By Norman Latov, MD, PhD
Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director of the Neuropathy Center, Weill Cornell Medicine
SYNOPSIS: Hereditary transthyretin-mediated amyloidosis with polyneuropathy is effectively treated by patisiran, a lipid nanoparticle ribonucleic acid interference that binds to transthyretin (TTR) messenger RNA and inhibits TTR production in the liver, resulting in reduction of the serum TTR concentration. Treatment effect has been sustained during a five-year open-label extension study.
SOURCE: Adams D, Polydefkis M, Gonzalez-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol 2021;20:49-59.
In an interim 12-month analysis of an ongoing five-year open-label extension trial of patisiran in patients with hereditary transthyretin-mediated amyloidosis (hTTRA), continued treatment with patisiran appeared to maintain efficacy with an acceptable safety profile. The trial involved 211 patients at 43 clinical centers in 19 countries who completed Phase II or Phase III trials previously, that showed that patisiran reduced serum concentrations of transthyretin (TTR), with significant improvement in the neuropathy. Based on those studies, patisiran was approved by the Food and Drug Administration for treatment of hTTRA in 2018.
The aim of the extension trial was to assess the long-term efficacy and safety of patisiran, administered by infusion every three weeks. The primary outcome measure was the modified Neuropathy Impairment Score +7 (mNIS+7) and secondary measures included quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Of the 211 patients in the extension trial, 189 completed the 12-month efficacy assessment. The interim analysis showed that in patients treated previously with patisiran, the improvement in the outcome measures was maintained through the extension period, and that in patients previously on placebo, treatment with patisiran resulted in improvement of the neuropathy with reduction of serum TTR concentrations consistent with the results of the prior clinical trials.
In the course of the study, 21 subjects (10%) died, nine were withdrawn because of adverse events, four were withdrawn as the result of physician or patient decisions, and 39% reported serious adverse events. These events were largely the result of amyloidosis-related cardiac or renal disease rather than a result of the drug itself and occurred more often in patients with more severe neuropathy and greater disease who previously were in the placebo group. Overall, adverse events were reported in 97% of the patients, with the majority mild or moderate in severity and temporally related to the infusions.
A rare disease that is estimated to affect approximately 10,000 people globally, hTTRA is caused by mutations in the TTR gene that promote aggregation of TTR and deposition of amyloid fibrils in the peripheral nerves, heart, and other tissues. Typically, patients develop neuropathy and cardiomyopathy which, if left untreated, have a median survival of four to seven years after diagnosis.
Patisiran is a lipid nanoparticle ribonucleic acid interference (RNAi) that binds to TTR messenger RNA and inhibits TTR production in the liver, resulting in reduction of the serum TTR concentration. In a previous Phase III trial, treatment with patisiran for 18 months was shown to reduce serum TTR concentration and to improve motor, sensory, and autonomic nerve functions, with a similar incidence of adverse events as in the placebo group. The current interim analysis of an ongoing, five-year open-label extension study showed that the improvement was sustained for a period of 12 months on continued treatment, with an acceptable safety profile.
Historically, hTTRA neuropathy was treated by liver transplant, which slowed, but did not prevent, progression of the neuropathy. More recently, treatment with inotersen, an antisense nucleotide inhibitor of TTR protein synthesis, also was reported to result in sustained improvement.1 The availability of effective therapy that can maintain improvement increases the importance of early diagnosis and treatment that can prevent irreversible damage and progression to disability and death. The diagnosis of hTTRA neuropathy should be considered in anyone with neuropathy of otherwise unknown etiology, and especially if there is autonomic involvement, or if it is associated with cardiac or renal disease. Less common presentations include carpal tunnel syndrome, spinal stenosis, small fiber neuropathy, or chronic inflammatory demyelinating polyneuropathy that is resistant to therapy. Diagnosis involves deoxyribonucleic acid testing, biopsy, and amyloid typing.2
- Brannagan TH, Wang AK, Coelho T, et al. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: A 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol 2020;27:1374-1381.
- Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol 2020; Jan 6. doi: 10.1007/s00415-019-09688-0. [Online ahead of print].