Fitusiran

QFITLIA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors. QFITLIA is an antithrombin-directed small interfering ribonucleic acid indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients aged 12 years and older with hemophilia A or B with or without factor VIII or IX inhibitors. ( 1 )

QFITLIA is a clear, colorless to pale yellow solution in a single-dose: Injection: 50 mg/0.5 mL prefilled pen Injection: 20 mg/0.2 mL vial Injection: 50 mg/0.5 mL (100 mg/mL) in a single-dose prefilled pen 20 mg/0.2 mL (100 mg/mL) in a single-dose vial ( 3 )

None. None ( 4 )

7.1 Hypercoagulability with Concomitant Use of CFC or BPA QFITLIA prophylaxis leads to increased thrombin generation with additive increase in peak thrombin when used concomitantly with CFC or BPA [see Boxed Warning , Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Thrombotic Events [see Boxed Warning and Warnings and Precautions (5.1) ] Acute and Recurrent Gallbladder Disease [see Boxed Warning and Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Common adverse reactions (incidence >10%) are viral infection, nasopharyngitis, and bacterial infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation 1-800-745-4447 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 pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QFITLIA as fixed doses and AT-DR (N=335). The safety of the QFITLIA AT-DR was assessed in 286 adult and pediatric male patients with hemophilia A or B with or without inhibitors [see Clinical Studies (14) ] . Among patients who received the AT-DR, 93% were exposed for 6 months or longer and 83% were exposed for 12 months or longer. The median duration of exposure across the studies was 674 days (with a maximum of 896 days). Serious adverse reactions occurred in 4/286 (1.4%) patients who received the AT-DR, two of whom had serious adverse reactions of cholecystitis. Permanent discontinuation of QFITLIA due to an adverse reaction occurred in 4/286 (1.4%) patients receiving the AT-DR and included liver injury, post-operative deep vein thrombosis, cerebral infarction and pruritus. Dosage interruptions of QFITLIA due to an adverse reaction occurred in 2/286 (0.7%) patients receiving the AT-DR and included increased serum transaminases. The most common adverse reactions (≥10%) reported in patients treated with the AT-DR were viral infection, nasopharyngitis, and bacterial infection. Table 3: Adverse Reactions Reported in ≥5% of Patients from Pooled Clinical Studies with QFITLIA AT-DR Adverse Reaction Number of Patients (%) N=286 Viral infection Includes similar terms. 29 Nasopharyngitis 26 Bacterial infection 11 Hepatic Injury Hepatic injury includes: alanine aminotransferase increased, aspartate aminotransferase increased, liver injury. 8 Arthralgia 8 Prothrombin fragment 1.2 increased 7 Injection site reaction injection site reactions: includes injection site bruising, injection site erythema, injection site pain, injection site hematoma, injection site atrophy, injection site hemorrhage, injection site discomfort, injection site swelling, injection site discoloration, injection site pruritus, injection site induration, injection site nodule, injection site mass, injection site vesicles, injection site deformation, injection site rash, injection site joint pain and application site erythema. 6 Headache 5 Cough 5 Clinically relevant adverse reactions in less than 5% of patients include: Dyspepsia Abdominal pain

Avoid use in patients with established hepatic impairment (Child-Pugh Class A, B and C) ( 8.6 ). To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary There are no available data on QFITLIA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproduction studies in pregnant animals have not been conducted with fitusiran. It is not known whether QFITLIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. QFITLIA should be used during pregnancy only if the potential benefit justifies the potential risks, including those to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of fitusiran or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether QFITLIA is safe for use during breastfeeding. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QFITLIA and any potential adverse effects on the breastfed infant from QFITLIA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Females Use of QFITLIA in women using hormonal contraceptives may increase the risk of thrombotic events. Estrogen based hormonal contraceptives are an established risk factor for thrombosis in women with inherited AT deficiency. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraception prior to starting treatment with and while receiving QFITLIA.

8.4 Pediatric Use The safety and effectiveness of QFITLIA for the treatment of hemophilia A or B with or without factor VIII or IX inhibitors have been established in pediatric patients aged 12 years and older. Use of QFITLIA in pediatric patients with hemophilia A and B is supported by evidence from adequate and well-controlled studies in adult and pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] . A total of 60 pediatric patients ages 12 to 17 were treated with QFITLIA in the clinical studies. The safety and effectiveness of QFITLIA have not been established in pediatric patients below 12 years of age.

8.5 Geriatric Use There were 3 patients with hemophilia 65 years of age and older in the clinical studies on QFITLIA. Clinical studies of QFITLIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment Serum transaminase elevations have been observed in the clinical studies [see Warnings and Precautions (5.3) ] . Avoid use of QFITLIA in patients with established hepatic impairment (Child-Pugh Class A, B and C).

Risk Summary There are no available data on QFITLIA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproduction studies in pregnant animals have not been conducted with fitusiran. It is not known whether QFITLIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. QFITLIA should be used during pregnancy only if the potential benefit justifies the potential risks, including those to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

The safety and effectiveness of QFITLIA for the treatment of hemophilia A or B with or without factor VIII or IX inhibitors have been established in pediatric patients aged 12 years and older. Use of QFITLIA in pediatric patients with hemophilia A and B is supported by evidence from adequate and well-controlled studies in adult and pediatric patients [see Adverse Reactions (6.1) and Clinical Studies (14) ] . A total of 60 pediatric patients ages 12 to 17 were treated with QFITLIA in the clinical studies. The safety and effectiveness of QFITLIA have not been established in pediatric patients below 12 years of age.

There were 3 patients with hemophilia 65 years of age and older in the clinical studies on QFITLIA. Clinical studies of QFITLIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

QFITLIA injection contains fitusiran, an antithrombin-directed double-stranded small interfering ribonucleic acid (siRNA), which is covalently linked to a ligand containing a triantennary N-acetylgalactosamine (GalNAc) moiety. The molecular formula of fitusiran sodium is C 520 H 636 F 21 N 175 Na 43 O 309 P 43 S 6 and the molecular weight is 17,193 Da. Fitusiran drug substance is a white to pale yellow powder and freely soluble in water and phosphate buffered saline. The pH of a 1% aqueous solution of fitusiran drug substance in 50 mM KCl is 5.4 (4.4–7.3). It has the following structural formula: QFITLIA is supplied as a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous administration. Each 50 mg single-dose prefilled pen delivers 50 mg fitusiran (equivalent to 53.0 mg fitusiran sodium) in 0.5 mL, and also contains dibasic sodium phosphate (0.585 mg), monobasic sodium phosphate (0.044 mg), sodium chloride (2.455 mg), and Water for Injection, USP. Phosphoric acid (concentrated) and sodium hydroxide may be added to adjust to pH 7.0. Each 20 mg single-dose vial delivers 20 mg fitusiran (equivalent to 21.2 mg fitusiran sodium) in 0.2 mL, and also contains dibasic sodium phosphate (0.234 mg), monobasic sodium phosphate (0.018 mg), sodium chloride (0.982 mg), and Water for Injection, USP. Phosphoric acid (concentrated) and sodium hydroxide may be added to adjust to pH 7.0. Chemical Structure

QFITLIA is a double-stranded siRNA that causes degradation of AT messenger RNA (mRNA) through RNA interference, reducing plasma AT levels.

In clinical studies with QFITLIA in hemophilia patients, the primary pharmacodynamic (PD) measure was plasma AT activity. Lower AT activity levels were associated with lower annualized bleeding rates (ABR); however, persistent AT activity <15% is a risk factor for thrombotic events. In Study LTE15174, the mean (SD) AT activity on the AT-DR was 24% (4.64). Simulations to estimate time for AT activity to reach steady state found that regardless of the dose regimen, more than 99% of participants reached steady state AT levels (defined as <10% variability among consecutive measures) within 23 weeks following initiation of QFITLIA dosing or following dose escalation or de-escalation. The duration of persistent AT activity <60% (non-negligible impact of QFITLIA on coagulation) following QFITLIA treatment discontinuation was estimated to be approximately 6 months, after which standard doses of CFC/BPA may be administered. In patients with AT activity <15%, the time required prior to initiation of a lower dose was estimated to be 12 weeks to maximize the AT activity recovery to the target range of 15% to 35%. Extent of AT reduction with QFITLIA did not differ between patients with hemophilia A or B, with or without inhibitors.

The pharmacokinetic (PK) properties of fitusiran were evaluated following administration of QFITLIA in patients with hemophilia A or B, with or without inhibitors as summarized in Table 4. QFITLIA PD is driven by liver PK rather than plasma PK. The QFITLIA dosing strategy is based on maintaining plasma AT activity levels between 15–35% with 10, 20 or 50 mg dosing every month or every two months. Table 4: Pharmacokinetic Parameters of QFITLIA PK Parameters Unless otherwise indicated, the PK parameters in this table are from Study LTE15174. All PK parameters are estimated using non-compartmental analysis and are presented as Mean (SD) [CV%], except for t max which is presented as median (range) QFITLIA 20 mg QFITLIA 50 mg AUC = area under the plasma concentration-time curve extrapolated to infinity; CL/F = apparent clearance; C max = maximum plasma concentration; CV = coefficient of variation; PK = pharmacokinetic(s); SD = standard deviation; t 1/2 = terminal elimination half-life; t max = time to maximum concentration; Vss/F = apparent volume of distribution General Information Steady State Exposure: C max (ng/mL) 34.4 (10.1) [29%] 84.1 (58.7) [70%] AUC (ng ∙ h/mL) 491 (83.8) [17%] 1290 (377) [29%] Dose Proportionality QFITLIA exhibited a dose proportional increase in plasma exposure after SC administration. Accumulation Study TDR14767 (ALN-AT3SC-001) No accumulation of QFITLIA was observed following multiple once monthly dosing. Absorption t max (h) 2.88 (0.5 – 4.33) 3.78 (0.42 – 11.9) Distribution QFITLIA distributes primarily to the liver after subcutaneous injection. Vss/F 431 (135) [31%] 570 (713) [125%] Protein Binding In vitro data 96.6% at clinically relevant exposure (0.5 microgram/ml) Elimination t 1/2 (h) 5.57 (2.36) [42%] 7.98 (4.74) [59%] CL/F 41.9 (8.39) [20%] 50.8 (71.1) [140%] Metabolism Primary Pathway QFITLIA is metabolized by endo- and exo-nucleases to oligonucleotides of varying lengths, which are further metabolized to oligonucleotides of even shorter lengths. QFITLIA is not a substrate for CYP450 or transporters. Main Metabolite AS(N-1)3' Excretion Primary Pathway Not evaluated 14.6% (mean) of the administered 50 mg dose of QFITLIA is recovered unchanged in 0–24 hour urine Specific Populations QFITLIA has only been studied in male patients. The pharmacokinetics of fitusiran is not influenced by race. QFITLIA has not been studied in children <12 years old. No clinical study to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of QFITLIA was conducted. In the pivotal studies, 12 patients had mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m 2 ) and 1 patient had moderate renal impairment (eGFR 30 mL/min/1.73 m 2 to <60 mL/min/1.73 m 2 ). Population PK analysis indicated no impact of renal impairment on the exposure (C max and AUC) of QFITLIA in patients with mild renal impairment. Drug Interaction Studies Clinical Studies No clinical drug-drug interaction studies have been conducted to evaluate the potential of QFITLIA to interact with other co-administered drugs which are either substrates, inhibitors or inducers of CYP isozymes, or are substrates or inhibitors of drug transporters. In Vitro Studies Results from in vitro studies evaluating the potential of co-administered drugs to increase the PK exposure of QFITLIA, and the potential of QFITLIA to increase the PK exposure of co-administered drugs, indicate that CYP- or transporter-mediated interactions between QFITLIA and co-administered drugs are unlikely at clinically relevant concentrations.

, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested following subcutaneous administration at doses of 0.03, 0.1 or 0.3 mg/kg/week in males and 0.1, 0.3, or 1 mg/kg/week in females. All doses in males and females were below the maximum recommended human dose (MRHD) of 50 mg per month based on body surface area (BSA) comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran. Fitusiran was not carcinogenic in Tg-rasH2 mice following subcutaneous administration at doses of 0.05, 0.15, or 0.5 mg/kg/week in males and 0.025, 0.08, or 0.25 mg/kg/week in females for 26 weeks. Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats). In a chronic repeat dose toxicology study in Sprague Dawley rats, fitusiran-treated males received subcutaneous doses of 0.25, 0.5, or 1 mg/kg/week for 16 weeks then were cohabitated with fitusiran-naïve females. No adverse effects on male fertility endpoints were observed. All doses used in males were below the MRHD based on BSA comparisons due to the sensitivity of wild type animals to the pharmacological effects of fitusiran.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Use of BPAs or CFCs Advise the patient and/or caregiver to discontinue prophylactic use of BPA or CFC no later than 7 days after starting QFITLIA to reduce the risk of thrombotic events. Discuss the appropriate dosing and frequency of BPA or CFC for breakthrough bleed management with the patient and/or caregiver prior to starting QFITLIA prophylaxis [see Dosage and Administration (2.3) ] . Thrombotic Events Advise the patient and/or caregiver of the risk of thrombotic events while receiving QFITLIA. Inform the patient and/or caregiver of the need for periodic measurements of AT activity that may result in changes to the QFITLIA dose and/or frequency of administration to reduce the risk for thrombosis. Educate patients on the signs and symptoms of thrombotic events and to seek immediate medical attention if new symptoms of thrombotic events occur [see Warnings and Precautions (5.1) ] . Acute and Recurrent Gallbladder Disease Inform the patient and/or caregiver of the risk of acute and recurrent gallbladder disease while receiving QFITLIA. Educate patients on the signs and symptoms of gallbladder disease and to seek medical attention if new symptoms of gallbladder disease occur [see Warnings and Precautions (5.2) ] . Hepatotoxicity Inform the patient and/or caregiver of the risk of hepatotoxicity and that blood tests to monitor for this risk will be obtained before starting QFITLIA and periodically during treatment. Inform patients to seek medical attention if symptoms of hepatotoxicity occur [see Warnings and Precautions (5.3) ] . Administration Instructions Provide training to the patient and/or caregiver on proper subcutaneous injection technique, including aseptic technique, and the preparation and administration of QFITLIA prior to use [see Dosage and Administration (2.4) ] .

50 mg Prefilled Pen Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. QFITLIA may be stored at room temperature between 15°C to 30°C (59°F to 86°F) for a single period of up to 3 months within the expiration date printed on the label. Discard no later than 3 months after removal from the refrigerator or at the expiration date, whichever comes first. After storage at room temperature, do not return the product to the refrigerator. 20 mg Vial Store QFITLIA either in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature between 15°C to 30°C (59°F to 86°F), in the original carton to protect from light. After storage at room temperature, do not return the product to the refrigerator. Do not shake QFITLIA at any time. Do not heat QFITLIA. Do not freeze. Do not put into direct sunlight.