Plozasiran

1 INDICATIONS AND USAGE REDEMPLO is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). REDEMPLO is an apolipoprotein C-III ( apoC-III )-directed small interfering ribonucleic acid (siRNA) indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of REDEMPLO is 25 mg injected subcutaneously once every 3 months. ( 2.1 ) Inject REDEMPLO subcutaneously into the front of the thigh or abdomen. The outer area of the upper arm can be used as an injection site if a healthcare provider or caregiver administers the injection. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of REDEMPLO is 25 mg injected subcutaneously once every 3 months. 2.2 Important Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of REDEMPLO [see Instructions for Use ] . Adhere to a low-fat diet (less than or equal to 20 grams fat per day) in conjunction with REDEMPLO. Visually inspect the REDEMPLO pre-filled syringe prior to administration. The solution should be clear and colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Inject REDEMPLO subcutaneously into the front of the thigh or abdomen. The outer area of the upper arm can be used as an injection site if a healthcare provider or caregiver administers the injection. Do not inject REDEMPLO in an area where the skin is damaged (tender, bruised, red, hard, or cut). Do not inject into areas with scars or stretch marks. If a dose is missed, administer REDEMPLO as soon as possible. Resume dosing every 3 months from the date of the most recently administered dose.

6 ADVERSE REACTIONS Most common adverse reactions in REDEMPLO treated patients (incidence ≥10% of patients treated with REDEMPLO and >5% more frequently than with placebo) are hyperglycemia, headache, nausea, and injection site reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Arrowhead Pharmaceuticals Inc. at 1-844-REDEMPLO (1-844-733-3675), or https://arrowheadpharma.com/safetyreporting, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REDEMPLO cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of REDEMPLO was evaluated in 75 patients with FCS enrolled in Trial 1 (NCT05089084) [see Clinical Studies ( 14 )] . In this trial, patients received at least one dose of REDEMPLO 25 mg (N=26) or 50 mg of plozasiran (N=24) and 25 patients received placebo. Plozasiran 50 mg is not an approved dosage regimen for FCS [see Dosage and Administration ( 2.1 )] . Across treatment groups, the mean age was 46 years and 49% of patients were male. Seventy-three percent (73%) of patients were White, 21% were Asian, and 5% were reported as other races; 3% identified as Hispanic or Latino ethnicity. Fifty (50) patients were exposed to REDEMPLO for a median of 11.6 months; 26 patients were treated with REDEMPLO 25 mg every 3 months for a median of 11.8 months. Adverse reactions led to discontinuation of treatment in 3 (6.0%) of REDEMPLO-treated patients and 0% of placebo-treated patients. The reasons for REDEMPLO treatment discontinuation were hyperglycemia and urticaria. Adverse reactions occurring in greater than or equal to 10% of REDEMPLO-treated patients and greater than 5% more frequently than in placebo-treated patients are listed below in Table 1 . Table 1. Adverse Reactions Occurring in Greater than or Equal to 10% of REDEMPLO-treated Patients and Greater than 5% More Frequently than with Placebo in Trial 1 1 Grouped terms composed of several similar terms Adverse Reactions Placebo (N=25) (%) REDEMPLO (N=50) (%) Hyperglycemia 1 2 (8%) 10 (20%) Headache 2 (8%) 8 (16%) Nausea 2 (8%) 7 (14%) Injection site reaction 1 1 (4%) 5 (10%) Laboratory Tests Increase in Glucose: Mean increases from baseline in HbA1c (up to 0.36%) and fasting glucose (up to 9 mg/dL) were observed over time in the 25 mg REDEMPLO group. The incidence of hyperglycemia (defined as adverse events consistent with diabetes mellitus or hyperglycemia, new antidiabetic medication, or laboratory values) was higher in 25 mg REDEMPLO-treated patients without a medical history of diabetes at baseline (40%) compared to placebo-treated patients (20%). Increase in Liver Enzymes: Increases from baseline liver enzymes within the normal range were observed with plozasiran treatment in the FCS population. These increases occurred within the first 3 months of treatment and stabilized. Increase in LDL-cholesterol: Increases in low-density lipoprotein cholesterol (LDL-C) and total apolipoprotein B (apoB) were observed in the FCS population treated with REDEMPLO compared to those treated with placebo [see Clinical Studies ( 14 )] . Despite increases in the LDL-C, the average LDL-C value at Month 12 was less than 50 mg/dL in the 25 mg REDEMPLO group.

12.3 Pharmacokinetics REDEMPLO exhibited linear and time-invariant pharmacokinetics following subcutaneous injections within the dose range of 10 mg to 100 mg. The following pharmacokinetic parameters were observed in healthy adults after receiving a 25 mg dose of REDEMPLO. Absorption Plozasiran peak plasma concentration (C max ) is 68.5 ng/mL. The median time to reach C max (T max ) is 6 hours. Distribution Plozasiran is 78% protein bound in vitro at the clinically relevant plasma concentrations. Following subcutaneous multiple administration of 25 mg plozasiran, the apparent volume of distribution is approximately 146 L. Plozasiran is distributed in plasma and extracellular body water before its uptake by hepatocytes to decrease apoC-III mRNA expression and reduce serum triglycerides. Elimination The terminal elimination half-life of plozasiran in plasma is approximately 3 to 4 hours. The mean apparent systemic clearance is 33.8 L/hour. Metabolism Plozasiran is primarily metabolized by nucleases to shorter oligonucleotides of varying lengths. Excretion Approximately 16 to 19% of REDEMPLO dose is excreted in urine. Specific Populations No clinically significant differences in plozasiran pharmacokinetics based on age, sex, race, mild and moderate renal impairment (eGFR ≥30 to <90 mL/min), or mild hepatic impairment (total bilirubin ≤1 times ULN and AST >1 times ULN, or total bilirubin >1.0 to 1.5 times ULN and any AST) were found in the population pharmacokinetic analysis. The impact of severe renal impairment, end-stage renal impairment, or moderate to severe hepatic impairment is not known. Drug Interaction Studies In Vitro Assessment of Drug Interactions CYP450 Enzymes Plozasiran is not a substrate, inhibitor, or inducer of CYP450 enzymes at clinically relevant concentrations. Transporter Systems Plozasiran is not a substrate or an inhibitor of P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.