (FAP). June 26, 2014. Updated February 11, 2021. Accessed July 12, 2022.

8. Yarlas A, Lovley A, McCausland K, et al. Early data on long-term impact of inotersen on quality-of-life in patients with hereditary transthyretin amyloidosis polyneuropathy: open-label extension of NEURO-TTR. Neurol Ther. 2021;10(2):865-886. doi:10.1007/s40120-021-00268-x

9. 24 month open label study of the tolerability and efficacy of inotersen in TTR amyloid cardiomyopathy patients. October 11, 2018. Updated December 7, 2020. Accessed July 12, 2022.

10. Benson MD, Dasgupta NR, Rissing SM, Smith J, Feigenbaum H. Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid. 2017;24(4):219-225. doi:10.1080/13506129.2017.1374946

11. ATTR expanded access program (EAP) by Ionis. January 17, 2018. Updated August 5, 2019. Accessed July 12, 2022.

Reviewed by Debjyoti Talukdar, MD, on 7/18/2022.