ADBRY SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in greater detail elsewhere in the labeling:

• Hypersensitivity
• Conjunctivitis and Keratitis

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 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 study, 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

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.

Safety 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.

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 maintenance treatment period of the monotherapy trials (ECZTRA 1 and ECZTRA 2) from 16 to 52 weeks, conjunctivitis was reported in 8.9% of subjects treated with ADBRY 300 mg every other week (20 events per 100 subject-years of exposure) and in 6.3% of subjects treated with ADBRY 300 mg every 4 weeks (14 events per 100 subject-years of exposure) compared to 7.7% of subjects treated with ADBRY 300 mg every other week in the initial treatment period (30 events per 100 subject-years of exposure). Conjunctivitis (including no serious events, 1 severe event, and 1 event that led to discontinuation) was reported in 24 subjects in the combined (every other week and every 4 weeks) ADBRY groups. A similar pattern was seen during the continuation treatment period of an additional 16 weeks in the ADBRY combination ECZTRA 3.

Keratitis (including keratoconjunctivitis) was reported in 0.5% of subjects treated with ADBRY and 0% treated with placebo during the initial treatment period of up to 16 weeks in the pool of 5 trials. Keratitis (including 1 ulcerative keratitis) was reported in 0.2% of subjects treated with ADBRY (0.9 events per 100 subject-years of exposure) and 0.2% of subjects treated with placebo (0.6 events per 100 subject-years of exposure). Keratoconjunctivitis (including 1 atopic keratoconjunctivitis) was reported in 0.3% of subjects treated with ADBRY (1.2 events per 100 subject-years of exposure), and in no subjects treated with placebo. In the ADBRY group, 9 subjects reported 10 events of keratitis or keratoconjunctivitis, with 5 events resolved during the trial following the initial treatment period. None of the events were serious or led to treatment discontinuation.

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, compared to keratitis event rate of 2 per 100 subject-years for ADBRY 300 mg every other week in the initial treatment period.

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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with ADBRY. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other tralokinumab products may be misleading.

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 meaningful 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).