Tegsedi (Inotersen)

Tegsedi (inotersen or ISIS 420915) is an approved treatment for adult patients with familial amyloid polyneuropathy (FAP). It is a once-weekly injection that is administered under the skin (subcutaneously).

Ionis Pharmaceuticals developed Tegsedi under the name IONIS-TTRRx, and the global marketing license of the treatment is held by Ionis and its subsidiary, Akcea Therapeutics. PTC Therapeutics has licensed commercialization rights for Tegsedi in Latin America.

How does Tegsedi work?

FAP is a hereditary progressive condition caused by a mutation in the transthyretin (TTR) gene, which contains the information necessary for the production of the TTR protein. The mutation results in the production and accumulation of an abnormal form of TTR protein, especially in the heart, kidneys, nervous system, and eyes. These abnormal protein deposits, called amyloids, damage these organs over time and lead to the symptoms of FAP

Tegsedi is designed to interfere with the production of TTR and prevent the buildup of amyloid deposits.

For a protein to be produced, the coding gene is first copied into an intermediary molecule called a messenger RNA or mRNA. This molecule is then read by the protein-making machinery of the cell, and a protein is synthesized.

Tegsedi is a chemically modified RNA molecule (a so-called antisense oligonucleotide) that binds to TTR mRNA and stops it from being read, thereby halting TTR protein production. Tegsedi does not differentiate between normal and mutated TTR mRNA ­­­­and  the treatment slows down the synthesis of all TTR protein.

Tegsedi in clinical trials

A Phase 2/3 clinical trial (NCT01737398) called the NEURO-TTR Study tested the efficacy of Tegsedi in slowing down or stopping nerve damage in 172 adults with FAP over 15 months. The patients were randomly grouped to either receive 300 mg of Tegsedi a week or a placebo. Results showed that Tegsedi slowed the progression of nerve cell damage and improved the quality of life of the patients, irrespective of disease stage, heart involvement, and type of mutation. The most commonly reported side effects were kidney disease (glomerulonephritis) and low platelet counts (thrombocytopenia), both of which could be managed with better monitoring.

Before its approval by the U.S. Food and Drug Administration (FDA), an expanded access program (NCT03400098) was designed to provide Tegsedi to a maximum of 100 patients, 18 years and older, who have no or limited access to any treatment options in the U.S.

A Phase 2 clinical trial (NCT03702829) is currently recruiting participants in Brigham and Women’s Hospital, Boston, Massachusetts, to test the long-term (two years) tolerability and safety of Tegsedi in FAP patients with amyloid deposits in the heart (cardiac amyloidosis). The trial aims to recruit 50 patients, ages, 18 to 85 to receive 300 mg of Tegsedi weekly. The study includes follow-up visits after three weeks, six weeks, 12 months, and 24 months of treatment. The impact of the treatment on disease progression will be monitored using cardiac biomarkers, the six-minute walk test for physical function, echocardiograms, and magnetic resonance imaging (MRI). The trial is estimated to be completed in March 2022.

A long-term Phase 3 trial (NCT02175004) tested the  safety and efficacy of Tegsedi over five years in 135 adults with FAP who had completed the NEURO-TTR study: 85 who were continuing with Tegsedi and 50 who switched from placebo to the therapy in this trial, which concluded in early 2021. An interim analysis showed continued benefit in patients on continuous treatment, and improvements or disease stabilization over  time in those previously on a placebo.

Other information

The European Commission approved the use of Tegsedi in the E.U. in July 2018 for adults with stage 1 and 2 polyneuropathies. It also provided authorization to market Tegsedi in European countries. The FDA and Health Canada followed suit in October 2018, granting Tegsedi approval for use in adult FAP patients in the U.S. and Canada. Tegsedi has also received marketing approval from the Brazilian Health Regulatory Agency, ANVISA.

Tegsedi has been shown to cause low platelet counts and glomerulonephritis. Therefore, according to FDA warning, Tegsedi is not recommended for patients with existing thrombocytopenia. Platelet counts should be very closely monitored in patients taking Tegsedi. Furthermore, Tegsedi treatment should not be started in patients with weak kidney function or glomerulonephritis as indicated by their creatinine levels.


Last updated: June 11, 2021


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