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Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG2000 -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.

Authors+Show Affiliations

Alnylam Pharmaceuticals, Cambridge, MA, USA.Alnylam Pharmaceuticals, Cambridge, MA, USA.Alnylam Pharmaceuticals, Cambridge, MA, USA.Alnylam Pharmaceuticals, Cambridge, MA, USA.Alnylam Pharmaceuticals, Cambridge, MA, USA.Alnylam Pharmaceuticals, Cambridge, MA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31322739

Citation

Zhang, Xiaoping, et al. "Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis." Journal of Clinical Pharmacology, 2019.
Zhang X, Goel V, Attarwala H, et al. Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. J Clin Pharmacol. 2019.
Zhang, X., Goel, V., Attarwala, H., Sweetser, M. T., Clausen, V. A., & Robbie, G. J. (2019). Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. Journal of Clinical Pharmacology, doi:10.1002/jcph.1480.
Zhang X, et al. Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. J Clin Pharmacol. 2019 Jul 19; PubMed PMID: 31322739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis. AU - Zhang,Xiaoping, AU - Goel,Varun, AU - Attarwala,Husain, AU - Sweetser,Marianne T, AU - Clausen,Valerie A, AU - Robbie,Gabriel J, Y1 - 2019/07/19/ PY - 2019/02/25/received PY - 2019/06/12/accepted PY - 2019/7/20/entrez KW - exposure-response KW - hereditary transthyretin-mediated amyloidosis (hATTR) KW - patisiran KW - pharmacodynamics (PD) KW - pharmacokinetics (PK) KW - small interfering ribonucleic acid (siRNA) JF - Journal of clinical pharmacology JO - J Clin Pharmacol N2 - Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG2000 -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis. SN - 1552-4604 UR - https://www.unboundmedicine.com/medline/citation/31322739/Patisiran_Pharmacokinetics,_Pharmacodynamics,_and_Exposure-Response_Analyses_in_the_Phase_3_APOLLO_Trial_in_Patients_With_Hereditary_Transthyretin-Mediated_(hATTR)_Amyloidosis L2 - https://doi.org/10.1002/jcph.1480 DB - PRIME DP - Unbound Medicine ER -