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<title>12 CLINICAL PHARMACOLOGY </title>
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<code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/>
<title>12.1 Mechanism of Action </title>
<text>
<paragraph>Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.</paragraph>
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<title>12.2 Pharmacodynamics </title>
<text>
<paragraph>In Study 1 <content styleCode="italics">[see <linkHtml href="#ID_d00cc070-1e13-49ba-8b28-82c396df837d">Clinical Studies (14)</linkHtml>]</content>, following administration of the recommended WAINUA dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race.</paragraph>
<paragraph>Eplontersen also reduced the mean steady state serum vitamin A by 71% by Week 37 <content styleCode="italics">[see <linkHtml href="#ID_cd493879-fa68-44c1-a822-836796722d62">Warnings and Precautions (5.1)].</linkHtml>
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<content styleCode="bold">
<content styleCode="underline">Cardiac Electrophysiology</content>
</content>
</title>
<text>
<paragraph>At a dose 2.7-times the maximum recommended dose for WAINUA, clinically significant QTc interval prolongation was not observed.</paragraph>
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<code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/>
<title>12.3 Pharmacokinetics </title>
<text>
<paragraph>The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis.</paragraph>
<paragraph>Eplontersen C<sub>max</sub> and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7-times the recommended dose) in healthy volunteers. </paragraph>
<paragraph>Population estimates (mean ± SD) of steady state maximum concentrations (C<sub>max</sub>), and area under the curve (AUC<sub>τ</sub>) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C<sub>max</sub> and AUC was observed in repeated dosing (once every 4 weeks). </paragraph>
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<content styleCode="bold">
<content styleCode="underline">Absorption</content>
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<text>
<paragraph>Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates.</paragraph>
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<content styleCode="bold">
<content styleCode="underline">Distribution</content>
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<text>
<paragraph>Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen is bound to human plasma proteins (>98%) <content styleCode="italics">in vitro</content>. The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L.</paragraph>
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<content styleCode="bold">
<content styleCode="underline">Elimination</content>
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<text>
<paragraph>The terminal elimination half-life is approximately 3 weeks.</paragraph>
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<content styleCode="bold">Metabolism </content>
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<text>
<paragraph>Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.</paragraph>
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<id root="84aeecde-77cc-404b-93b7-381fc9ba78a2"/>
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<title>
<content styleCode="bold">Excretion </content>
</title>
<text>
<paragraph>The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours.</paragraph>
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<effectiveTime value="20240925"/>
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<content styleCode="bold">
<content styleCode="underline">Specific Populations</content>
</content>
</title>
<text>
<paragraph>Population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on age, body weight, sex, race, Val30Met variant status, mild and moderate renal impairment (eGFR≥30 to <90 mL/min), or mild hepatic impairment (total bilirubin ≤1 x ULN and AST > 1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). Eplontersen has not been studied in patients with severe renal impairment, end-stage renal disease, or in patients with moderate to severe hepatic impairment, or in patients with prior liver transplant.</paragraph>
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<content styleCode="bold">
<content styleCode="underline">Drug Interaction Studies</content>
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<text>
<paragraph>No clinical drug-drug interaction studies have been performed with eplontersen. <content styleCode="italics">In vitro</content> studies show that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.</paragraph>
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<id root="c2c8532a-d23e-41be-b7cb-f4960ed422ab"/>
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<title>12.6 Immunogenicity </title>
<text>
<paragraph>The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the study described below with the incidence of anti-drug antibodies in other studies, including those of eplontersen.</paragraph>
<paragraph>In Study 1, with duration of treatment up to 85 weeks (mean treatment duration of 445 days (63.2 weeks), range: 57 to 582 days), 53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C<sub>max</sub> or AUC, but increased C<sub>trough</sub>. Although anti-drug antibody development was not found to affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of WAINUA in these patients, the available data are too limited to make definitive conclusions.</paragraph>
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