Tegsedi (inotersen) and Onpattro (patisiran) are both effective treatments to stop the progression of familial amyloid polyneuropathy (FAP), alleviate gastrointestinal symptoms, and improve patients’ overall quality of life, a review study has found.
FAP, also known as hereditary transthyretin amyloidosis, is a rare progressive disease caused by genetic mutations in the TTR gene, which provides instructions for making a protein called transthyretin (TTR).
When mutations occur, the structure of transthyretin changes, preventing it from binding to other TTR proteins, a process necessary for its normal transport function. The abnormal TTR protein then starts to form amyloid deposits that accumulate in tissues — including the nerves, heart, kidneys, and eyes — slowly causing damage and eventually giving rise to symptoms associated with FAP.
Tegsedi, originally developed by Ionis Pharmaceuticals and now licensed to Ionis and Akcea Therapeutics, and Onpattro, developed by Alnylam Pharmaceuticals, are two types of RNA-targeted therapies approved for the treatment of FAP. For reference, RNA is the molecule that serves as the template for the production of a protein.
Tegsedi is a chemically modified RNA molecule (antisense oligonucleotide), whereas Onpattro is made up of small lipid nanoparticles that contain small interfering RNAs. Both medications work by preventing mutated TTR messenger RNA from being translated into an abnormal TTR protein, reducing the accumulation of amyloid deposits in tissues.
This review focused on summarizing the main findings of clinical trials that had been designed to assess the effectiveness of Tegsedi and Onpattro in FAP patients, especially regarding clinical objectives evaluating the effects of the medications on patients’ autonomic nervous system (a non-conscious part of the nervous system that controls several body functions).
The randomized, double-blinded, placebo-controlled Phase 2/3 NEURO-TTR trial (NCT01737398) assessed the efficacy of Tegsedi in reducing disease progression and improving quality of life in a group of 172 adults with FAP over a period of 15 months.
To measure disease activity and progression, the modified neuropathy impairment score plus 7 was used, while the Norfolk quality of life diabethic neuropathy questionnaire was used to evaluate patients’ quality of life.
Trial findings showed that disease progression was halted in 36% of those treated with Tegsedi. In addition, half of the patients on Tegsedi reported significant improvements in their overall quality of life.
The randomized, double-blinded, placebo-controlled Phase 3 APOLLO trial (NCT01960348) focused on assessing the safety and effectiveness of Onpattro in a group of 200 adults with FAP over a period of 18 months.
Results showed that FAP stabilized in 74% of the patients who had been treated with Onpattro. In addition, 51% of the patients on Onpattro reported significant improvements in their overall quality of life.
Moreover, treatment with Onpattro also minimized the impact of FAP on patients’ autonomic function, measured by the composite autonomic symptom score, and nutritional status, suggesting the medication had a positive effect on patients’ gastrointestinal autonomic function.
“Autonomic dysfunction and gastrointestinal involvement are [some of] the main manifestations of [FAP], responsible for poor quality of life and survival of … patients,” the authors wrote.
“Both drugs were able to demonstrate effectiveness in halting disease progression and even offering potential improvement in the different domains of the neuropathy and quality of life. … The information on their impact on autonomic parameters is limited, warranting further dedicated studies,” they added.