Donidalorsen

1 INDICATIONS AND USAGE DAWNZERA™ is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. DAWNZERA is a prekallikrein directed antisense oligonucleotide indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of DAWNZERA is 80 mg administered subcutaneously every 4 weeks. A dosage of 80 mg every 8 weeks may also be considered. ( 2.1 ) See full prescribing information for administration instructions. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of DAWNZERA is 80 mg administered subcutaneously every 4 weeks. A dosage of 80 mg administered subcutaneously every 8 weeks may be considered. Missed Dose(s) If a dose of DAWNZERA is missed, administer DAWNZERA as soon as possible. Resume treatment at the recommended dosing frequency from the date of the most recently administered dose. 2.2 Administration Instructions For subcutaneous use. DAWNZERA is intended for self-administration or administration by a caregiver. Prior to treatment initiation, train patients and/or caregivers on proper preparation and subcutaneous administration technique of DAWNZERA autoinjector [see Instructions for Use ] . Remove the single‑dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods. Inspect DAWNZERA visually for particulate matter and discoloration prior to administration. The solution should appear clear and colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Administer DAWNZERA subcutaneously into the abdomen or upper thigh region. The back of the upper arm can also be used as an injection site if a caregiver or healthcare provider administers the injection.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Risk of Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥ 5%) are injection site reactions, upper respiratory tract infection, urinary tract infection, and abdominal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ionis Pharmaceuticals at 1-833-644-6647 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 a drug 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 DAWNZERA reflects the exposure in a total of 171 adult and pediatric patients 12 years and older with hereditary angioedema (HAE) from a placebo-controlled trial (OASIS-HAE) [see Clinical Studies (14) ] , and 2 other clinical studies. The average duration of DAWNZERA treatment exposure across the 3 clinical studies was 14 months. The safety data below is based on the 24-week multicenter, randomized, double-blind, placebo-controlled trial (OASIS-HAE), in which patients received at least one subcutaneous dose of DAWNZERA 80 mg once every 4 weeks (n=45), DAWNZERA 80 mg once every 8 weeks (n=23), or matching placebo (n=22). Demographics of the patients in OASIS-HAE are summarized in Clinical Studies [see Clinical Studies (14) ] . Table 1 provides the most common adverse reactions with DAWNZERA with incidence ≥5% and more common than placebo. Table 1: Adverse Reactions with DAWNZERA with Incidence ≥5% and More Common than Placebo in Patients with HAE (OASIS-HAE) N = number of patients; n = number of patients experiencing the event; q4wks = every 4 weeks; q8wks = every 8 weeks. * Injection site reactions include: erythema, discoloration, pain, pruritus, induration, bruising, haematoma, hypersensitivity, swelling, reaction, and urticaria. † All injection site reactions were mild, nonserious, and the majority of them resolved without receiving any treatment. Adverse Reaction DAWNZERA Placebo (N=22) 80 mg q4wks (N=45) 80 mg q8wks (N=23) n (%) n (%) n (%) Injection site reactions*† 11 (24) 1 (4) 1 (5) Upper respiratory tract infection 4 (9) 2 (9) 1 (5) Urinary tract infection 4 (9) 2 (9) 0 Abdominal discomfort 3 (7) 0 0 Specific Adverse Reactions Hypersensitivity Reactions, Including Anaphylaxis In clinical trials, hypersensitivity reactions, including anaphylaxis, have occurred. Symptoms included generalized rash, dyspnea, chest pain, and peri-oral swelling. Laboratory Tests Decrease in Platelet Count : DAWNZERA can cause reductions in platelet count. In OASIS-HAE, the mean platelet count at baseline was 266,000/mm 3 for the DAWNZERA 80 mg every 4 weeks group, 265,000/mm 3 for the DAWNZERA 80 mg every 8 weeks group, and 245,000/mm 3 for the placebo group. The mean percent change in platelet count at Week 25 was -9.6% for the DAWNZERA 80 mg every 4 weeks group, -7.9% for the DAWNZERA 80 mg every 8 weeks group, and -1.4% for the placebo group. In OASIS-HAE and 2 other clinical studies no DAWNZERA-treated patient had a platelet count of <50,000/mm 3 , and there were no major bleeding events associated with a low platelet count. Increase in Liver Function Tests : Increases from baseline in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) were observed with DAWNZERA use. The increased levels were generally below 3 times the upper limit of normal and stabilized. Discontinuations due to liver function test increases were infrequent.

12.3 Pharmacokinetics The pharmacokinetic properties of DAWNZERA were evaluated following subcutaneous administration of multiple doses every 4 weeks in healthy subjects and every 4 weeks or every 8 weeks in patients with HAE. The pharmacokinetics of DAWNZERA were similar between healthy subjects and patients with HAE. Donidalorsen exposure (area under the plasma concentration‑time curve [AUC]) at steady state following subcutaneous administration in healthy subjects increased in a greater than dose‑proportional manner over the dose range of 0.25 times the maximum recommended dosage to 80 mg every 4 weeks. Geometric Mean (Coefficient of Variation [CV%]) of steady‑state maximum plasma concentration (C max,ss ), trough plasma concentration (C trough,ss ), and area under the plasma concentration‑time curve over the dosing interval (AUC τ ,ss ) are presented in Table 2. No accumulation of donidalorsen C max and AUC was observed in plasma after repeated dosing every 4 weeks. However, a 2-fold increase of plasma donidalorsen C trough was observed following repeated dosing every 4 weeks. Table 2: Summary of Geometric Mean (CV%) Steady-State Donidalorsen Pharmacokinetic Parameters Following Dosage of DAWNZERA 80 mg Every 4 Weeks or 80 mg Every 8 Weeks in Patients with HAE AUC τ,ss = area under the plasma concentration time curve over each dosing interval at steady state; C max,ss = maximum plasma concentration at steady state; C trough,ss = trough plasma concentration at steady state; q4wks = every 4 weeks; q8wks = every 8 weeks. Pharmacokinetic Parameters (Geometric Mean) DAWNZERA 80 mg q4wks 80 mg q8wks C max,ss (ng/mL) 417 (81%) 416 (78%) C trough,ss (ng/mL) 0.755 (63%) 0.255 (73%) AUC τ,ss (ng·h/mL) 5240 (52%) 5210 (52%) Absorption Following subcutaneous administration, donidalorsen is absorbed with the median (range) time to maximum plasma concentration of approximately 2 (0.25, 8) hours post dose. Distribution Donidalorsen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The apparent volume of distribution for the central (V c /F) and peripheral (V p /F) compartment were 69.8 L and 1840 L, respectively. Donidalorsen is highly bound to human plasma proteins (>98% bound) in vitro. Elimination The terminal plasma elimination half-life of donidalorsen in a typical patient with HAE is approximately 1 month. The half-life of the initial rapid clearance phase, reflecting tissue distribution, was approximately 5 hours. Metabolism The oligonucleotide moiety of donidalorsen is expected to be metabolized by endo‑ and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Based on in vitro studies, donidalorsen is not a substrate of cytochrome P450 (CYP) enzymes. The linker that covalently connects the ASO to the GalNAc residues is cleaved via hydrolysis and undergoes dephosphorylation and subsequent oxidative metabolism to form inactive metabolites, which are minimally released in circulation. The most abundant linker-related metabolite (M8) is a substrate of CYP3A4. Excretion The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose in healthy subjects within 24 hours post-dose. The renal route of elimination is minor for linker-related metabolites. Specific Populations No clinically meaningful differences in the pharmacokinetics or pharmacodynamics of donidalorsen were observed based on age (12 to 68 years), body weight (37 to 152 kg), sex, race (68% White, 24% Black, and 4% Asian), ethnicity, disease status (healthy subjects or subjects with HAE), mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m 2 ), or mild hepatic impairment (defined using NCI-ODWG Criteria: total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST). Donidalorsen has not been studied in patients with moderate or severe renal impairment, end‑stage renal disease, or moderate or severe hepatic impairment. Drug Interaction Studies No clinical drug‑drug interaction studies have been performed with donidalorsen. In vitro studies show that donidalorsen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor/inducer of CYP enzymes. In vitro studies show that linker-related metabolite M8 is not an inhibitor or inducer of CYP enzymes. M8 is a substrate of transporters bile salt export pump (BSEP) and organic anion transporting polypeptide 1B3 (OATP1B3), and is an inhibitor of multidrug and toxin extrusion protein 1 (MATE1) transporter.