Abstract
Background and Objective
Variants of the transthyretin (TTR) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition of misfolded TTR protein as amyloid in organs and tissues. Patisiran is an RNA interference (RNAi) therapeutic that suppresses the hepatic production of TTR protein. Patisiran improves multiple clinical manifestations of hATTR amyloidosis in patients without liver transplantation (LT). Because the liver is the predominant source of circulating TTR, LT has been prescribed to eliminate the production of the variant TTR. However, the continued production of wild-type TTR can contribute to disease progression after LT. Patisiran could potentially address an unmet need in these affected patients. This clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) and pharmacodynamics (PD) of patisiran in patients with hATTR amyloidosis with polyneuropathy progression after LT. In this paper, we describe the PK/PD of patisiran in post-LT patients and compare it with prior patisiran studies in healthy subjects and patients without LT.
Methods
In an open-label study, patients (N = 23) with hATTR amyloidosis with polyneuropathy progression after LT received 0.3 mg/kg patisiran intravenously every 3 weeks (q3w) for 12 months. As a post hoc analysis, the PK and PD results from the current study were compared with prior patisiran studies in healthy volunteers from a Phase 1 study and in patients with hATTR amyloidosis without LT from Phase 2 and 3 studies.
Results
The PK profile of patisiran siRNA (ALN-18328) and its 2 lipid excipients, DLin-MC3-DMA and PEG2000-C-DMG, in hATTR amyloidosis patients after LT was consistent with prior patisiran studies in non-LT subjects. Plasma PK profiles of ALN-18328 and DLin-MC3-DMA exhibited 2 phases, the first characterized by a short distribution half-life and the second by a minor peak and relatively long elimination half-life. The plasma concentrations of PEG2000-C-DMG reached Cmax at the end of infusion and declined in a multiphasic manner. There was no appreciable accumulation at steady state. Consistent with prior studies in non-LT subjects, the post-LT patients showed a robust, and sustained TTR reduction; with median TTR reduction from baseline of 91% (average of Month 6 and Month 12). No anti-drug antibodies were observed in any patient.
Conclusions
The consistency of patisiran PK and PD between patients with and without LT suggests that neither LT nor concomitantly administered immunosuppressants influence hepatic uptake or RNAi activity of patisiran. The patisiran dosing regimen of 0.3 mg/kg q3w is appropriate for hATTR amyloidosis patients with or without LT.
Clinical Trial Registration No
NCT03862807.
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The authors thank the study investigators for conducting the study.
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This work was supported by Alnylam Pharmaceuticals Inc. Alnylam Pharmaceuticals Inc. contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the manuscript for publication.
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Prajakta Badri, Bahru Habtemariam, Megan Melch, Valerie A. Clausen, Seth Arum, Xingyu Li, Patrick Y. Jay, John Vest, Gabriel J. Robbie are or were Alnylam Pharmaceutical employees and may hold Alnylam stocks or options.
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This study was conducted in accordance with the Good Clinical Practice Guideline as defined by the International Conference on Harmonisation, the Declaration of Helsinki, and all applicable federal and local regulations. The study was approved by independent institutional review boards.
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PB, MM and XL contributed to the data analyses for this manuscript, interpretation of results, writing and reviewing of the manuscript. BH, VC, SA, PJ, JV and GR contributed to the study design, interpretation of results, and writing and reviewing of the manuscript.
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Badri, P., Habtemariam, B., Melch, M. et al. Pharmacokinetics and Pharmacodynamics of Patisiran in Patients with hATTR Amyloidosis and with Polyneuropathy After Liver Transplantation. Clin Pharmacokinet 62, 1509–1522 (2023). https://doi.org/10.1007/s40262-023-01292-w
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DOI: https://doi.org/10.1007/s40262-023-01292-w