By Norman Latov, MD, PhD
Synopsis: A five-year study on patisiran for hereditary transthyretin (TTR) amyloid polyneuropathy found that 65% of patients had stable or improved neuropathy, with better outcomes linked to early treatment. Despite efficacy, 19.4% of patients died. The study underscores the importance of early diagnosis and intervention in managing this progressive disease.
Source: Adams D, Wixner J, Polydefkis M, et al; Patisiran Global OLE Study Group. Five-year results with patisiran for hereditary transthyretin amyloidosis with polyneuropathy: A randomized clinical trial with open-label extension. JAMA Neurol. 2025; Jan 13. doi: 10.1001/jamaneurol.2024.4631. [Online ahead of print].
Adams and colleagues reported on the long-term efficacy and safety of patisiran for treatment of hereditary transthyretin amyloid polyneuropathy. The study included 138 of 211 eligible patients who enrolled and completed an open-label extension study from 43 hospitals or clinical centers in 19 countries. Outcome criteria included measures of neuropathy disability, severity, impairment, quality of life, and nutritional status.
Of the 138 patients completing the study, 89 (65%) had stable or modest improvement from baseline in the neuropathy measures over the five years of the study. Seventy-three patients (35%) were withdrawn from the study. Adverse events, including diarrhea or edema, or infusion-related reactions led to study withdrawal in 47 subjects (22%). Overall, 41 patients (19.4%) died during the study.
Lower baseline neuropathy scores and earlier treatment were associated with significantly improved survival. The authors emphasized the importance of early diagnosis and treatment.
Commentary
Hereditary transthyretin amyloidosis (ATTR) is an autosomal-dominant disorder caused by mutations of the transthyretin (TTR) gene, leading to the misfolding and deposition of amyloid fibrils in tissues, with the most severe disease manifestations being neuropathy and cardiomyopathy. Progression is variable, depending on the specific mutation, but patients worsen steadily over time. Those with the most common late-onset Val30Met mutation require a walking aid within two to 3.8 years of symptom onset, and require the use of a wheelchair within four to seven years. Median survival after the diagnosis of neuropathy is 4.7 years.
This contrasts with the stabilization or improvement over an average of five years in 65% of patients treated with patisiran in the current study. Still, approximately 20% of subjects died in the course of the study, so there is room for improvement. The authors indicated that earlier diagnosis and treatment would improve outcomes.
Patisiran belongs to a class of drugs called ribonucleic acid interference (RNAi) agents composed of complementary RNA sequences that bind to, silence, and degrade the mRNA coding for TTR. This results in decreased hepatic production of both the mutated and nonmutated protein, with an 80% reduction in mean TTR levels within two weeks of a single infusion of patisiran.
Other U.S. Food and Drug Administration (FDA)-approved RNAi therapies for ATTR amyloid neuropathy include vutrisiran, inotersen, and eplontersen. Both patisiran and vutrisiran have been shown to induce a sustained improvement in the neuropathy, quality of life, and cardiac symptoms over prolonged treatment periods.1 Inotersen has been shown to slow progression, and eplontersen has been shown to prevent progression of the neuropathy.2 However, competition does not appear to affect pricing, with costs being approximately $500,000 per year. Tafamidis, which is a TTR stabilizer that prevents TTR tetramer dissociation and amyloid fiber formation, is FDA-approved for ATTR amyloid cardiomyopathy but not for neuropathy, although it also is approved for neuropathy by the European Medical Agency.3
Despite being a potentially devastating disease that can be arrested with early intervention, the diagnosis of amyloid neuropathy often is delayed or missed, even if reliable deoxyribonucleic acid tests are available.3 The clinical presentation is highly variable, and it can begin subtly with carpal tunnel syndrome or small fiber neuropathy that often is idiopathic, so that it is not routinely tested for. The differential diagnosis includes primary amyloidosis, which results from tissue deposition of immunoglobulin light chains. Deposition of wild-type or non-mutated TTR in amyloid cardiomyopathy rarely is associated with neuropathy, so that other causes for neuropathy should be considered in such patients. The diagnosis of hereditary amyloid neuropathy should be suspected and tested for in any patient with progressive neuropathy of otherwise unknown etiology, especially if autonomic symptoms or cardiac disease are present, even in the absence of a family history of neuropathy.
Norman Latov, MD, PhD, is Professor of Neurology, Weill Cornell Medicine.
References
- Karimi MA, Moallem FE, Gholami Chahkand MS, et al. Assessing the effectiveness and safety of patisiran and vutrisiran in ATTRv amyloidosis with polyneuropathy: A systematic review. Front Neurol. 2024;15:1465747.
- Conceição I , Berk JL , Weiler M, et al. Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: Analysis from NEURO-TTRansform. J Neurol. 2024;271(10):6655-6666.
- Chaompoopong P, Mauermann ML, Siddiqi H, Peltier A. Amyloid neuropathy: From pathophysiology to treatment in light-chain amyloidosis and hereditary transthyretin amyloidosis. Ann Neurol. 2024;96(3):423-440.
A five-year study on patisiran for hereditary transthyretin (TTR) amyloid polyneuropathy found that 65% of patients had stable or improved neuropathy, with better outcomes linked to early treatment. Despite efficacy, 19.4% of patients died. The study underscores the importance of early diagnosis and intervention in managing this progressive disease.
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