Now that the range of systemic therapeutics for atopic dermatitis has been expanded and the two monoclonal antibodies dupilumab and tralokinumab as well as three Janus kinase inhibitors have been approved in Switzerland, long-term data on efficacy and safety are increasingly becoming the focus of interest. There are interesting new analyses on this. In addition, phase II and phase III study data are now available for new systemic active substances.
Today, atopic dermatitis (AD) is understood as an immune-mediated skin disease that is based on type 2 inflammation. The genetically determined immunological imbalance is characterized by an increased TH2 response and is associated with the production of inflammatory cytokines such as IL-4, IL-5, IL-13 and IL-31 [1]. Another important factor in the pathomechanism of AD is a genetically determined barrier disorder of the skin, triggered by mutations of barrier or structural proteins, which favors the penetration of irritants, allergens and microbes into the skin [2,3]. Until 2017, the systemic therapies recommended in the AWMF guidelines were limited to conventional immunosuppressants such as ciclosporin, but since then the armamentarium has fortunately been greatly expanded by the market launch of targeted immunomodulatory biologics and JAK inhibitors (box).
Th2 cytokines as target structures In addition to the specific cytokine blockade of interleukin (IL)-4 and/or IL-13 by the monoclonal antibodies dupilumab (Dupixent®) and tralokinumab (Adtralza®), oral Janus kinase (JAK) inhibitors targeting the JAK-1/2 signaling pathway are available in the form of baricitinib (Olumiant®), abrocitinib (Cibinqo®) and upadacitinib (Rinvoq®) [1,4]. In addition, the biologic lebrikizumab, a monoclonal antibody that binds with high affinity to IL-13 and thus prevents the formation of the IL-4Rα/IL-13Rα1 heterodimer complex and subsequent signal transmission, was recently approved in the EU [6]. |
Dupilumab has proven to be an effective and safe treatment option since its introduction and is the only systemic therapy approved for infants from 6 months of age [4]. Tralokinumab is also available as an active substance that inhibits IL-13 in isolation and for which long-term data are now also available that demonstrate a favorable risk-benefit profile. While tralokinumab is only officially approved for adults in Switzerland, it is approved in the EU for ≥12-year-old AD patients [4,5]. Lebrikizumab also inhibits isolated IL-13 and was already approved in the EU a few months ago for the indication AD [6].
Tralokinumab in ≥12 year olds: Long-term data up to 4.5 years available
After the efficacy and safety of tralokinumab had been proven in the randomized controlled phase III ECZTRA 6 study (NCT03526861) in 12-17-year-old patients with inadequately controlled moderate to severe AD for up to 52 weeks, Wollenberg et al. Long-term data from participants enrolled in the open-label ECZTEND extension study (NCT03587805) [7]. These were 127 adolescents who were treated with tralokinumab for up to 2 years (≤52 weeks in the main study and ≤56 weeks in ECZTEND). Patients were treated with subcutaneous tralokinumab 300 mg (twice weekly, q2w) and optionally with topical corticosteroids (TCS). At week 56 of the extension study, the following results were achieved compared to the baseline value of the main study:
- EASI-75 and EASI-90, i.e. at least 75% or 90% improvement in EASI, were achieved by 84.4% and 69.7% respectively (mNRI: 82.8% and 66.4%)
- EASI ≤7 (no or only slightly pronounced AD) was found in 82.6% (mNRI: 81.0%) of study participants
- in the weekly WP-NRS achieved a value ≤4 (no to mild itching) 64.2% (mNRI: 62.9%),
- CDLQI ≤6 (no or only minor impairment) achieved 81.6% (mNRI: 77.6%).
The safety profile in the extension study was consistent with that of the ECZTRA 6 study. In summary, treatment with tralokinumab in adolescents with moderate to severe AD resulted in long-term disease control over a period of up to 2 years.
As shown in an analysis by Reich et al. Tralokinumab proved to be well tolerated in adolescent and adult AD patients over a period of up to 4.5 years [8]. The analysis is based on a data set from the 16-week initial period of the main ECZTEND studies and a combined data set from the main studies and the subsequent extension study. All treatment-related adverse events (AE) and adverse events of special interests (AESI ) were recorded and the proportion of patients with AE and AESI and the incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated.
- 2693 patients aged ≥12 years received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks.
- The total exposure time amounted to 5320.2 patient years. An AE occurred in 2307 patients, which corresponds to an IR of 202.0. Of these, 97.3% were mild to moderate.
- Serious adverse events (SAEs) were reported in 226 patients, corresponding to an IR of 4.5. SAEs were classified as possibly or probably treatment-related by the investigator in 50 patients (IR = 0.9).
- The number of treatment discontinuations due to AEs was low (IR = 2.8). AEs that led to discontinuation of treatment with an IR >0.1 included atopic dermatitis (IR = 0.5) and injection site reactions (IR = 0.2).
- The most frequently reported adverse reactions were nasopharyngitis (IR = 18.4), upper respiratory tract infection (IR = 6.9), conjunctivitis (IR = 5.0), injection site reactions (IR = 3.6) and allergic conjunctivitis (IR = 2.7).
- The rates of AESIs (eye diseases, skin infections requiring systemic treatment, eczema herpeticum, malignant diseases) were at placebo level.
In summary, the pattern of adverse events in the combined data set over a period of up to 4.5 years was the same as in the first placebo-controlled treatment phase and no new safety signals were detected.
Lebrikizumab in ≥18-year-olds: 1- and 2-year data available
Simpson et al. reported an analysis of pooled data from the Phase III studies Advocate 1 (NCT04146363) and ADvocate 2 (NCT04178967) [9]. Responders at week 16 (EASI75 or IGA 0/1 with improvement ≥2 points) were randomized in a 2:2:1 ratio into three study arms (lebrikizumab q2w, lebrikizumab q4w, placebo) and followed up for 36 weeks. In addition, data from the clinical Phase III study ADjoin (NCT04392154) was analyzed. In this study, responders from the Phase III ADhere study (NCT04250337, induction treatment with lebrikizumab in combination with topical corticosteroids) were randomized again in a 2:1 ratio and received lebrikizumab (LEB) q2w or q4w for 100 weeks. To assess symptom progression, the mean percentage change in affected body surface area (BSA) from baseline was calculated for ADvocate 1&2 at week 52 and for ADjoin at week 56.
In ADvocate 1&2, BSA improved after 52 weeks in all three study arms (discontinuation of LEB, LEB Q2W, LEB Q4W) in the head and neck (-74.04; -79.28 and -81.60%), in the lower extremities (-68.34; -82.30 and -82.51%), in the upper extremities (-62.52; -78.47 and -79.43%) and in the trunk (-72.01; -84.82 and -86.30%).
In ADjoin, the BSA in the two treatment arms LEB q2w and LEB q4w improved after 56 weeks in the head and neck area (-91.26% and -92.76% respectively), in the lower extremities (-90.81% and -84.16% respectively), in the upper extremities (-98.36% and -92.06% respectively) and in the trunk area (-92.22% and -89.73% respectively).
In summary, lebrikizumab as monotherapy and in combination with TCS at week 56 reduced the affected body surface area and severity of AD of all affected body regions, including the head and neck region – a particularly distressing and difficult to treat area [9].
Guttman-Yassky et al. summarized the 2-year efficacy and safety data of lebrikizumab in AD [10]. Patients in ADvocate1&2 who had achieved either EASI 75 or IGA 0/1 (without rescue medication) at week 16 were randomized again in a 2:2:1 ratio to lebrikizumab 250 mg q2w, lebrikizumab 250 mg q4w or placebo (discontinuation of lebrikizumab). Patients who had completed Advocate 1&2 by week 52 were eligible for inclusion in ADjoin. ADjoin included participants from ADhere who had achieved either EASI 75 or IGA 0/1 (without rescue medication) at week 16. These were randomized in a 2:1 ratio to lebrikizumab 250mg q2w or lebrikizumab 250mg q4w. The following results were documented in week 104:
IGA 0/1 was retained in ADvocate1&2 by 86.4% (38 of 44) under LEB q2w and by 76.4% (42 of 55) under LEB q4w. In ADhere, the corresponding rates were 83.9% (26 of 31) under LEB q2w and 78.6% (11 of 14).
EASI 75 persisted in 95.6% (65 of 68) under LEB q2w and 96.3% (77 of 80) under LEB q4w of ADvocate1&2 patients. In ADhere, the corresponding rates were 95.1% (39 of 41) under LEB q2w and 96.0% (24 of 25) under LEB q4w.
During the ADjoin study, 62.2% of patients reported AEs, most of which were mild (n=84) or moderate (n=72). Serious AEs were reported by 3.8% of patients. Reports of side effects that led to discontinuation of treatment were received from 2.3% of patients. The safety profile of LEB in ADjoin is similar to that observed in ADvocate1&2 and ADhere. In summary, the present analysis shows that the efficacy of lebrikizumab was maintained over a period of 2 years in both treatment arms (250 mg q2w and q4w). The safety profile of lebrikizumab in ADjoin is consistent with previous studies in patients with moderate to severe AD.
Congress: Dermatology compact & practical
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- Wollenberg A, et al: Long term efficacy of tralokinumab in adolescents with moderate to severe atopic dermatitis, KoPra 2024, P043, JDDG 2024; 22, Issue S1: 1-40.
- Reich K, et al: Safety of tralokinumab for the treatment of atopic dermatitis in patients with up to 4.5 years of treatment: an updated integrated analysis of eight clinical trials, KoPra 2024, P042, JDDG 2024; 22, Issue S1: 1-40.
- Simpson E, et al: Lebrikizumab reduces the severity of atopic dermatitis and the affected body surface area in different body regions including the head and neck area, KoPra 2024, P013, JDDG 2024; 22, Issue S1: 1-40.
- Guttman-Yassky E, et al: Consistent efficacy and safety of lebrikizumab in patients with moderate to severe atopic dermatitis over two years, KoPra 2024, P012, JDDG 2024; 22, Issue S1: 1-40.
- Moniaga CS, et al: The Pathology of Type 2 Inflammation-Associated Itch in Atopic Dermatitis. Diagnostics 2021, 11, 2090. www.mdpi.com/2075-4418/11/11/2090#,(last accessed 14.05.2024).
DERMATOLOGIE PRAXIS 2024; 34(3): 38-40 (published on 17.6.24, ahead of print)