Targeting Interleukin 13 for the Treatment of Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that has a significant impact on a patient’s quality of life and requires ongoing management. Conventional topical and systemic therapies do not target specific components of AD pathogenesis and, therefore, have limited efficacy and may be associated with long-term toxicity. Thus, AD management is challenging, with a significant proportion of patients not achieving clear skin or a reduction in pruritus. There remains a large unmet need for effective therapeutic strategies with favorable safety profiles that can be used long-term in patients with refractory AD. The emergence of targeted biological and small molecule therapies has effectively broadened available treatment options for moderate-to-severe AD. Most recently, interleukin 13 (IL-13) inhibitors were shown to be efficacious and well-tolerated, with tralokinumab already approved for use in this patient population. It is important for dermatologists to be aware of the evidence behind this emerging class of biologic agents to guide treatment choices and improve outcomes in patients with AD. The main objective of this paper is to review the current literature regarding the efficacy and safety of current and emerging anti-IL-13 monoclonal antibodies, including tralokinumab, lebrikizumab, cendakimab, and eblasakimab, for the treatment of moderate-to-severe AD.

Full text

Citation: Lytvyn, Y.; Gooderham, M.
Targeting Interleukin 13 for the
Treatment of Atopic Dermatitis.
Pharmaceutics 2023,15, 568.
https://doi.org/10.3390/
pharmaceutics15020568
Academic Editor: Bozena B.
Michniak-Kohn
Received: 23 November 2022
Revised: 24 January 2023
Accepted: 6 February 2023
Published: 8 February 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
pharmaceutics
Review
Targeting Interleukin 13 for the Treatment of Atopic Dermatitis
Yuliya Lytvyn 1and Melinda Gooderham 2,3,4,*
1Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
2SKiN Centre for Dermatology, Peterborough, ON K9J 5K2, Canada
3Probity Medical Research, Waterloo, ON N2J 1C4, Canada
4Department of Family Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
*Correspondence: mgooderham@centrefordermatology.com
Abstract:
Atopic dermatitis (AD) is a common chronic inflammatory skin condition that has a
significant impact on a patient’s quality of life and requires ongoing management. Conventional
topical and systemic therapies do not target specific components of AD pathogenesis and, therefore,
have limited efficacy and may be associated with long-term toxicity. Thus, AD management is
challenging, with a significant proportion of patients not achieving clear skin or a reduction in
pruritus. There remains a large unmet need for effective therapeutic strategies with favorable safety
profiles that can be used long-term in patients with refractory AD. The emergence of targeted
biological and small molecule therapies has effectively broadened available treatment options for
moderate-to-severe AD. Most recently, interleukin 13 (IL-13) inhibitors were shown to be efficacious
and well-tolerated, with tralokinumab already approved for use in this patient population. It is
important for dermatologists to be aware of the evidence behind this emerging class of biologic
agents to guide treatment choices and improve outcomes in patients with AD. The main objective
of this paper is to review the current literature regarding the efficacy and safety of current and
emerging anti-IL-13 monoclonal antibodies, including tralokinumab, lebrikizumab, cendakimab, and
eblasakimab, for the treatment of moderate-to-severe AD.
Keywords:
interleukin 13; lebrikizumab; tralokinumab; cendakimab; eblasakimab; atopic dermatitis
1. Introduction
Atopic dermatitis (AD) is one of the most common chronic inflammatory skin con-
ditions which impacts 15–20% of people in developed countries [
1
–
4
], with 80% of cases
typically onsetting in infancy or childhood [
5
]. AD is characterized by localized or dissem-
inated pruritic, xerotic, and erythematous lesions which are frequently accompanied by
sleep disturbances, reduced productivity, decreased self-esteem, social isolation, depres-
sion, and suicidal ideation in severe cases [
6
–
10
]. Thus, the relapsing chronic symptoms
of AD have a significant impact on quality of life and require ongoing long-term manage-
ment [
6
,
11
,
12
]. Moderate-to-severe AD constitutes about 20% of the cases and requires
treatment with phototherapy and/or conventional systemic immunosuppressive agents,
such as corticosteroids, methotrexate, mycophenolate mofetil, cyclosporin A, and aza-
thioprine [
11
,
13
–
16
]. These conventional therapies do not target specific components of
AD pathogenesis and, therefore, often have limited efficacy and may be associated with
long-term toxicity, posing challenges in AD management [7,8,15,17,18].
In recent years, the emergence of targeted biological and small molecule therapies
has effectively broadened the available treatment options for moderate-to-severe AD. The
first available biological agent for this patient population was dupilumab, an inhibitor of
interleukin-4 (IL-4) receptor-
α
, which blocks IL-4 and IL-13 signaling and prevents the
downstream inflammatory cascade [
19
–
21
]. Despite the demonstrated efficacy and safety
of dupilumab in AD treatment, only 40% of patients were shown to achieve clear or almost
clear skin in clinical trials [
22
–
24
], and real-world data suggest about a 70% improvement
Pharmaceutics 2023,15, 568. https://doi.org/10.3390/pharmaceutics15020568 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2023,15, 568 2 of 18
in the clinical severity score (Eczema Area and Severity Index, EASI) after 3 months
of treatment [
25
]. Moreover, dupilumab’s use may be limited by potential associated
adverse effects in 8–38% of patients, such as conjunctivitis, injection site reactions, and
persistent head and neck erythema [
25
–
27
]. It is believed that inhibition of IL-13 is the
dominant mechanism of dupilumab’s effectiveness in treating AD [
28
,
29
]. JAK-STAT
pathway inhibitors were also shown to be safe and efficacious for use in AD, and, thus,
abrocitinib and upadacitinib have both been approved by the European Commission,
Health Canada, and the FDA for use in moderate-to-severe AD [
30
]. Most recently, IL-13
inhibitors have been studied for the management of AD. The main objective of this paper
is to review the current literature regarding the efficacy and safety of current and emerging
IL-13 monoclonal antibodies, including tralokinumab, lebrikizumab, cendakimab, and
eblasakimab, for the treatment of moderate-to-severe AD.
2. Methods
A search was conducted from the study’s inception up until 30 October 2022, in
the OVID PubMed, Medline, and Google Scholar databases and on ClinicalTrials.gov.
The following specific keywords present in the title, abstract, or body were used for the
search: “interleukin 13,” “lebrikizumab”, “tralokinumab”, “cendakimab”, “eblasakimab”,
“atopic dermatitis,” and “eczema.” Review articles and clinical trials were included in
our summary of the literature. The reference lists of included articles were reviewed for
retrieval of relevant studies not identified in the original search. Only studies involving
human patients published in the English language were included.
3. The Role of Interleukin 13 in the Pathogenesis of Atopic Dermatitis
The pathogenesis of AD is multifactorial, driven by an interplay of environmental
and genetic factors that trigger inflammation, dysbiosis, and immune dysregulation of
the cutaneous epidermal layer [
18
,
31
,
32
]. This markedly increases transdermal water loss
and facilitates permeation by irritants, microbes, and allergens [
32
–
35
]. An aberrant type
2 immune response is triggered by these antigens stimulating naïve T cells to commit to
the Th2 lineage [
20
,
36
,
37
]. This ultimately leads to the overproduction of cytokines central
to atopic manifestations of AD and pruritus, namely IL-4, IL-5, IL-13, and IL-31 [
38
,
39
].
IL-4 and IL-13 contribute to epidermal barrier dysfunction by stimulating the production
of immunoglobulin E (IgE), recruiting eosinophils, amplifying Th2 cell differentiation,
and reducing filaggrin expression [
18
,
37
,
40
]. IL-4 and IL-13 also decrease anti-microbial
peptide (AMP) production by keratinocytes, which predisposes the skin to Staphylococcus
aureus colonization [
20
]. This may explain the altered skin microbiome in AD, whereby an
abundance of S. aureus and a decrease in bacterial diversity further disrupt the epidermal
barrier [33,41–50].
IL-4 and IL-13 are produced predominantly by activated Th2 cells, type 2 innate lym-
phoid cells (ILC2s), and, to a lesser extent, by type 2 CD8(+) T cells (Tc2), basophils,
eosinophils, and mast cells. IL-4 and IL-13 trigger a signaling cascade via a shared
heterodimeric receptor formed by IL-4 receptor
α
(IL-4R
α
) and IL-13 receptor
α
1 (IL-
13R
α
1) [
20
,
39
,
51
]. The binding of either IL-4 or IL-13 to IL-13R
α
1 recruits IL-4R
α
, caus-
ing dimerization of the receptors, activation of Janus kinase 1 (JAK1) and tyrosine ki-
nase 2 (TYK2), and phosphorylation of a signal transducer and activator of transcription
6 (STAT6), which promotes Th2 differentiation [
8
,
20
,
52
]. IL-13 also has a high affinity
for the IL-13R
α
2 receptor, which plays a role in the endogenous regulation of IL-13 and
in the itch–scratch cycle, collagen deposition, and fibrotic tissue remodeling [
34
,
53
,
54
].
Thus, IL-13 may contribute to histamine-independent stimulation of afferent nerve endings
and pruritus [
34
]. Interestingly, skin biopsy samples of patients with AD demonstrate
significant overexpression of IL-13 in lesional and non-lesional skin, and only a mild IL-4
overexpression is detectable in 40% of AD lesions [
28
,
55
]. Moreover, IL-13 overexpression
in peripheral blood T cells was shown to correlate with disease severity, while a decrease
in its concentration correlates with improved clinical outcomes [
55
–
61
]. Overall, IL-13 is

Pharmaceutics 2023,15, 568 3 of 18
emerging to play an increasingly prominent role in the epidermal barrier dysfunction and
inflammatory processes associated with AD [20,62].
4. Therapies Targeting Interleukin-13 for Management of Atopic Dermatitis
IL-13 is a promising drug target for the management of AD, with a great potential for
efficacy and limited toxicity [
28
]. Therefore, four selective IL-13 inhibitors have emerged
which are currently at various stages of development or approval. Tralokinumab has
recently been approved for use in patients with moderate-to-severe AD by Health Canada,
the FDA, and the European Commission. Lebrikizumab is currently in the late stages of
clinical development, while cendakimab and eblasakimab are being investigated in phase
II trials. See Figure 1for the mechanisms of action of these agents.
Pharmaceutics 2023, 15, x FOR PEER REVIEW 3 of 17
peripheral blood T cells was shown to correlate with disease severity, while a decrease in
its concentration correlates with improved clinical outcomes [55–61]. Overall, IL-13 is
emerging to play an increasingly prominent role in the epidermal barrier dysfunction and
inflammatory processes associated with AD [20,62].
4. Therapies Targeting Interleukin-13 for Management of Atopic Dermatitis
IL-13 is a promising drug target for the management of AD, with a great potential for
efficacy and limited toxicity [28]. Therefore, four selective IL-13 inhibitors have emerged
which are currently at various stages of development or approval. Tralokinumab has re-
cently been approved for use in patients with moderate-to-severe AD by Health Canada,
the FDA, and the European Commission. Lebrikizumab is currently in the late stages of
clinical development, while cendakimab and eblasakimab are being investigated in phase
II trials. See Figure 1 for the mechanisms of action of these agents.
Figure 1. Mechanisms of IL-13 inhibition by dupilumab, lebrikizumab, tralokinumab, and eblasa-
kimab in atopic dermatitis [18,20,63]. Dupilumab binds to the IL-4Rα subunit of IL-4 and IL-13 re-
ceptor complexes to reduce inflammatory signaling. Lebrikizumab is a fully human IgG4 that binds
to IL-13 and prevents the formation of the IL-13Rα1/IL-4Rα heterodimer receptor signaling com-
plex. Tralokinumab is fully human IgG4λ that binds to IL-13 preventing binding to the IL-13 recep-
tor. Eblasakimab is a monoclonal antibody that targets IL13Rα1 to block IL-13 signal transduction.
It, therefore, interferes with IL-4 signaling elicited via the type 2 receptor, but not the type 1 receptor.
This figure was created with Biorender at www.biorender.com.
5. Use of Tralokinumab to Manage Patients with Atopic Dermatitis
5.1. Overview of Tralokinumab
Tralokinumab is approved for use in patients 18 years of age or older with moderate-
to-severe AD refractory to topical therapies. It is a fully humanized IgG4λ anti-IL-13 mon-
oclonal antibody that competitively blocks the binding of IL-13 to both IL-13Rα1 and IL-
13Rα2 receptor chains (Figure 1) [18,53,63–65]. In vitro studies confirmed the suppression
of inflammation and restoration of the skin barrier by tralokinumab [65]. In these studies,
tralokinumab treatment normalized the upregulated type 2 inflammatory markers and
the downregulated genes related to terminal keratinocyte differentiation (i.e., filaggrin
and loricrin) in primary human epidermal keratinocytes and human dermal fibroblasts
pre-treated with IL-13 [65]. Recent investigations of the skin of patients with AD treated
with tralokinumab showed increased microbial diversity, decreased Staphylococcus au-
reus, and increased coagulase-negative Staphylococci with treatment [66]. Therefore,
Figure 1.
Mechanisms of IL-13 inhibition by dupilumab, lebrikizumab, tralokinumab, and
eblasakimab in atopic dermatitis [
18
,
20
,
63
]. Dupilumab binds to the IL-4R
α
subunit of IL-4 and IL-13
receptor complexes to reduce inflammatory signaling. Lebrikizumab is a fully human IgG4 that binds
to IL-13 and prevents the formation of the IL-13R
α
1/IL-4R
α
heterodimer receptor signaling complex.
Tralokinumab is fully human IgG4
λ
that binds to IL-13 preventing binding to the IL-13 receptor.
Eblasakimab is a monoclonal antibody that targets IL13R
α
1 to block IL-13 signal transduction. It,
therefore, interferes with IL-4 signaling elicited via the type 2 receptor, but not the type 1 receptor.
This figure was created with Biorender at www.biorender.com.
5. Use of Tralokinumab to Manage Patients with Atopic Dermatitis
5.1. Overview of Tralokinumab
Tralokinumab is approved for use in patients 18 years of age or older with moderate-
to-severe AD refractory to topical therapies. It is a fully humanized IgG4
λ
anti-IL-13
monoclonal antibody that competitively blocks the binding of IL-13 to both IL-13R
α
1
and IL-13R
α
2 receptor chains (Figure 1) [
18
,
53
,
63
–
65
].
In vitro
studies confirmed the
suppression of inflammation and restoration of the skin barrier by tralokinumab [
65
]. In
these studies, tralokinumab treatment normalized the upregulated type 2 inflammatory
markers and the downregulated genes related to terminal keratinocyte differentiation
(i.e., filaggrin and loricrin) in primary human epidermal keratinocytes and human dermal
fibroblasts pre-treated with IL-13 [
65
]. Recent investigations of the skin of patients with AD
treated with tralokinumab showed increased microbial diversity, decreased Staphylococcus
aureus, and increased coagulase-negative Staphylococci with treatment [
66
]. Therefore,
tralokinumab may improve the dysbiosis of bacterial growth observed in the skin of patients
with AD. The bioavailability of tralokinumab in human studies is 61%, with peak serum
concentrations reached after 3–9 days (median: 5 days) and a mean half-life of 19.3 days
when administered subcutaneously and 21.4 days when administered intravenously [67].

Pharmaceutics 2023,15, 568 4 of 18
5.2. Clinical Efficacy of Tralokinumab in Patients with Atopic Dermatitis
There were significant clinical benefits observed with the use of tralokinumab to man-
age patients with AD in phase II and phase III trials (Table 1, Table 2). There have been three
randomized, double-blind, placebo-controlled, 52-week, phase III trials completed with
tralokinumab in patients with AD: ECZTRA 1 (NCT03131648), ECZTRA 2 (NCT03160885),
and ECZTRA 3 (NCT03363854). ECZTRA 1 and 2 included 807 and 794 patients with AD,
respectively. Patients were randomized to receive subcutaneous tralokinumab monother-
apy with a 600 mg loading dose followed by 300 mg every other week (Q2W) or a placebo
for 16 weeks [
68
]. The eligibility criteria included patients with AD suitable for systemic
therapy with an Investigator’s Global Assessment (IGA) score of
≥
3, an EASI score of
≥
12,
a body surface area (BSA) of
≥
10%, and a pruritus numeric rating score (NRS) of
≥
4 [
68
].
In both trials, tralokinumab showed superiority to the placebo in reaching the co-primary
endpoints of achieving an IGA of 0 or 1 and an EASI of 75 by week 16 of treatment [
68
].
In the ECZTRA 1 trial, 15.8% of patients treated with tralokinumab achieved IGA scores
of 0 or 1, compared to 7.1% of patients treated with a placebo (p= 0.002). EASI 75 was
achieved in 25.0% of patients treated with tralokinumab compared to 12.7% of patients
receiving a placebo (p= 0.001) [
68
]. Similarly, in the ECZTRA 2 trial, significantly more
patients treated with tralokinumab achieved IGA 0 or 1 (22.2% vs. 10.9%, p< 0.001) and
EASI 75 (33.2% vs. 11.4%, p< 0.001) compared to placebo [
68
]. Finally, a significantly larger
proportion of patients achieved EASI 50 or EASI 90 in the tralokinumab group compared
to the placebo group by week 16 [68].
Patients treated with tralokinumab who achieved primary endpoints by week 16 were
re-randomized into three groups for the following 36 weeks: tralokinumab 300 mg Q2W,
tralokinumab 300 mg Q4W, and placebo [
68
]. The patients that had a clinical response
to placebos were maintained on placebos; however, they were not incorporated into the
analysis after week 16 [
68
]. Patients that did not obtain a clinical response with placebos
were treated with open-label tralokinumab 300 mg Q2W with optional topical corticos-
teroids [
68
]. If patients experienced a loss of effect between weeks 16 and 52, they were
switched to the open-label tralokinumab group [
68
]. Rescue treatment was used to con-
trol unbearable symptoms, and patients continued in the open-label or randomized arm;
however, they were considered non-responders in the final analysis [
68
]. By week 52, in
the ECZTRA 1 trial, there were no significant differences observed in the percentage of
patients reaching IGA scores of 0 or 1 without rescue medication (51% tralokinumab Q2W
vs. 47% placebo, p= 0.68) or in the percentage of patients maintaining or reaching EASI
75 (60% tralokinumab Q2W vs. 33% placebo, p= 0.056) [
68
]. Responses in the IGA and
EASI 75 in the tralokinumab group improved further at week 52 compared to week 16,
suggesting peak efficacy occurs at a later time point [
68
]. In the ECZTRA 2 trial, IGA
scores of 0 or 1 were reported in 59% of patients that continued tralokinumab Q2W treat-
ment compared, to 25% that were re-randomized from tralokinumab Q2W to the placebo
(p= 0.004) [
68
]. Similarly, an EASI 75 score was maintained in 56% of patients continu-
ing tralokinumab Q2W treatment and 21% of patients that were switched to the placebo
(p= 0.001) [
68
]. The long-term outcomes of tralokinumab treatment showed greater differ-
ences in the tralokinumab group compared to the placebo group in the ECZTRA 2 trial,
which could be due to the greater use of topical corticosteroids in ECZTRA 1 by 35.8% of
patients compared to 22.8% of patients in the ECZTRA 2 trial [
68
]. Patients treated with
Q4W tralokinumab had lower frequencies of IGA 0 or 1 and EASI 75 at 52 weeks compared
to the Q2W treatment schedule in both the ECZTRA 1 and ECZTRA 2 trials [
68
]. Greater
improvements in eczema-related sleep loss and pruritus were reported in the tralokinumab
group compared to the placebo group in both trials in the secondary endpoint analysis [
68
].
The tralokinumab group had a greater proportion of patients with pruritus NRS reductions
of
≥
4 (ECZTRA 1: 20.0% vs. 10.3%, p= 0.002; ECZTRA 2: 25.0% vs. 9.5%, p< 0.001),
reductions in SCORAD (ECZTRA 1:
−
25.2 vs. 14.7, p< 0.001; ECZTRA 2:
−
28.1 vs.
−
14.0,
p< 0.001), and reductions in the Dermatology Life Quality Index (DLQI) (ECZTRA 1:
−7.1 vs. −5.0, p= 0.002; ECZTRA 2: −8.8 vs. −4.9, p< 0.001) [68].

Pharmaceutics 2023,15, 568 5 of 18
Table 1.
Summary of primary and select secondary outcomes for phase II clinical trials completed with tralokinumab treatment in patients with moderate-to-severe
atopic dermatitis.
Clinical Trial Eligibility
(Sample Size)
Treatment Groups
(Duration) EASI EASI 50 EASI 75 IGA 0 or 1 SCORAD 50 NRS DLQI
Tralokinumab
NCT02347176
[69]
18–75 years
SCORAD ≥25
EASI ≥12
BSA ≥10% IGA ≥3
(N = 204)
45 mg tralokinumab
Q2W + TCS
(12 weeks)
−10.78
(p= 0.143) 54.3% N/A 11.6%
(p= 0.974) 26.9% −1.80 N/A
150 mg tralokinumab
Q2W + TCS
(12 weeks)
−15.14
(p= 0.027) 67.3% N/A 19.5%
(p= 0.281) 44.2% −1.59 N/A
300 mg tralokinumab
Q2W + TCS
(12 weeks)
−15.72
(p= 0.011)
73.4%
(p= 0.03)
42.5%
(p= 0.003)
26.7%
(p= 0.061) 44.1% −2.17 N/A
Placebo + TCS
(12 weeks) −10.78 51.9% 15.5% 11.8% 19.5% −1.03 N/A
Lebrikizumab
TREBLE
(NCT02340234)
[70]
18–75 years
EASI ≥14
BSA ≥10% IGA ≥3
Pruritis VAS ≥3
(N = 212)
Lebrikizumab 125 mg
single dose N/A 69.2% 38.5% 21.2% N/A N/A N/A
Lebrikizumab 250 mg
single dose N/A 69.5% 49.1% 28.3% N/A N/A N/A
Lebrikizumab 125 mg
Q4W + TCS
(12 weeks)
N/A 82.4%
(p= 0.026)
54.9%
(p= 0.036) 33.3% N/A N/A N/A
Placebo + TCS
(12 weeks) N/A 62.3% 34.0% 18.9% N/A N/A N/A

Pharmaceutics 2023,15, 568 6 of 18
Table 1. Cont.
Clinical Trial Eligibility
(Sample Size)
Treatment Groups
(Duration) EASI EASI 50 EASI 75 IGA 0 or 1 SCORAD 50 NRS DLQI
NCT03443024
[26]
18–75 years
EASI ≥16
BSA ≥10% IGA ≥3
(N = 280)
Lebrikizumab 250 mg
loading dose + 125 mg
Q4W (16 weeks)
−62.34%
(p= 0.0165)
66.4%
(p= 0.0554)
43.3%
(p= 0.0610)
26.6%
(p= 0.1917) N/A −35.94% (p
= 0.0047) N/A
Lebrikizumab 500 mg
loading dose + 250 mg
lebrikizumab Q4W
(16 weeks)
−69.21%
(p= 0.0022)
77.0%
(p= 0.0037)
56.1%
(p= 0.0021)
33.7%
(p= 0.0392) N/A −49.6%
(p= 0.0002) N/A
Lebrikizumab 500 mg
loading dose + 250 mg
lebrikizumab Q2W
(16 weeks)
−72.09%
(p= 0.0005)
81.0%
(p= 0.0008)
60.6%
(p= 0.0005)
44.6%
(p= 0.0023) N/A −60.63% (p
< 0.0001) N/A
Placebo (16 weeks) −41.12% 45.8% 24.3% 15.3% N/A 4.26 N/A
EASI: Eczema Area and Severity Index; IGA: Investigator’s Global Assessment; N/A: not applicable; NRS: numerical rating scale; TCS: topical corticosteroid. p-values are all compared
to the respective placebo group.
Table 2.
Summary of primary and select secondary outcomes for phase III clinical trials completed with tralokinumab and lebrikizumab treatment in patients with
moderate-to-severe atopic dermatitis.
Clinical Trial Eligibility
(Sample Size)
Treatment Groups
(Duration) EASI EASI 90 EASI 75 IGA 0 or 1 SCORAD
Change NRS Change DLQI
Change
Tralokinumab
ECZTRA 1
(NCT03131648)
≥18 years
BSA ≥10%
(N = 802)
Tralokinumab 300 mg
Q2W (16 weeks)
−15.5
(p< 0.001)
14.5%
(p< 0.001)
25.0%
(p< 0.001)
15.8%
(p= 0.002)
−25.2
(p< 0.001)
−2.6
(p< 0.001)
−7.1
(p= 0.002)
Placebo (16 weeks) −9.0 4.1% 12.7% 7.1% −14.7 −1.7 −5.0
Tralokinumab 300 mg
Q2W (52 weeks) N/A N/A 59.6%
(p= 0.056)
51.3%
(p= 0.68) N/A N/A N/A
Tralokinumab 300 mg
Q4W (52 weeks) N/A N/A 49.1%
(p= 0.27)
38.95%
(p= 0.50) N/A N/A N/A
Placebo (52 weeks) N/A N/A 33.3% 47.4% N/A N/A N/A

Pharmaceutics 2023,15, 568 7 of 18
Table 2. Cont.
Clinical Trial Eligibility
(Sample Size)
Treatment Groups
(Duration) EASI EASI 90 EASI 75 IGA 0 or 1 SCORAD
Change NRS Change DLQI
Change
ECZTRA 2
(NCT03160885)
≥18 years
BSA ≥10%
(N = 794)
Tralokinumab 300 mg
Q2W (16 weeks)
−16.9
(p< 0.001)
18.3%
(p< 0.001)
33.2%
(p< 0.001)
22.2%
(p< 0.001)
−28.1
(p< 0.001)
−2.9
(p< 0.001)
−8.8
(p< 0.001)
Placebo (16 weeks) −7.0 5.5% 11.4% 10.9% −14.0 −1.6 −4.9
Tralokinumab 300 mg
Q2W (52 weeks) N/A N/A 55.8%
(p< 0.001)
59.3%
(p= 0.004) N/A N/A N/A
Tralokinumab 300 mg
Q4W (52 weeks) N/A N/A 51.4%
(p= 0.001)
44.9%
(p= 0.084) N/A N/A N/A
Placebo (52 weeks) N/A N/A 21.4% 25.0% N/A N/A N/A
ECZTRA 3
(NCT03363854)
≥18 years
BSA ≥10%
(N = 380)
Tralokinumab 600 mg
loading dose + 300 mg
Q2W + TCS
(16 weeks)
−21.0
(p< 0.001)
32.9%
(p= 0.022)
56.0%
(p< 0.001)
38.9%
(p= 0.015)
−37.7
(p< 0.001)
−4.1
(p< 0.001)
−11.7
(p< 0.001)
Placebo + TCS
(16 weeks) −15.6 21.4% 35.7% 26.2% −26.8 −2.9 −8.8
Tralokinumab 600 mg
loading dose + 300 mg
Q2W + TCS
(32 weeks)
N/A N/A 92.5% 89.6% N/A N/A N/A
Tralokinumab 600 mg
loading dose + 300 mg
Q4W + TCS
(32 weeks)
N/A N/A 90.8% 77.6% N/A N/A N/A

Pharmaceutics 2023,15, 568 8 of 18
Table 2. Cont.
Clinical Trial Eligibility
(Sample Size)
Treatment Groups
(Duration) EASI EASI 90 EASI 75 IGA 0 or 1 SCORAD
Change NRS Change DLQI
Change
Lebrikizumab
ADVOCATE 1
(NCT04146363)
≥12 years
EASI ≥16
BSA ≥10% IGA ≥3
(N = 424)
Lebrikizumab 500 mg
loading dose + 250 mg
Q2W (16 weeks)
−64.75%
(p< 0.001)
38.2%
(p< 0.001)
59.3%
(p< 0.001)
43.0%
(p< 0.001)
−47.26
(p< 0.001)
−45.75%
(p< 0.001)
−8.78
(p< 0.001)
Placebo (16 weeks) −26.16% 9.1% 16.4% 12.8% −16.79 −15.24% −2.94
Lebrikizumab Q2W
(52 weeks) N/A N/A 79.2%
(p< 0.05)
75.8%
(p< 0.001) N/A N/A N/A
Lebrikizumab Q4W
(52 weeks) N/A N/A 77.4%
(p< 0.05)
74.2%
(p< 0.001) N/A N/A N/A
Lebrikizumab
Withdrawal
(52 weeks)
N/A N/A 61.3% 46.5% N/A N/A N/A
ADVOCATE 2
(NCT04178967)
≥12 years
EASI ≥16
BSA ≥10% IGA ≥3
(N = 445)
Lebrikizumab 500 mg
loading dose + 250 mg
Q2W (16 weeks)
−60.61%
(p< 0.001)
30.2%
(p< 0.001)
50.8%
(p< 0.001)
33.1%
(p< 0.001)
−43.85%
(p< 0.001)
−35.7%
(p< 0.001)
−6.99%
(p< 0.001)
Placebo
(16 weeks) −28.22% 9.4% 18.2% 10.9% −13.87% −8.91% −2.47%
Lebrikizumab Q2W
(52 weeks) N/A N/A 79.2%
(p< 0.05)
64.6%
(p< 0.001) N/A N/A N/A
Lebrikizumab Q4W
(52 weeks) N/A N/A 84.7%
(p< 0.05)
80.6%
(p< 0.001) N/A N/A N/A
Lebrikizumab
Withdrawal
(52 weeks)
N/A N/A 72.0% 49.8%
(p< 0.001) N/A N/A N/A
ADhere
(NCT04250337)
≥12 years
EASI ≥16
BSA ≥10% IGA ≥3
(N = 228)
Lebrikizumab 500 mg
loading dose + 250 mg
Q2W + TCS
(16 weeks)
−76.76%
(p< 0.001)
41.2%
(p= 0.008)
69.5%
(p< 0.001)
41.2%
(p= 0.011)
−55.04%
(p< 0.001)
−50.68%
(p= 0.017263)
−9.79
(p= 0.001031)
Placebo + TCS
(16 weeks) −53.12% 21.7% 42.2% 22.1% −37.35% −35.47% −6.46
EASI: Eczema Area and Severity Index; IGA: Investigator’s Global Assessment; N/A: not applicable; NRS: numerical rating scale; TCS: topical corticosteroid. p-values are all compared
to the respective placebo group.

Pharmaceutics 2023,15, 568 9 of 18
ECZTRA 3 (NCT03363854) was another randomized, double-blind, placebo-controlled,
52-week, phase III trial designed to assess the efficacy and safety of tralokinumab in com-
bination with topical corticosteroids (TCS) in patients with moderate-to-severe AD [
71
].
This trial included 380 patients with AD for
≥
1 year with an unsatisfactory response to
topical therapies or with a history of systemic medication therapy in the past year [
71
].
Eligibility criteria were similar to the monotherapy studies. Patients were provided with
TCS throughout the study to use as needed and were randomized into a 16-week treat-
ment with tralokinumab 300 mg Q2W after a 600 mg loading dose or a placebo [
71
].
At 16 weeks, significantly more tralokinumab + TCS-treated patients achieved an IGA
score of 0 or 1 (38.9% vs. 26.2%, p= 0.015) and an EASI 75 response (56.0% vs. 35.7%,
p< 0.001
) compared to patients receiving placebo + TCS [
71
]. Tralokinumab + TCS was
also superior to
placebo + TCS
in EASI 50, EASI 90, DLQI, and pruritus NRS [
71
]. Patients
in the tralokinumab-treated group required about 50% less cumulative TCS and rescue
medications compared to the placebo group (p= 0.004) [71].
Similar to the ECZTRA 1 and 2 trials, if patients obtained a clinical response of IGA
0 or 1 or EASI 75 at week 16 (responders) in ECZTRA 3, they were re-randomized to
either continue tralokinumab 300 mg Q2W or receive tralokinumab 300 mg Q4W for
another 16 weeks [
71
]. The remaining patients who did not achieve a clinical response
(non-responders) in the placebo or tralokinumab groups initiated tralokinumab Q2W [
71
].
All patients continued to receive TCS as needed throughout the trial [
71
]. By week 32,
89.6% of patients treated with tralokinumab Q2W maintained IGA scores of 0 or 1, and
92.5% maintained the EASI 75 response without needing rescue therapy [
71
]. The response
was maintained in the tralokinumab Q4W group in 77.6% and 90.8% of patients for IGA
0 or 1 and EASI 75, respectively [
71
]. There was no significant increase in TCS use in either
treatment group [
71
]. An EASI 90 response, which was observed in approximately 60% of
week 16 responders, was improved over the 32 weeks of treatment and was observed in
72.5% and 63.8% of patients treated with Q2W and Q4W tralokinumab, respectively [
71
].
Furthermore, a reduction of
≥
4 points in the NRS pruritus score was achieved by 45.4%
of the tralokinumab + TCS patients compared to 34.1% of patients in the placebo + TCS
group (p< 0.001), as well as an improvement in the total DLQI score (
−
11.7 vs.
−
8.8,
respectively, p< 0.001), and SCORAD scores (−37.7 vs. −26.8, respectively, p< 0.001) [71].
Patients who were non-responders at week 16 continued to improve with tralokinumab
Q2W, with 30.5% more responders for IGA 0 or 1 and 55.8% more responders for EASI
75 at week 32 [
71
]. A post hoc analysis of data pooled from all patients on tralokinumab
Q2W, independent from the response achieved at week 16, showed that at week 32, the
EASI 50 response was maintained from week 16 to 32 in 81% of patients, while EASI 75 and
EASI 90 rates progressively increased over time to 70.2% and 50.4%, respectively [
72
].
Finally, preliminary results of the ECZTEND trial were recently presented at the 2022
Annual Meeting of the American Academy of Dermatology. In this trial, a longer-term,
2-year continuous treatment with tralokinumab Q2W and optional TCS was studied in
1442 patients with AD [
73
]. A high level of response rates was sustained after 2 years of
treatment, where 85.1% of treated patients achieved EASI 75, 65% achieved EASI 90, 50.5%
had clear or almost clear skin measured via the IGA, 60.6% had pruritus NRS
≤
3, and
76.4% had DLQI ≤5 [73].
5.3. Safety of Tralokinumab in Patients with Atopic Dermatitis
In the phase III trials ECZTRA 1 and ECZTRA 2, tralokinumab exhibited a similar
safety profile to the phase IIb study over 16 and 52 weeks of treatment, with a similar
incidence of mild to moderate adverse events in the tralokinumab and placebo groups. In
ECZTRA 1, 23% of patients treated with tralokinumab reported upper respiratory tract
infections (URTI; vs. 21% in the placebo group), and 7% of patients reported conjunctivitis
(vs. 2% in the placebo group) [
68
]. Similarly, in the ECZTRA 2 trial, 10% of patients
treated with tralokinumab reported URTI (vs. 9% in the placebo group) and 3% of patients
reported conjunctivitis (vs. 2% in the placebo group) [
68
]. All cases of conjunctivitis

Pharmaceutics 2023,15, 568 10 of 18
were mild and resolved by the end of the treatment period, except for one patient who
discontinued the study treatment [
68
]. In contrast, worsening of AD, incidents of eczema
herpeticum, and skin infections were more frequently seen in the placebo group [
68
]. In
the maintenance period, AEs occurred more frequently in the tralokinumab Q2W group
than in the tralokinumab Q4W group, with a low number of events leading to permanent
interruption [
68
]. The safety profile, including the frequency and severity of adverse events
that emerged from the ECZTRA 3 trial, was comparable with that of the ECZTRA 1 and
2 trials. The tralokinumab safety profile did not appear to differ with the addition of
a TCS. In ECZTRA 3, URTI was again the most common AE in 19% of patients treated
with tralokinumab (vs. 11% in the placebo group), followed by conjunctivitis in 11% of
tralokinumab-treated patients (vs. 3% in the placebo group) [
71
]. Headache was reported in
9% of tralokinumab patients compared to 5% in the placebo group [
71
]. Skin infections that
required systemic management were more frequent in the placebo group [
71
]. AEs were
less frequent and less severe in the tralokinumab Q4W group compared to the tralokinumab
Q2W groups [
71
]. Four patients discontinued due to adverse events; however, none of these
AEs were severe: two were due to AD worsening, one was due to herpetic eczema, and
one was due to a prostate cancer diagnosis [
71
]. A total of 13 serious adverse events (SAEs)
were recorded, with no difference between groups [
71
]. A recently presented analysis from
ECZTRA 1, 2, 3, 5, and phase IIb trials of safety data pooled from patients with AD treated
with tralokinumab Q2W with TCS for 16 weeks showed a greater proportion of patients
experiencing conjunctivitis compared to placebo groups (5.4% vs. 1.9%) and a similar rate of
all adverse events (65.7% vs. 67.2%, respectively), serious AEs (
2.1% vs. 2.8%
, respectively),
mild AEs (53.2% vs. 49.0%, respectively), moderate AEs (31.5% vs. 39.0%, respectively),
severe AEs (4.6% vs. 6.3%, respectively), and AEs leading to drug withdrawal (2.3% vs.
2.8%, respectively) [
73
]. The most frequently reported adverse events in the pooled data
were viral URTIs (15.7% vs. 12.2%, respectively) and AD (15.4% vs. 26.2%, respectively) [
73
].
Finally, the recently presented safety analysis set from the 2-year ECZTEND trial showed
78.2% of patients reporting AEs, with 7.0% being serious AEs, 66.3% being mild, 46.3%
being moderate, and 7.1% being severe [
73
]. Only 2.4% of patients reported AEs that
led to drug withdrawal. The most frequently reported AEs were viral URTI in 20.5% of
patients, AD in 17.8% of patients, and conjunctivitis in 5.3% of patients; the proportion of
patients experiencing the latter was similar to previously reported trials [
73
]. Although
tralokinumab use is associated with an increased incidence of conjunctivitis, cases reported
in clinical trials with 16 weeks of treatment were mostly mild and transient [74].
6. Use of Lebrikizumab to Manage Patients with Atopic Dermatitis
6.1. Overview of Lebrikizumab
Lebrikizumab is a humanized monoclonal antibody that binds soluble IL-13 at the
non-receptor binding domain with a high affinity [
18
]. A bound IL-13 is able to form a
complex with IL-13R
α
1; however, it prevents heterodimerization with IL-4R
α
and prevents
signal transduction [
18
]. Therefore, lebrikizumab inhibits the IL-4R
α
–IL-13R
α
1 signal-
ing complex while continuing to regulate endogenous IL-13 via stimulation of IL-13R
α
2
(Figure 1) [
75
]. Pharmacokinetic data for lebrikizumab are available from a large meta-
analysis of 11 studies, which pooled data from 2148 patients receiving either 37.5 mg or
125 mg of lebrikizumab Q4W [
76
]. The bioavailability of lebrikizumab was 85.6% with a
0.156 L/day clearance, and an elimination half-life of 25.7 days [76].
6.2. Clinical Efficacy of Lebrikizumab in Patients with Atopic Dermatitis
Results from the first induction period of two monotherapy phase III studies for
lebrikizumab management of AD have recently been presented and are consistent with
those observed in the phase II trials (Table 1, Table 2) [
77
]. ADVOCATE 1 (NCT04146363)
and ADVOCATE 2 (NCT04178967) are randomized, double-blind, placebo-controlled,
parallel-group, 52-week trials that included 851 patients aged 12 years or older with
moderate-to-severe AD, with inadequate responses to topical treatments, IGA scores of

Pharmaceutics 2023,15, 568 11 of 18
≥
3, and who were naïve to dupilumab and tralokinumab treatments [
77
]. Patients were
randomized to receive a lebrikizumab 500 mg loading dose followed by 250 mg Q2W
or placebo [
77
]. After 16 weeks of treatment in the ADVOCATE 1 trial, the co-primary
endpoint IGA response of 0 or 1 was reached in 43.0% of patients in the lebrikizumab
group compared to 12.8% in the placebo group (p< 0.001), and EASI 75 in 59.3% of patients
compared to 16.4%, respectively (p< 0.001) [
77
]. Similarly, after 16 weeks of treatment
in the ADVOCATE 2 trial, 33.1% of patients in the lebrikizumab group reached IGA
0 or 1 compared to 10.9% in the placebo group (p< 0.001), and EASI 75 was reached
by 50.8% compared to 18.2%, respectively (p< 0.001) [
77
]. In both trials, a significantly
greater proportion of patients achieved secondary endpoints in the lebrikizumab treatment
group compared to the placebo group, such as EASI 90 (ADVOCATE 1: 38.2% vs. 9.1%,
respectively, p< 0.001; ADVOCATE 2: 30.2% vs. 9.4%, respectively, p< 0.001), pruritus
NRS
≥
4 point improvement (ADVOCATE 1: 46.3% vs. 12.7%, respectively, p< 0.001;
ADVOCATE 2: 38.3% vs. 11.3%, respectively, p< 0.001), sleep-loss scale score
≥
4 point
improvement (ADVOCATE 1: 38.7% vs. 5.1%, respectively, p< 0.001; ADVOCATE 2:
26.5% vs. 7.8%, respectively, p< 0.001), and DLQI
≥
4 point improvement (ADVOCATE 1:
75.5% vs. 33.8%, respectively, p< 0.001; ADVOCATE 2: 64.4% vs. 34.6%, respectively,
p< 0.001) [77].
After week 16, patients were re-randomized to either continue receiving 250 mg lebrik-
izumab Q2W or receive 250 mg lebrikizumab Q4W or a placebo for another 36 weeks [
78
].
Participants that required rescue therapy in the first 16 weeks or did not maintain an
EASI
≥
50 after 16 weeks of treatment received open-label lebrikizumab Q2W for the
next 36 weeks [
78
]. The maintenance period (weeks 16 to 52) of the ADVOCATE 1 and
ADVOCATE 2 trials has been completed and the preliminary results were presented at
the European Academy of Dermatology and Venereology 2022 meeting [
78
]. The efficacy
achieved by week 16 with the lebrikizumab treatment was reported to be maintained at
52 weeks [
78
]. By week 52 of treatment, clear or almost clear skin measured via IGA was
achieved in a greater proportion of patients treated with Q2W and Q4W lebrikizumab
regimens compared to the withdrawal group (ADVOCATE 1: 75.8% and 74.2% vs. 46.5%,
respectively; ADVOCATE 2: 64.6% and 80.6% vs. 49.8%, respectively) [
78
]. EASI 75 was
maintained in a greater proportion of patients treated with Q2W and Q4W lebrikizumab
regimens compared to the withdrawal group (ADVOCATE 1: 79.2% and 79.2% vs. 61.3%,
respectively; ADVOCATE 2: 77.4% and 84.7% vs. 72.0%, respectively) [
78
]. Overall, 81.2%
and 90.3% of patients treated with lebrikizumab Q2W in ADVOCATE 1 and 2, respectively,
and 80.4% and 88.1% in the Q4W group achieved a
≥
4-point improvement in pruritus NRS
compared to 65.4% and 67.6% of patients in the lebrikizumab withdrawal group [78].
ADhere (NCT04250337) is a randomized, double-blind, parallel-group, placebo-controlled
combination trial that recruited 228 adolescents and adults aged 12 years or older with
moderate-to-severe AD for 1 or more years with inadequate responses to topical or systemic
treatment, an IGA score of
≥
3, an EASI score
≥
16, and a BSA
≥
10 [
79
]. Patients were
randomized to receive a lebrikizumab 500 mg loading dose followed by 250 mg Q2W or a
placebo Q2W, where both treatment groups were treated with concomitant TCS [
79
]. After
16 weeks of treatment, the co-primary endpoint IGA response of 0 or 1 was reached in 41.2%
of patients in the lebrikizumab + TCS group compared to 22.1% in the placebo + TCS group
(p= 0.011), and EASI 75 was reached in 69.5% compared to 42.2% of patients, respectively
(p< 0.001) [
79
]. Similarly, a significantly greater proportion of patients achieved secondary
endpoints in the lebrikizumab + TCS treatment group compared to the
placebo + TCS
group, such as EASI 90 (41.2% vs. 21.7%, respectively, p= 0.008), pruritus
NRS ≥4
point
improvement (50.6% vs. 31.9%, respectively, p= 0.017), percent improvement in pruri-
tus NRS (50.68% vs. 35.47%, respectively, p= 0.017), and DLQI
≥
4 point improvement
(77.4% vs. 58.7%, respectively, p< 0.036) [79].

Pharmaceutics 2023,15, 568 12 of 18
6.3. Safety of Lebrikizumab in Patients with Atopic Dermatitis
Lebrikizumab is well tolerated, with a similar safety profile reported in phase II and
phase III trials to date. While only preliminary long-term data are available from the phase
III trials, lebrikizumab safety data appear to be similar to that of a placebo when treated
for up to 16 weeks [
77
]. In the ADVOCATE 1 and 2 trials, the proportion of patients
experiencing AEs was similar in the lebrikizumab-treated and placebo groups, with the
majority of AEs being mild or moderate in severity (ADVOCATE 1: 45.4% vs. 51.5%,
respectively; ADVOCATE 2: 53.0% vs. 66.2%, respectively) [
77
]. The proportion of patients
reporting conjunctivitis in the treatment group appears to be greater compared to the
placebo group in both studies (ADVOCATE 1: 7.4% vs. 2.8%, respectively; ADVOCATE 2:
7.8% vs. 2.1%, respectively) [
77
]. However, all conjunctivitis treatment-emergent AEs were
mild-to-moderate in severity and did not lead to treatment discontinuation [
77
]. Infections
with herpes were similar among the treatment and placebo groups (ADVOCATE 1: 3.2%
vs. 4.3%, respectively; ADVOCATE 2: 2.8% vs. 4.1%, respectively) [
77
]. Preliminary data
at 52 weeks of treatment indicated that 58.1% and 68.1% of lebrikizumab-treated patients
in ADVOCATE 1 and 2, respectively, reported AEs, the majority of which were mild to
moderate in severity [
78
]. None of the severe AEs which were reported by 3.3% and 2.6%
of patients in ADVOCATE 1 and 2, respectively, were related to the study drug, as was
assessed by the study investigators [
78
]. The most common AEs in the lebrikizumab-treated
patients in ADVOCATE 1 and 2 were AD (7.8 and 10.1%, respectively), nasopharyngitis
(6.8% and 9.6%, respectively), conjunctivitis (8.3% and 8.1%, respectively), herpes infections
(5.0 and 4.8%, respectively), and skin infections (3.0% and 4.9%, respectively) [78].
ADhere phase III study safety data are only available up to week 28 of treatment, with
43.1% of patients in the lebrikizumab group and 34.7% of patients in the placebo group
reporting AEs [
79
]. Conjunctivitis was reported in 4.6% of patients in the treatment arm
and none in the placebo arm to date [
79
]. Safety data from the maintenance phases of both
phase III trials will be important to improve our understanding of the safety profile of
lebrikizumab longer term [
79
]. Nevertheless, the safety data available to date in patients
with AD are consistent with those previously reported in several asthma trials of over
2000 patients since 2011 [80–84].
6.4. Future IL-13 Inhibitors
Eblasakimab and cendakimab are two more IL-13 inhibitors being developed in the
pipeline and are currently being investigated in phase II trials (NCT04800315). Eblasakimab
is a monoclonal antibody that targets the IL-13R
α
1, a subunit of the type 2 receptor,
interfering with the signaling of IL-13 and IL-4 (Figure 1). Early data presented at the
Annual Meeting of the American Academy of Dermatology 2022 showed significant efficacy
after 8 weeks of treatment [
85
]. These were preliminary reported data in a small sample
size of patients with AD that were randomized to receive a placebo (n = 16) or eblasakimab
at one of three doses: 200 mg (n = 4), 400 mg (n = 7), or 600 mg (n = 22) [
85
]. A significant
reduction in EASI was reported: 50% in the 200 mg group, 63% in the 400 mg group, and
61% in the 600 mg group, as opposed to 32% in the placebo group (p= 0.023) [
85
]. EASI
50 was achieved in 50% of patients in the 200 mg group, 71% in the 400 mg group, and
77% in the 600 mg group, compared to 38% in the placebo group (p= 0.016) [
85
]. EASI
75 was achieved in 50% of patients in the 200 mg group, 57% in the 400 mg group, and 50%
in the 600 mg group, as opposed to 13% in the placebo group (p= 0.018) [
85
]. Finally, the
peak pruritus NRS decreased by 37% in the group of patients treated with eblasakimab
600 mg, which was a significant improvement in comparison to the 16% decrease in the
group treated with placebos (p= 0.032) [
85
]. Although eblasakimab shows great promise in
efficacy for the treatment of AD, this preliminary study is limited by a lack of available long-
term and safety data as well as a small sample size. Thus, further trial data for eblasakimab
and cendakimab are awaited.

Pharmaceutics 2023,15, 568 13 of 18
7. Discussion
For many decades, conventional therapy for AD comprised topical and oral immuno-
suppression as well as phototherapy. Approval of dupilumab triggered a significant leap
forward into an era of rapid development of targeted biological therapy for AD manage-
ment. The next targeted therapies approved were the JAK inhibitors abrocitinib, baricitinib,
and upadacitinib, as well as an IL-13 inhibitor, tralokinumab. It is important to carefully
study each biological and small molecule class to define how the nuanced differences can
be used to benefit each individual patient.
Overall, growing evidence suggests that targeted IL-13 inhibitors offer a great advan-
tage in developing efficacious and safe management strategies for patients with moderate-
to-severe AD. The two most studied IL-13 inhibitors, tralokinumab and lebrikizumab,
were shown to be efficacious in phase III trials, with the response being maintained over
time. Treatment with these agents also results in significant improvements in pruritus and
quality of life. The detailed mechanisms of IL-13 inhibition in tralokinumab, lebrikizumab,
and eblasakimab are distinct (Figure 1). Tralokinumab binds IL-13 in the IL-13R
α
bind-
ing site and blocks IL-13 interaction with both IL- 13R
α
1 and IL-13R
α
2. Lebrikizumab
binds IL-13 at the IL-4R
α
- binding site and inhibits IL-4R
α
and IL-13R
α
1 receptors’ sig-
naling. It is unknown whether differences in the mechanisms of IL-13 inhibition result
in clinical implications, given that there are no available direct comparison studies and
different study design, duration, and TCS use are present in the available phase III studies.
While the mechanistic differences between tralokinumab and lebrikizumab are more subtle,
dupilumab differs by targeting the IL-4R
α
receptor subunit and inhibiting the binding of
both IL-4 and IL13. Thus, results of current clinical programs investigating these agents
will help elucidate important new insights into the roles of IL-13, IL-13R
α
2, IL-13R
α
1, type
1 and type 2 receptors in the regulation of inflammatory skin conditions. Moreover, direct
head-to-head comparison trials are needed to elucidate the differences in the efficacy of
dupilumab, selective IL-13 and JAK 1 inhibitors. While these targeted therapies offer a
great advantage for an improved efficacy and safety profile, there remains a proportion of
patients that do not respond to treatment, which is likely a consequence of the heterogeneity
in the pathogenesis of AD. Thus, the identification of biomarkers that help predict the
response to treatment is an area of unmet need. For example, in phase II tralokinumab
trials, periostin and DPP-4 were used as biomarkers for IL-13 activity and were shown to
be associated with a response to treatment [
69
]. Further development of such biomarkers
will help advance the era of personalized medicine. Finally, despite all the benefits of
targeted therapy that were discussed, there remain challenges with subcutaneous injection
administration of biological agents for patients with needle phobia, the need for cold chain
delivery, and the long half-life of these agents.
In terms of differences in safety among different biologic agents and small molecule
therapies, JAK inhibitors have a class warning for thrombosis, major cardiovascular events,
and malignancies that have not been reported in trials of dupilumab and selective IL-13
inhibitors. In addition, JAKs have a side effect profile that includes an increased risk of
infections, such as viral infections including eczema herpeticum and herpes zoster [
86
].
Although head-to-head data comparing dupilumab to JAK inhibitors have been pub-
lished, there are no direct head-to-head comparison trials available with the current or
emerging IL-13 inhibitors. In phase III trials, all agents that inhibit IL-13, specifically
dupilumab, tralokinumab, lebrikizumab, cendakimab, and eblasakimab, have been re-
ported to have a considerably increased risk of conjunctivitis, injection site reactions, and
head and neck erythema. Interestingly, there appears to be a larger risk of conjunctivitis
with dupilumab (up to 22% in phase III trials) compared to tralokinumab (~11%) or lebrik-
izumab (~3%) [
22
,
23
,
87
,
88
]. Real-world analyses and direct head-to-head comparison trials
are needed to confirm these observations. While the pathogenesis of conjunctivitis in this
setting is not completely understood, it is hypothesized to be the consequence of Demodex
mite proliferation, direct IL-13-mediated reduction in goblet cells, or OX40-related inflam-
mation [
87
,
88
]. Biopsies obtained from AD patients that developed conjunctivitis while

Pharmaceutics 2023,15, 568 14 of 18
being treated with dupilumab confirmed a substantial decrease in the number of intraep-
ithelial goblet cells [
89
]. Similar to dupilumab-associated conjunctivitis, this association
with selective IL-13 inhibitors could be initially managed with warm compresses, artificial
tears, sodium hyaluronate, or antihistamine drops while continuing the use of the biological
agent. A consultation with ophthalmology is warranted if a patient develops eye pain,
vision changes, purulent discharge, conjunctival scarring, or corneal involvement. Resistant
or severe conjunctivitis cases may require anti-inflammatory steroid drops, calcineurin
inhibitors, or cyclosporine [90].
8. Conclusions
Improving the knowledge of the complex inflammatory mechanisms involved in
AD pathogenesis has led to an increase in the use of targeted biological therapies for
the effective and safe management of this chronic skin condition. IL-13 is thought to
be the main mediator implicated in the inflammation, epidermal barrier dysfunction,
and pruritus associated with AD. Thus, selective IL-13 inhibitors, such as tralokinumab,
lebrikizumab, and eblasakimab, have shown good efficacy in the treatment of moderate-to-
severe AD. While these agents have favorable safety profiles, there remains an increased
risk of conjunctivitis, requiring monitoring. Although access to biological agents remains
to be a challenge for some patients, the emergence of these therapies significantly increased
the effective options available to manage patients with this skin condition. Further long-
term studies are ongoing to continue investigating how the use of IL-13 inhibitors can be
further utilized to therapeutically manage patients with moderate-to-severe AD.
Author Contributions:
Y.L. and M.G. conducted the search and wrote and reviewed the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest:
Melinda Gooderham has been an investigator, speaker and/or advisor for:
abbvie, Amgen, Akros, Arcutis, Aristea, AnaptysBio, Bausch Health, BMS, Boehringer Ingelheim,
Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma,
MedImmune, Merck, Moonlake, Meiji, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi
Genzyme, Sun Pharma, and UCB. The company had no role in the design of the study; in the
collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to
publish the results.
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