How Tegsedi works
FAP is a hereditary progressive condition caused by a mutation in the transthyretin (TTR) gene, which contains 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 cause 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 (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 — the treatment slows down the synthesis of both forms.
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 (cardiomyopathy), 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 underway 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, 18 to 85 years old, 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 MRI. The trial is not yet open for recruitment.
An ongoing Phase 3 trial (NCT02175004) is also testing the long-term safety and efficacy of Tegsedi in FAP patients. This is a five-year open-label study that will evaluate the patient’s ability to tolerate the extended dosing regimen of Tegsedi in an estimated 135 eligible FAP patients, 18 years and older.
The European Commission approved the use of Tegsedi in the E.U. in July 2018 for adults with stage one and two polyneuropathies. It also provided authorization to market Tegsedi in those 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 been shown to cause low platelet counts and glomerulonephritis. Therefore, according to its 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.
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