N E W S & A N A LY S I S

FROM THE ANALYST’S COUCH

The atopic dermatitis market

Eleni Pantazi, Gianluca Valenza, Manuela Hess and Bashar Hamad Pink sofa from Zuktenvos / Alamy Stock Photo

Atopic dermatitis (AD), also known as atopic Pharmaceuticals/Sanofi), the first biologic both IL-4 and IL-13. Based on the results of
eczema, is an inflammation of the skin that is treatment for AD. Crisabarole inhibits three phase III trials — SOLO1, SOLO2 and
often associated with other atopic disorders, phosphodiesterase 4 (PDE4) and dupilumab CHRONOS — dupilumab was approved by
such as allergic rhinitis and asthma. The binds to the interleukin-4 receptor subunit-α the FDA and the European Medicines Agency
disease is believed to be related to interactions (IL-4Rα). Several other agents with similar (EMA) for adults with moderate-to-severe
between genes and the environment, mechanisms are under investigation (TABLE 1). AD whose disease is not adequately
which promote skin barrier dysfunction controlled by topical therapies or for whom
and immune system dysregulation that PDE4 inhibitors. PDE4 degrades cAMP, those therapies are not advisable (see Further
causes immunoglobulin E (IgE)-mediated a critical immune modulator. The FDA information). The safety profile is good; the
sensitization. AD usually presents in approval of crisaborole was based on two main safety concern is the elevated risk of
childhood; 45% of patients are diagnosed by double-blind, vehicle-controlled phase conjunctivitis. Dupilumab demonstrated
6 months of age. Studies estimate that the III registrational studies (AD-301 and strong potential in a phase II trial in the
prevalence of AD is 15–30% in children and AD-302), in over 1,500 patients with AD paediatric population and has progressed to
2–10% in adults in industrialized countries. (see Further information). Medimetriks also a phase III paediatric trial. AstraZeneca is
The unmet need in AD is high; treatment has a topical, non-steroidal PDE4 inhibitor also developing an anti-IL-4Rα monoclonal
options are often not efficacious and are in development for the treatment of AD, antibody (mAb), MEDI-9314, which is
associated with safety concerns. MM36 (formerly OPA-15406, acquired from currently in a phase I trial.
Otsuka Pharmaceuticals). In the phase II IL-13-targeting compounds, such as
Current treatment MUSE study, MM36 was safe, well tolerated tralokinumab and lebrikizumab, are also
Topical agents are the backbone of AD and provided rapid itch relief in paediatric in clinical trials. Tralokinumab is a human
therapy and are often used in conjunction or adolescent patients with AD. Medimetriks anti-IL-13 mAb developed by Cambridge
with systemic therapy or phototherapy in plans to start pivotal trials in Q1 2018. Antibody Technology (acquired by
patients with severe disease. Emolients AstraZeneca in 2006) that is in a phase III
are used first, followed by topical Interleukins. Cytokines that are secreted by T study for the treatment of severe asthma.
corticosteroids if emolients are ineffective. helper 2 (TH2) cells, such as IL-4, IL-13, IL-5 Following completion of a phase II trial
Chronic treatment with topical steroids and IL-31, have also been targeted in AD. in AD, LEO Pharma acquired the global
bears the risk of skin atrophy and systemic Dupilumab is a subcutaneously administered license to tralokinumab in skin diseases
absorption; topical calcineurin inhibitors IL-4Rα inhibitor and blocks the signalling of and advanced the compound to phase III. ▶
(TCIs, such as tacrolimus (Protopic; LEO
Pharma) and pimecrolimus (Elidel; Valeant Table 1 | Current status of selected agents for atopic dermatitis in development
Pharmaceuticals)) are second-line topical Drug Developers Mechanism of Atopic dermatitis Highest
treatment options that reduce inflammation action indication stage
without causing skin atrophy. Off-label Crisaborole Pfizer PDE4 inhibitor Mild-to-moderate Approved
systemic therapies, such as cyclosporine
(only licensed in the European Union), Dupilumab Regeneron/Sanofi Anti-IL-4Rα mAb Moderate-to-severe Approved
azathioprine, methotrexate, mycophenolate Tralokinumab AstraZeneca/LEO Anti-IL-13 mAb Moderate-to-severe Phase III
mofetil and interferon-γ have shown efficacy ANB-020 AnaptysBio Anti-IL-33 mAb Moderate-to-severe Phase II
in patients with severe AD. Although oral
Baricitinib Eli Lilly & Company JAK1/2 inhibitor Moderate-to-severe Phase II
steroids (such as prednisone) are approved for
AD, long-term treatment is generally avoided BMS-981164 BMS Anti-IL-31 mAb Moderate-to-severe Phase II
because of the risk of adverse effects. Data Lebrikizumab Roche Anti-IL-13 mAb Moderate-to-severe Phase II
regarding the effectiveness and long-term Mepolizumab GSK Anti-IL-5 mAb Moderate-to-severe Phase II
safety of systemic therapies in AD are
MM36 Medimetriks PDE4 inhibitor Mild-to-moderate Phase II
insufficient and standardized guidelines are
lacking, therefore treatment approaches differ Nemolizumab Chugai/Galderma Anti-IL-31Rα mAb Moderate-to-severe Phase II
between countries. PF-04965842 Pfizer JAK1 inhibitor Moderate-to-severe Phase II
Tezepelumab AstraZeneca Anti-TSLP mAb Moderate-to-severe Phase II
Emerging therapies
The AD treatment landscape is expected Upadacitinib AbbVie JAK1 inhibitor Moderate-to-severe Phase II
to change substantially with the recent ZPL-389 Ziarco/Novartis H4R antagonist Moderate-to-severe Phase II
approvals of crisaborole (Eucrisa; Pfizer), MEDI-9314 AstraZeneca Anti-IL-4Rα mAb Moderate-to-severe Phase I
the first non-steroidal topical treatment for H4R, histamine 4 receptor; IL-4Rα, interleukin-4 receptor subunit-α; IL-31R, IL-31 receptor; JAK, Janus kinase;
AD, and dupilumab (Dupixent; Regeneron mAb, monoclonal antibody; TSLP, thymic stromal lymphopoietin; PDE4, phosphodiesterase 4.

NATURE REVIEWS | DRUG DISCOVERY ADVANCE ONLINE PUBLICATION | 1

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 N E W S & A N A LY S I S

FROM THE ANALYST’S COUCH

▶ Lebrikizumab (Roche) is a humanized mAb
specific to IL-13. In the phase II TREBLE
study, lebrikizumab and topical corticosteroid
treatment significantly increased the
proportion of patients with improved
symptoms using multiple scoring systems.
Dermira acquired exclusive, worldwide
rights to develop lebrikizumab for AD
and other indications and plans to initiate
a phase IIb study in Q1 2018. However,
because substantial improvements were also
seen in the placebo-treated group in the
phase II studies of both tralokinumab and
lebrikizumab, due to the concomitant usage
of corticosteroids, both drugs will be tested in
phase III monotherapy studies.
IL-5 induces eosinophil differentiation,
activation, mobilization and survival.
Mepolizumab (GlaxoSmithKline), a
fully humanized mAb specific to IL-5,
demonstrated a modest improvement in
some but not all measures of AD (Allergy 60,
693–696; 2005). A new phase II trial started
recruiting in March 2017.
Nemolizumab (Chugai/Galderma) is a
humanized mAb that targets IL-31Rα. In a
phase II study, nemolizumab demonstrated
a significant improvement in pruritus
score (N. Engl. J. Med. 376, 826–835; 2017).
Long-term data from 64 weeks of treatment
showed that these improvements are
durable, although concomitant use of topical
corticosteroids may be beneficial. However,
despite the reduction in itching there was
a modest reduction in the underlying
inflammation, perhaps underscoring the
role of IL-31 in the nervous system rather
than the immune system. The safety profile
of nemolizumab is still unclear and there are
indications of exacerbations and oedema in
the treatment group. Bristol-Myers Squibb
has also developed an anti-IL-31 antibody
(BMS-981164). Although a phase I trial
was completed in April 2015, there is no
indication of further clinical development.
Antibodies that target other cytokines are
also in development. An antibody targeting
IL-33 (ANB020; AnaptysBio) has progressed
to a phase II trial, and tezepelumab
(in-licensed by AstraZeneca from Amgen),
JAK inhibitors are being investigated for the
treatment of AD. Baricitinib (Incyte/Eli Lilly
& Company) is a reversible oral inhibitor of
JAK1 and JAK2. In a phase II randomized
study in patients with moderate-to-severe
AD, baricitinib in combination with topical
corticosteroids significantly improved clinical
and patient-reported outcome. Incyte and
Eli Lilly plan to initiate a phase III trial later
this year. Upadacitinib (ABT-494; AbbVie),
is a second-generation oral inhibitor with
high selectivity for JAK1. In a phase II trial,
50% of patients receiving the highest dose
achieved a 90% reduction in AD severity
and a 69% reduction in itch by week 16,
making upadacitinib arguably the most
promising JAK inhibitor. AbbVie plans to
initiate phase III studies in 2018. Pfizer is also
developing PF-04965842, a small molecule
inhibitor of JAK1. In a phase IIb study in AD,
PF-04965842 achieved significantly higher
response rates and improvement in pruritus
versus placebo (Br. J. Dermatol. http://dx.doi.
org/10.1111/bjd.16004 (2017)).
Histamine. Histamine is an abundantly
expressed cell signalling molecule with four
known receptors. Inhibition of the histamine
H4 receptor (H4R), the most recently
identified receptor, reduces TH2-driven
inflammation and pruritus. ZPL-389 is an
oral H4R antagonist that is being developed
by Ziarco and Novartis. In a phase IIa study,
ZPL-389 significantly improved dermatitis
scores but not itch. ZPL-389 is currently
being evaluated in a phase IIb study.
Market indicators
The current AD drug market is worth
between US$570 million and ~$3.3 billion
(FIG. 1). The uncertainty in market value
is mostly driven by the use of topical
corticosteroids in other skin conditions as
well as the off-label use of systemic therapies
in the treatment of AD. For this analysis, we
assumed a value of $3.3 billion.
The AD market is highly genericized
and so has a modest compound annual
growth rate of 4% over the past 4 years.
Topical corticosteroids dominate the
Systemic therapy PDE4
(29%; $957 million) (0.3%; $11 million)
$3.7 billion
Topical modulator Topical steroids
(10%; $344 million) (61%; $2.0 billion)
Figure 1 | Global sales of atopic dermatitis
drug classes. Sales in US$ over the 12 months
Nature
to Q1 2017. Source: IMSReviews DrugMidas.
Health,| IMS Discovery
PDE4, phosphodiesterase 4.
patent-protected brands, and they generated
sales of $344 million during this period. The
US is the largest national market, accounting
for 54% of sales.
The AD drug market is projected to more
than double by 2022, driven primarily by
the launch of dupilumab, for which analysts
expect peak sales of the drug to reach
$2.5–4.0 billion. According to Sanofi’s Q2
2017 earnings release, since its launch in
March 2017, over 5,100 physicians in the US
have prescribed dupilumab to over 13,000
patients (as of 26 July 2017), generating
sales of $26 million in Q2 2017. However, as
biologics are expected to be expensive, they
will tend to be a last line of therapy, with
low-cost, generic topical or oral systemic
therapies being the preferred first lines. This
may create a barrier for market penetration
beyond patients with severe disease.
Eleni Pantazi, Gianluca Valenza, Manuela Hess and
Bashar Hamad are at QuintilesIMS, One IMS Drive,
Plymouth Meeting, Pennsylvania 19462, USA.
Correspondence to B.H
BHamad@imscg.com
doi:10.1038/nrd.2017.192
Published online 6 Nov 2017

which targets thymic stromal lymphopoietin,
has completed a phase IIb trial, although no
data have been reported.
JAK inhibitors. The Janus kinase–signal
transducer and activator of transcription
(JAK–STAT) pathway has a critical role in
the regulation of the immune system, and
market, with sales estimated at $2.0 billion
over the 12 months to Q1 2017, accounting
for 61% of the market. Systemic therapies
have estimated sales of $957 million. As
systemic therapies are used off label in the
United States and some European countries,
we assume 15% of this market is in AD.
Tacrolimus and pimecrolimus are the two key
Competing interests statement
The authors declare no competing interests.
FURTHER INFORMATION
Dupilumab label: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2017/761055lbl.pdf
Crisaborole label: https://www.accessdata.fda.gov/
drugsatfda_docs/label/2016/207695s000lbl.pdf
ALL LINKS ARE ACTIVE IN THE ONLINE PDF

2 | ADVANCE ONLINE PUBLICATION www.nature.com/nrd

©
2
0
1
7
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.