OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Patisiran – Onpattro®

DRUG CLASS

Genetic Disorder Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 03 January 2023

Abbreviations: mRNA, messenger RNA; siRNA, small interfering RNA.

• FDA. Patisiran. Clinical Review. 2018. Available at:
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2018/210922Orig1s000MultiR​.pdf .

  (The FDA clinical review of patisiran for efficacy and safety reported that ALT elevations arose in 20% of patisiran- vs 10% of placebo-recipients in preregistration controlled trials, but that all elevations were transient, less than 5 times the ULN, and were not associated with jaundice or symptoms; in addition, there were no hepatic serious adverse events or deaths).
• Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109. [PMC free article: PMC4559363] [PubMed: 26338094]

  (Among 29 patients with hereditary transthyretin amyloidosis with polyneuropathy treated with varying doses regimens of patisiran, there was a rapid marked decline in serum transthyretin levels [averaging -85%] and adverse events were mild-to-moderate, mostly infusion reactions, not requiring discontinuation, and “no clinically significant changes in liver function tests…were recorded”).
• Butler JS, Chan A, Costelha S, Fishman S, Willoughby JL, Borland TD, Milstein S, et al. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid. 2016;23:109–18. [PMC free article: PMC4898164] [PubMed: 27033334]

  (In a murine model of hereditary transthyretin-mediated amyloidosis, patisiran resulted in knock down of transthyretin and dose related regression of amyloid deposits).
• Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:11–21. [PubMed: 29972753]

  (Among 245 patients with hereditary transthyretin amyloidosis treated with patisiran [0.3 mg/kg] or placebo intravenously every 3 weeks for up to 6 months, neuropathy and quality of life scores improved with patisiran therapy and usually worsened with placebo, while adverse event rates were similar in the two groups except for infusion reactions [19% vs 9%] and peripheral edema [30% vs 22%], and there were no “clinically relevant changes in laboratory values” including indicators of liver function).
• Hoy SM. Patisiran: first global approval. Drugs. 2018 Oct;78(15):1625–1631. [PubMed: 30251172]

  (Review of the mechanism of action, structure, history of development, clinical efficacy and safety of patisiran shortly after its approval for use in hereditary transthyretin amyloidosis with polyneuropathy, mentions that there were no treatment related serious adverse events; no mention of ALT elevations or hepatotoxicity).
• Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–46. [PubMed: 30846871]

  (Extensive review of gene silencing using RNA interference pathways and the potential of RNAi therapeutics which have promise in many genetic and acquired diseases including transthyretin amyloidosis [transthyretin], HIV infection [CCR5], HBV [HBV mRNA], alpha-1-antitrypsin deficiency [zz A1AT], hypercholesterolemia [PCSK9]).
• Zhang X, Goel V, Attarwala H, Sweetser MT, Clausen VA, Robbie GJ. Patisiran pharmacokinetics, pharmacodynamics, and exposure-response analyses in the phase 3 APOLLO Trial in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. J Clin Pharmacol. 2020;60:37–49. [PMC free article: PMC6972979] [PubMed: 31322739]

  (Pharmacokinetic studies conducted on 145 patients with hereditary transthyretin amyloidosis treated with patisiran for 18 months demonstrated stable drug levels and only 5 subjects developed anti-drug antibodies [3.4%] that had no appreciable effects on drug levels, efficacy or safety).
• Coelho T, Adams D, Conceição I, Waddington-Cruz M, Schmidt HH, Buades J, Campistol J, et al. A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. Orphanet J Rare Dis. 2020;15:179. [PMC free article: PMC7341568] [PubMed: 32641071]

  (Among 27 patients with transthyretin amyloidosis participating in a phase 2 trial of patisiran which was then continued for 24 months, improvements in neuropathy and quality of life were sustained and adverse events were generally mild, with no discontinuations for adverse events and no significant changes in liver biochemical test results).
• Adams D, Polydefkis M, González-Duarte A, Wixner J, Kristen AV, Schmidt HH, Berk JL, et al. patisiran Global OLE study group. 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. [PubMed: 33212063]

  (Among 211 patients with hereditary transthyretin amyloidosis and polyneuropathy enrolled in an open label extension study after phase 2 and 3 controlled trials of patisiran, improvements in neuropathy and quality of life scores arose in placebo groups when crossed over to active therapy and were sustained in active treatment groups, and there were “no clinically relevant safety concerns…related to hepatic events”).
• Luigetti M, Servidei S. Patisiran in hereditary transthyretin-mediated amyloidosis. Lancet Neurol. 2021;20:21–23. [PubMed: 33212064]

  (Editorial in response to Adams [2021] summarizing results on the efficacy of patisiran in hereditary transthyretin amyloidosis and discussing the uncertainty related to long term therapy and treatment of advanced disease and cardiomyopathy).
• Suzuki Y, Ishihara H. Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. Drug Metab Pharmacokinet. 2021;41:100424. [PMC free article: PMC8502116] [PubMed: 34757287]

  (Description of the lipid components used to create nanoparticles for administration of patisiran, the lipids protecting the RNA against nuclease digestion and allowing uptake by hepatocytes [via the LDL receptor] and release of the siRNA with acidification of the endosomes containing the incorporated patisiran).
• Schmidt HH, Wixner J, Planté-Bordeneuve V, Muñoz-Beamud F, Lladó L, Gillmore JD, Mazzeo A, et al. Patisiran Post-LT Study Group. Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. 2022;22:1646–1657. [PMC free article: PMC9310767] [PubMed: 35213769]

  (Among 12 patients with hereditary transthyretin amyloidosis with polyneuropathy who had undergone liver transplant but continued to have neuropathy were treated with patisiran for at least 12 months, neuropathy and autonomic syndrome scores improved while disability and nutrition status were stable; 11 [48%] patients developed ALT elevations that were usually transient and mild, one developed acute rejection and one cholangitis, but all abnormalities resolved despite continued patisiran therapy without dose modification).
• Aimo A, Castiglione V, Rapezzi C, Franzini M, Panichella G, Vergaro G, Gillmore J, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis. Nat Rev Cardiol. 2022;19(10):655–667. [PubMed: 35322226]

  (Extensive review of the molecular basis of hereditary transthyretin amyloidosis and the small molecule and RNA based therapies in current use and in experimental clinical trials, mentions the efficacy and relative safety of patisiran which has not been linked to instances of liver dysfunction).
• Di Stefano V, Fava A, Gentile L, Guaraldi P, Leonardi L, Poli L, Tagliapietra M, et al. Italian real-life experience of patients with hereditary transthyretin amyloidosis treated with patisiran. Pharmgenomics Pers Med. 2022;15:499–514. [PMC free article: PMC9113125] [PubMed: 35592550]

  (Case histories of 9 patients with transthyretin amyloidosis with polyneuropathy who were treated long term with patisiran in “Italian real-life” with clinical improvement and excellent tolerance; no mention of ALT elevations or hepatotoxicity).
• Maurer MS. Overview of current and emerging therapies for amyloid transthyretin cardiomyopathy. Am J Cardiol. 2022;185 Suppl 1:S23–S34. [PubMed: 36371281]

  (Review of the molecular basis of therapies for the cardiomyopathy of hereditary transthyretin-mediated amyloidosis including RNA silencing approaches such as patisiran and vutrisiran).
• Ranasinghe P, Addison ML, Dear JW, Webb DJ. Small interfering RNA: Discovery, pharmacology and clinical development–An introductory review. Br J Pharmacol. 2022 Oct 17; Epub ahead of print. [PubMed: 36250252]

  (Review of the history of development, mechanism of action, methods of delivery, clinical efficacy and safety of RNA silencing drugs including lumasiran, givosiran, inclisiran, patisiran and vutrisiran, discusses adverse events from patisiran of injection site reactions, but does not mention hepatotoxicity or ALT elevations).