Tralokinumab

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 )

ADBRY is a clear to opalescent, colorless to pale yellow solution available as: Injection: 150 mg/mL solution in a single-dose prefilled syringe with needle guard Injection: 300 mg/2 mL solution in a single-dose autoinjector Injection: 150 mg/mL solution in a single-dose prefilled syringe with needle guard. ( 3 ) 300 mg/2 mL solution in a single-dose autoinjector ( 3 )

ADBRY is contraindicated in patients who have known hypersensitivity to tralokinumab-ldrm or any excipients in ADBRY [see Warnings and Precautions (5.1) ] . Known hypersensitivity to tralokinumab-ldrm or any excipients in ADBRY. ( 4 )

Hypersensitivity: Hypersensitivity reactions, including anaphylaxis, and angioedema have occurred after administration of ADBRY. Discontinue ADBRY in the event of a hypersensitivity reaction. ( 5.1 ) Conjunctivitis and Keratitis: Patients should report new onset or worsening eye symptoms to their healthcare provider. ( 5.2 ) Parasitic (Helminth) Infections: Treat patients with pre-existing helminth infections before initiating treatment with ADBRY. If patients become infected while receiving ADBRY and do not respond to anti-helminth treatment, discontinue treatment with ADBRY until the infection resolves. ( 5.3 ) Risk of Infection with Live Vaccines: Avoid use of live vaccines. ( 5.4 )

5.1 Hypersensitivity Hypersensitivity reactions including anaphylaxis and angioedema have been reported with use of ADBRY. If a serious hypersensitivity reaction occurs, discontinue ADBRY immediately and initiate appropriate therapy.

5.2 Conjunctivitis and Keratitis Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received ADBRY. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period [see Adverse Reactions (6.1) ]. Advise patients to report new onset or worsening eye symptoms to their healthcare provider.

5.3 Parasitic (Helminth) Infections Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if ADBRY will influence the immune response against helminth infections by inhibiting IL-13 signaling. Treat patients with pre-existing helminth infections before initiating treatment with ADBRY. If patients become infected while receiving ADBRY and do not respond to antihelminth treatment, discontinue treatment with ADBRY until the infection resolves.

5.4 Risk of Infection with Live Vaccines ADBRY may alter a patient's immunity and increase the risk of infection following administration of live vaccines. Prior to initiating therapy with ADBRY, complete all age-appropriate vaccinations according to current immunization guidelines. Avoid use of live vaccines during treatment with ADBRY. Limited data are available regarding coadministration of ADBRY with non-live vaccines [see Clinical Pharmacology (12.2) ].

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. […]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADBRY during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/adbry-tralokinumab/. Risk Summary There are limited data from the use of ADBRY in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Monoclonal antibodies are actively transported across the placenta (see Clinical Considerations ) . In an enhanced pre-and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after intravenous administration of tralokinumab-ldrm during organogenesis through parturition at doses up to 10 times the maximum recommended human dose (MRHD). The 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% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses and peaks during the third trimester. Therefore, ADBRY may be present in infants exposed in utero . The potential clinical impact of tralokinumab-ldrm exposure in infants exposed in utero should be considered. Data Animal Data In a pre- and post-natal development study, intravenous doses up to 100 mg/kg tralokinumab-ldrm were administered to pregnant cynomolgus monkeys once every week from gestation day 20 to parturition. No maternal or developmental toxicity was observed at doses up to 100 mg/kg/week (10 times the MRHD on a mg/kg basis of 10 mg/kg/week). In an enhanced pre- and post-natal development study, intravenous doses up to 100 mg/kg tralokinumab-ldrm (10 times the MRHD on a mg/kg basis of 10 mg/kg/week) were administered to pregnant cynomolgus monkeys once every week from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.

8.2 Lactation Risk Summary There are no data on the presence of tralokinumab-ldrm in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is present in breast milk. The effects of local gastrointestinal exposure and limited systemic exposure to ADBRY on the breastfed infant are unknown. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for ADBRY and any potential adverse effects on the breastfed child from ADBRY or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of ADBRY have been established for the treatment of moderate-to-severe atopic dermatitis in 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. Use of ADBRY in this age group is supported by a multicenter, randomized, double-blind, placebo-controlled trial (ECZTRA 6) in 289 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis. Of the 289 subjects, 195 were treated with ADBRY and 94 were treated with matching placebo. The safety and effectiveness were consistent between subjects 12 to 17 years of age and adult subjects [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Safety and effectiveness of ADBRY have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Of the 1605 subjects exposed to ADBRY in 5 atopic dermatitis trials in the initial treatment period of up to 16 weeks, 77 subjects were 65 years or older. Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) ].

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.