Tralokinumab

12.1 Mechanism of Action Tralokinumab-ldrm is a human IgG4 monoclonal antibody that specifically binds to human interleukin-13 (IL-13) and inhibits its interaction with the IL-13 receptor α1 and α2 subunits (IL-13Rα1 and IL-13Rα2). IL-13 is a naturally occurring cytokine of the Type 2 immune response. Tralokinumab-ldrm inhibits the bioactivity of IL-13 by blocking IL-13 interaction with IL-13Rα1/IL-4Rα receptor complex. Tralokinumab-ldrm inhibits IL-13-induced responses including the release of proinflammatory cytokines, chemokines and IgE.

1 INDICATIONS AND USAGE ADBRY is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and pediatric patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. ADBRY can be used with or without topical corticosteroids. ADBRY is an interleukin-13 antagonist indicated for the treatment of moderate-to-severe atopic dermatitis in adults and pediatric patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. ADBRY can be used with or without topical corticosteroids. ( 1 )

2 DOSAGE AND ADMINISTRATION Prior to ADBRY initiation, complete all age appropriate vaccinations as recommended by current immunization guidelines ( 2.1 ) Administer ADBRY by subcutaneous injection. ( 2.2 ) In pediatric patients 12 years of age and older, it is recommended that ADBRY be given by or under supervision of an adult. ( 2.2 ) The recommended dosage of ADBRY ( 2.3 ) Dosage in Adults Initial Loading Dose Subsequent Dosage Prefilled syringe 600 mg (four 150 mg injections) 300 mg (two 150 mg injections) every other week Autoinjector 600 mg (two 300 mg injections) 300 mg (one 300 mg injection) every other week Dosage in Pediatric Patients 12 Years of Age and Older Initial Loading Dose Subsequent Dosage Prefilled syringe 300 mg (two 150 mg injections) 150 mg (one 150 mg injection) every other week A dosage of 300 mg every 4 weeks may be considered for adult patients below 100 kg who achieve clear or almost clear skin after 16 weeks of treatment. ( 2.3 ) 2.1 Vaccination Prior to Treatment Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with ADBRY [see Warnings and Precautions (5.4) ] . 2.2 Important Administration Instructions ADBRY is administered by subcutaneous injection. ADBRY is intended for use under the guidance of a healthcare provider. Provide proper training to patients and/or caregivers on the preparation and administration of ADBRY prior to use according to the "Instructions for Use" [see Instructions for Use ] . Use of the Autoinjector The ADBRY autoinjector is for use in adults only. A caregiver or adult patient may inject ADBRY using the autoinjector. Use of the Prefilled Syringe The ADBRY prefilled syringe is for use in adults and pediatric patients 12 years of age and older. A caregiver or patient 12 years of age and older may inject ADBRY using the prefilled syringe. In pediatric patients 12 years of age and older, administer ADBRY under the supervision of an adult. Administration Instructions Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection. DO NOT inject ADBRY into skin that is tender, damaged, bruised, or scarred. For adults taking the initial loading dose of 600 mg, administer each of the injections (four ADBRY 150 mg injections using prefilled syringes or two ADBRY 300 mg injections using autoinjectors) at different injection sites within the same body area. For the subsequent 300 mg doses using the prefilled syringe , administer the two ADBRY 150 mg injections at different injection sites within the same body area, rotating the body area with each subsequent set of injections. For the subsequent 300 mg doses using the autoinjector , administer one ADBRY 300 mg injection, rotating the body area with each subsequent injection For pediatric patients 12 years of age and older taking the initial loading dose of 300 mg, use prefilled syringes to administer the two ADBRY 150 mg injections at different injection sites within the same body area. For the subsequent 150 mg doses, use a prefilled syringe to administer one ADBRY 150 mg injection, rotating the body area with each subsequent injection. The ADBRY "Instructions for Use" contains more detailed instructions on the preparation and administration of ADBRY [see Instructions for Use ] . 2.3 Recommended Dosage Dosage in Adults The recommended dosage for adults is: Initial Loading Dose Subsequent Dosage Prefilled syringe 600 mg (four 150 mg injections) 300 mg (two 150 mg injections) every other week Autoinjector 600 mg (two 300 mg injections) 300 mg (one 300 mg injection) every other week After 16 weeks of treatment, for adult patients with body weight below 100 kg who achieve clear or almost clear skin, a dosage of 300 mg every 4 weeks may be considered. Dosage in Pediatric Patients 12 Years of Age and Older The recommended dosage for pediatric patients 12 years of age and older is: Initial Loading Dose Subsequent Dosage Prefilled syringe 300 mg (two 150 mg injections) 150 mg (one 150 mg injection) every other week 2.4 Concomitant Topical Therapies ADBRY can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. 2.5 Missed Doses If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. 2.6 Preparation for Use Before injection, remove ADBRY prefilled syringes or autoinjectors from the refrigerator and allow to reach room temperature (at least 30 minutes for the prefilled syringes and at least 45 minutes for the autoinjectors) without removing the needle cover or cap, respectively. After removal from the refrigerator, ADBRY may be kept at room temperature up to 30°C (86°F) and must be used within 14 days or discarded. Inspect ADBRY vis

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Conjunctivitis and Keratitis [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥ 1%) are upper respiratory tract infections, conjunctivitis, injection site reactions, and eosinophilia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LEO Pharma Inc. at 1-877-494-4536 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. Adverse Reactions from Clinical Trials in Adults The safety of ADBRY was evaluated in a pool of 5 randomized, double-blind, placebo-controlled trials in subjects with moderate-to-severe atopic dermatitis including three phase 3 Eczema Tralokinumab trials (ECZTRA 1, ECZTRA 2, and ECZTRA 3), a dose-finding trial, and a vaccine response trial. The safety population had a mean age of 37 years; 43% of subjects were female, 67% were White, 21% were Asian, and 9% were Black. In terms of co-morbid conditions, 39% of the subjects had asthma, 49% had hay fever, 36% had food allergy, and 21% had allergic conjunctivitis at baseline. In these 5 atopic dermatitis trials, 1964 subjects were treated with subcutaneous injections of ADBRY, with or without concomitant topical corticosteroids (TCS). A total of 807 subjects were treated with ADBRY for at least 1 year. ECZTRA 1 and ECZTRA 2 compared the safety of ADBRY monotherapy to placebo through Week 52. ECZTRA 3 compared the safety of ADBRY + TCS to placebo + TCS through Week 32. Weeks 0 to 16 (ECZTRA 1, ECZTRA 2, and ECZTRA 3): Table 1 summarizes the adverse reactions identified in the pool of 3 trials (ECZTRA 1, ECZTRA 2, and ECZTRA 3) and that occurred at a rate of at least 1% in the ADBRY 300 mg every other week monotherapy group, and in the ADBRY 300 mg every other week + TCS trial, all at a higher rate than placebo during the first 16 weeks of treatment. Table 1: Adverse Reactions Occurring in ≥1% of the ADBRY Monotherapy Group or the ADBRY + TCS Group in the Atopic Dermatitis Trials through Week 16 Adverse Reaction ADBRY Monotherapy Pooled analysis of ECZTRA 1 and ECZTRA 2. ADBRY + TCS Analysis of ECZTRA 3 where subjects were on background TCS therapy. ADBRY 300 mg Q2W ADBRY 600 mg at Week 0, followed by 300 mg every other week. PLACEBO ADBRY 300 mg Q2W + TCS PLACEBO + TCS N=1180 n (%) N=388 n (%) N=243 n (%) N=123 n (%) Upper respiratory tract infections Upper respiratory tract infections cluster includes upper respiratory tract infection, viral upper respiratory tract infection, pharyngitis, and nasopharyngitis; mainly reported as common cold. 281 (23.8) 79 (20.4) 73 (30.0) 19 (15.4) Conjunctivitis Conjunctivitis cluster includes conjunctivitis and allergic conjunctivitis. 88 (7.5) 12 (3.1) 33 (13.6) 6 (4.9) Injection site reactions Injection site reactions cluster includes pain, erythema, and swelling. 87 (7.4) 16 (4.1) 27 (11.1) 1 (0.8) Eosinophilia Eosinophilia cluster includes eosinophilia and eosinophil count increased. 17 (1.4) 2 (0.5) 3 (1.2) 0 In the monotherapy trials (ECZTRA 1 and ECZTRA 2) through Week 16, the proportion of subjects who discontinued treatment due to adverse reactions was 0.7% in the ADBRY 300 mg every other week group and 0% of the placebo group. In the concomitant TCS trial (ECZTRA 3) through Week 16, the proportion of subjects who discontinued treatment due to adverse reactions was 0.8% in the ADBRY 300 mg every other week +TCS group and 0% of the placebo + TCS group. The most common adverse reactions leading to discontinuation in the ADBRY group compared to the placebo group were injection site reaction (0.3% v. 0) and eosinophilia (0.3% v. 0) in ECZTRA 1 and ECZTRA 2; and injection site reaction (0.4% v. 0) and conjunctivitis (0.4% v. 0) in ECZTRA 3. Weeks 16-52 (ECZTRA 1 and ECZTRA 2) and Weeks 16-32 (ECZTRA 3): The safety profile of ADBRY 300 mg every other week with or without TCS during maintenance treatment was consistent with that in the initial 16-week treatment period. In addition, the frequency of adverse reactions with ADBRY 300 mg every other week and every 4 weeks in ECZTRA 1 and ECZTRA 2 was 44% and 34%, respectively, and 43% and 26% with ADBRY 300 mg + TCS every other week and every 4 weeks in ECZTRA 3, respectively. Adverse Reactions from Clinical Trials in Pediatric Subjects 12 Years of Age and Older The safety of tralokinumab was assessed in a trial of 289 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (ECZTRA 6). Of the 289 subjects, 195 were treated with ADBRY and 94 were treated with matching placebo. The safety profile of ADBRY in these subjects, assessed through the initial treatment per