Tralokinumab-Ldrm

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 visually for particulate matter and discoloration prior to administration. ADBRY injection is a clear to opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to opalescent, colorless to pale yellow). ADBRY does not contain preservatives; therefore, discard any unused product.

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 period of 16 weeks and the long-term period of 52 weeks, was comparable to the safety profile from trials in adults with atopic dermatitis. Safety through 268 weeks (ECZTEND) ECZTEND was an open-label, multicenter, long-term extension trial that further assessed the safety of ADBRY for up to 5 years of treatment in adults and pediatric subjects 12 years of age and older with moderate-to-severe atopic dermatitis who had previously participated in ADBRY trials. The safety data in ECZTEND reflect exposure to ADBRY in 1672 subjects who received 300 mg of ADBRY every two weeks (Q2W), including 1422 exposed for at least 52 weeks, 1184 exposed for at least 104 weeks, 701 exposed for at least 156 weeks, and 33 exposed for at least 264 weeks. The long-term safety profile was consistent with the safety profile observed up to week 16. Specific Adverse Reactions Conjunctivitis and Keratitis Conjunctivitis, including allergic conjunctivitis, was reported in 7.5% of subjects treated with ADBRY 300 mg every other week (29 events per 100 subject-years of exposure) and in 3.1% of subjects treated with placebo (12 events per 100 subject-years of exposure) in the initial treatment period of up to 16 weeks in the pool of 5 trials. In the ADBRY group, 126 subjects reported 145 events of conjunctivitis, with 114 events resolved at the end of initial treatment period. Conjunctivitis led to discontinuation of treatment in 2 subjects. During the initial treatment period of the monotherapy trials (ECZTRA 1 and ECZTRA 2), conjunctivitis was reported in 7.7% of subjects treated with ADBRY 300 mg every other week (30 events per 100 subject-years of exposure). During the maintenance treatment period of the monotherapy trials (ECZTRA 1 and ECZTRA 2) from 16 to 52 weeks, conjunctivitis was reported in 14 (8.9%) subjects treated with ADBRY 300 mg every other week (20 events per 100 subject-years of exposure) and in 10 (6.3%) subjects treated with ADBRY 300 mg every 4 weeks (14 events per 100 subject-years of exposure); and included no serious events, 1 severe event, and 1 event that led to discontinuation. A comparable pattern was seen during the continuation treatment period of an additional 16 weeks in the ADBRY combination trial ECZTRA 3. Keratoconjunctivitis (including 1 atopic keratoconjunctivitis (0.1%)) was reported in 5 (0.3%) subjects (1.2 events per 100 subject-years of exposure) treated with ADBRY and 0% of subjects treated with placebo during the initial treatment period of up to 16 weeks in the pool of 5 trials. Keratoconjunctivitis was reported as resolved in 2 out of 5 subjects by the end of trials. Keratitis (including 1 ulcerative keratitis (0.1%)) was reported in 4 (0.2%) subjects treated with ADBRY (0.9 events per 100 subject-years of exposure) and 1 (0.2%) subject (viral keratitis) treated with placebo (0.6 events per 100 subject-years of exposure) during the initial treatment period of up to 16 weeks in the pool of 5 trials. Keratitis was reported as resolved in all but 1 subject by the end of trials. None of the events were serious or led to treatment discontinuation. During the initial treatment period of the monotherapy trials (ECZTRA 1 and ECZTRA 2), keratitis event rate of 2 per 100 subject-years was reported for ADBRY 300 mg every other week. During the maintenance treatment period of the monotherapy trials (ECZTRA 1 and ECZTRA 2) from 16 to 52 weeks in the ADBRY 300 mg every other week group, keratitis was reported in 1 (0.6%) subject (ulcerative, severe, resolved after discontinuation) at an exposure-adjusted event rate of 1.2 per 100 subject-years, and keratoconjunctivitis (not serious or severe, resolved, not led to discontinuation) was reported in 3 (1.9%) subjects (3.6 events per 100 subject-years of exposure). No events of keratitis or keratoconjunctivitis was reported in ADBRY every 4 weeks or placebo groups. In the continuation treatment period of ECZTRA 3 (from 16 to 32 weeks), there were no additional events of keratitis reported for subjects randomized to ADBRY 300 mg + TCS. Eosinophil Counts ADBRY-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo. The mean and median increases in blood eosinophils from baseline to Week 4 were 190 and 100 cells/mcL, respectively. The increase in the ADBRY-treated subjects declined to baseline level with continued treatment. Eosinophilia (> 5000 cells/mcL) in the initial treatment period of up to 16 weeks was reported in 1.2% in the ADBRY-treated subjects and 0.3% in the placebo-treated subjects. The safety profile for subjects with eosinophilia was comparable to the safety profile for all subjects included in the pool of 5 atopic dermatitis trials.

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.

12.2 Pharmacodynamics ADBRY was associated with decreased concentrations of Th2 and Th22 immunity biomarkers in the blood, such as thymus and activation-regulated chemokine (TARC/CCL17), periostin, IL-22, lactate dehydrogenase (LDH) and serum IgE. ADBRY decreased expression of keratin 16 and Ki-67 in AD skin, and upregulated protein expression of loricrin. ADBRY suppressed expression of genes in the Th2 pathway, including CCL17, CCL18 and CCL26 as well as markers of Th17- and Th22-regulated genes in lesional skin. The clinical relevance of these is not fully understood. Immune Response to Non-live Vaccines during Treatment Immune responses to non-live vaccines were assessed in a trial in which adult subjects with atopic dermatitis were treated with an initial dose of 600 mg (four 150 mg injections) followed by 300 mg every other week administered as subcutaneous injection. After 12 weeks of ADBRY administration, subjects were vaccinated with a combined tetanus, diphtheria, and acellular pertussis vaccine, and a meningococcal vaccine. Antibody responses were assessed 4 weeks later. Antibody response to tetanus, diphtheria, acellular pertussis, and a meningococcal vaccine was similar in tralokinumab-ldrm treated and placebo treated subjects. Immune responses to other vaccines were not assessed.

12.3 Pharmacokinetics In adults, the mean (SD) steady-state trough concentration of tralokinumab-ldrm ranged from 98.0 (41.1) mcg/mL to 101.4 (42.7) mcg/mL following administration of ADBRY at 300 mg every other week. Tralokinumab-ldrm exposure increased proportionally over a dosage range up to 2100 mg for a 70 kg subject (30 mg/kg IV) (3.5 times the maximum approved recommended dosage). Steady-state tralokinumab-ldrm concentrations were achieved by week 16 following a 600 mg starting dose and 300 mg every other week. Absorption The absolute bioavailability of tralokinumab-ldrm was estimated to be 76%. The time to maximum tralokinumab-ldrm concentrations (t max ) was 5 to 8 days after administration. Distribution The volume of distribution of tralokinumab-ldrm was estimated to be approximately 4.2 L. Elimination The half-life of tralokinumab-ldrm was 3 weeks and systemic clearance was estimated to be 0.149 L/day. Metabolism Tralokinumab-ldrm is expected to be metabolized into small peptides by catabolic pathways. Specific Populations Geriatric Patients, Patients with Renal and Hepatic Impairment No clinically significant differences in the pharmacokinetics of tralokinumab-ldrm were observed based on age (ranged from 18 – 92 years), sex, mild to moderate renal impairment, or mild hepatic impairment. The effect of severe renal impairment or moderate to severe hepatic impairment on the pharmacokinetics of tralokinumab-ldrm is unknown. Pediatric Patients In subjects 12 to 17 years of age with atopic dermatitis, the mean (SD) steady-state trough concentration of tralokinumab-ldrm was 59.6 mcg/mL (19.4) and 112.8 mcg/mL (39.2) following administration of ADBRY at 150 mg and 300 mg every other week, respectively. Body Weight The exposure of tralokinumab-ldrm decreases with increasing body weight. After 300 mg dose every 4 weeks, the median tralokinumab-ldrm exposure (AUC) of subjects with body weight of above 100 kg is expected to be 1.46-fold lower than that of subjects weighing below 100 kg [see Dosage and Administration (2.2) ]. Drug Interaction Studies Cytochrome P450 Substrates The effects of tralokinumab on the pharmacokinetics of midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), and caffeine (CYP1A2 substrate) were evaluated in a clinical trial in 18-20 subjects with moderate to severe atopic dermatitis receiving an initial SC dose of 600 mg followed by 300 mg SC every other week for 14 weeks. No clinically significant changes in the exposure (AUC or Cmax) of the CYP450 substrates after multiple tralokinumab administrations were observed compared to that when administered alone.

12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials, including those of ADBRY or of other tralokinumab products. In ECZTRA 1, ECZTRA 2, and ECZTRA 3, and the vaccine-response trial, the incidence of anti-drug antibodies (ADA) during the initial 16-week treatment period was 1.4% for subjects treated with ADBRY 300 mg every other week and in 1.3% for subjects treated with placebo; neutralizing antibodies were seen in 0.1% of subjects treated with ADBRY and 0.2% of subjects treated with placebo. Across all trial periods, the ADA incidence for subjects who received ADBRY was 4.6%; 0.9% had persistent ADA and 1.0% had neutralizing antibodies. No clinically significant differences in the pharmacokinetics, safety, or efficacy of tralokinumab-ldrm were observed in patients who tested positive for anti-tralokinumab-ldrm antibody (including neutralizing antibodies). In the open-label long-term extension trial (ECZTEND), anti-drug-antibody (ADA) responses were assessed up to 248 weeks and were not associated with any impact on tralokinumab exposure or safety.