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Safety Data
In terms of safety, dupilumab therapy for AD was found to have an acceptable safety profile in
various phase 2, phase 3 and real-world studies. In the SOLO 1 and SOLO 2 phase 3 trials (Simpson
et al. 2016), the overall incidence of AEs was similar in the dupilumab and placebo groups. Most
AEs were mild. The most common AEs were exacerbations of AD, injection-site reactions and
nasopharyngitis. Rates of conjunctivitis were higher in the dupilumab groups than in placebo groups
(3–5% vs. 1%).
In a systematic review and meta-analysis of eight RCTs (Fleming and Drucker 2018), dupilumab
was associated with decreased risk for skin infections, and eczema herpeticum infections with no
increased risk of overall herpesvirus infections or overall infections compared to placebo.
Regarding conjunctivitis, a pooled analysis (Akinlade et al. 2019) analyzed 11 RCTs of
dupilumab in AD, asthma, CRSwNP and EoE. The incidence of conjunctivitis was higher in
dupilumab compared with placebo-treated patients in AD clinical trials (8.6 vs. 2.1%). Conjunctivitis
was mostly mild to moderate, with most cases resolved during the treatment period. More severe AD
at baseline, prior history of conjunctivitis and higher levels of serum T2 biomarkers (TARC, IgE,
BEC) were associated with increased conjunctivitis risk. Dupilumab treatment was not associated
with an increased incidence of conjunctivitis in asthma, CRSwNP and EoE trials. The pathogenesis
of conjunctivitis during dupilumab treatment for AD is unknown, although patients may be at
higher risk given the high prevalence of ocular disease in patients with AD. At this time, there is
no consensus on treatment for conjunctivitis in dupilumab-treated patients, although ophthalmic
preparations of corticosteroids, antibiotics, antihistamines and mast cell stabilizers were the most
common treatments used in these trials.
Although dupilumab-associated facial erythema was not reported in phase 3 RCTs for AD, there
have been reports in real-world studies (Waldman et al. 2020). The presence or absence of atopy
or dupilumab-induced ocular disorder did not significantly impact the development of dupilumab
facial redness (DFR). The majority of patients who developed this continued with their dupilumab
therapy regardless, however, indicating that DFR was less symptomatically burdensome than their
underlying skin condition.
Tralokinumab
Tralokinumab is an anti-IL-13, FDA-approved in late 2021 for the treatment of moderate-to-severe
AD in adult patients whose disease is not adequately controlled with topical prescription therapies
or when those therapies are not advisable.
Efficacy Data
In two dual phase 3 RCTs, ECZTRA 1 and ECZTRA 2 (Wollenberg et al. 2021a), significantly
more adults with moderate-to-severe AD treated with tralokinumab monotherapy achieved an
IGA 0/1 and EASI75 at week 16 compared with placebo. Treatment with tralokinumab also led
to significant improvement compared with placebo in all key secondary endpoints, including
pruritus, scoring atopic dermatitis (SCORAD) and Dermatology life quality index (DLQI) scores.
Improvements in pruritus and sleep scores were rapid and sustained, with significant improvements
compared with placebo as early as week 1. Additionally, treatment with tralokinumab led to a
10 times greater reduction in S. aureus colonization of lesional skin at week 16 compared with
placebo. Tralokimumab response was maintained in both q2w and q4w groups through 52 weeks,
though the response may be sustained as early as week 16. The subsequent ECZTRA 3 (Silverberg
et al. 2021a) and ECZTRA 7 (Gutermuth et al. 2021) RCTs demonstrated that tralokinumab with
concomitant TCS significantly improves AD signs and symptoms in adults with moderate-to-severe
AD, including those with severe CSA-refractory AD.
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Safety Data
In a pooled safety analysis (Simpson 2021), tralokinumab was found to be well tolerated with an
acceptable safety profile for the treatment of moderate-to-severe AD. The frequency of AEs was
similar for tralokinumab compared with placebo, with most AEs reported as mild to moderate in
severity. The most common AEs included AD, URTIs and conjunctivitis. Similar to dupilumab, the
incidence of conjunctivitis has been found to be significantly higher with tralokinumab compared with
placebo, with most events characterized as mild to moderate and transient (Wollenberg et al. 2021b).
Lebrikizumab
Lebrikizumab, an anti-IL-13 monoclonal antibody, is currently under investigation for AD.
Efficacy Data
In phase 2 TREBLE RCT (Simpson et al. 2018), significantly more patients achieved EASI50 with
lebrikizumab than with a placebo as well as an IGA 0/1 and SCORAD-50. In another phase 2 RCT
(Guttman-Yassky et al. 2020), significantly more patients treated with lebrikizumab demonstrated
dose-dependent improvements in EASI and pruritus NRS scores compared with placebo, with
improvement seen as early as day 2. Notably, 5 of 12 lebrikizumab patients with prior dupilumab
use (compared with 0/4 placebo patients) achieved EASI75 and 4 of 12 lebrikizumab patients
achieved IGA 0/1.
Safety Data
Lebrikizumab was found to be well tolerated with an acceptable safety profile in the above trials.
The frequencies of AEs were overall similar between lebrikizumab and placebo groups and mostly
mild to moderate in severity (Simpson et al. 2018). Common AEs included URTI, nasopharyngitis
and headaches (Guttman-Yassky et al. 2020). Of note, unlike in AD RCTs with dupilumab or
tralokinumab, the frequencies of conjunctivitis in lebrikizimab groups were low.
Anti-IL 31
Nemolizumab
IL-31 is a proinflammatory cytokine implicated in the pathogenesis of AD, playing a key role in
pruritus as well as dysregulation of the skin barrier (Kabashima et al. 2018). Nemolizumab is a
humanized monoclonal antibody against the IL-31 receptor A subunit, which is currently under
investigation for various dermatologic disorders, including AD, pruritus and prurigo nodularis.
Efficacy Data
In the phase 2 XCIMA trial (Ruzicka et al. 2017), nemolizumab treatment led to a significant,
dose-dependent improvement in the pruritus visual-analog scale (VAS), as compared with placebo.
Nemolizumab’s clinical efficacy was sustained and/or progressively improved up to 64 weeks
(Kabashima et al. 2018). In a subsequent phase 3 trial (Kabashima et al. 2020) of patients with
moderate-to-severe AD, treatment with nemolizumab concomitantly with topical agents led to
significantly greater improvement in pruritus compared with placebo as demonstrated by the LS
mean percent change in VAS. Additionally, nemolizumab led to improvement in AD severity, QoL
and sleep, although no inferences can be drawn from these measures as there was no adjustment for
multiple comparisons in this study.
Safety Data
Nemolizumab was overall well tolerated with an acceptable safety profile in the treatment of AD
as concluded by various phase 2 and 3 trials. Patients treated with nemolizumab or placebo had
similar frequencies of AEs, with most reported as mild to moderate in severity (Kabashima et al.
2020). The most commonly reported AEs included AD and nasopharyngitis. Skin infections were
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overall similar between both groups. Although there was no AE related to asthma reported in the
phase 3 trial, a dose-dependent increase in asthma events in patients with pre-existing asthma treated
with nemolizumab compared with placebo (11.2% vs. 1.8%) has been noted (Silverberg et al.
2020b). These events were typically mild and reversible, with no de novo cases of asthma reported.
Investigators postulated this may have been caused by improved QoL with an associated increase in
activity levels and/or respiratory infections. In the above phase 2 and 3 trials, peripheral edema was
reported in more patients compared with a placebo. With regards to laboratory parameters, treatment
with nemolizumab compared with placebo led to increased CK levels, although unclear if this was
clinically relevant.
Biologic Therapeutics and Atopic Dermatitis Key Points
• There are currently two biologics approved for moderate-to-severe AD, dupilumab and
tralokinumab with several other agents under investigation in clinical trials.
• As with asthma, there are no head-to-head comparator trials and such an approach to treatment
in AD must be individualized for each patient with consideration of comorbidities, available
safety data and patient preferences. See Table 2 for a comparison between available trial data.
• Notably, dupilumab was found to have unique safety signals in the management of AD, such as
conjunctivitis and facial erythema, though these were typically not treatment-limiting.
JAK Inhibitors
Janus Kinase (JAK) inhibitors represent a promising new therapy for the treatment of AD among
other dermatologic conditions. In brief review, the JAK family consists of four receptor-associated
kinases, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which are key components of the
JAK-signal transducers and activators of transcription (JAK-STAT) pathway. This pathway is
integral in signal transduction for many cytokines, including those implicated in the pathogenesis
of AD, such as IL-4, IL-5, IL-13, IL-31, IL-22 and TSLP. As a result of this, JAK inhibition has
been pursued as a novel treatment for AD (Chovatiya and Paller 2021). JAK inhibitors are synthetic
small molecular compounds and therefore not biologics. At the time of this publication, three JAK
inhibitors are currently FDA-approved for the treatment of AD. However, given the marked interest
and development in oral and topical JAK inhibitors, the landscape of AD therapeutics will likely
continue to expand. As such, we will review the current literature regarding JAK inhibitors for AD,
see Table 3.
Topical JAK Inhibitors
Ruxolitinib
Ruxolitinib is a selective JAK 1 and JAK 2 inhibitor. Its topical formulation is indicated for the
treatment of mild-to-moderate AD in adolescents (ages 12 years and older) and adults whose disease
is not well controlled with topical prescription therapies or when those are not recommended.
Efficacy Data
In the dual phase 3 TRuE-AD1 and TRuE-AD2 studies (Papp et al. 2021), significantly more patients
with mild-to-moderate AD treated with ruxolitinib achieved an IGA 0/1 and EASI75 compared with
vehicle. Additionally, a significant reduction in itch was noted as early as 12 hours after initial
application in the 1.5% ruxolitinib group.
Safety Data
In a pharmacokinetics analysis of the above RCTs, plasma concentrations of ruxolitinib were minimal
following topical application of ruxolitinib cream and as such serious systemic AEs commonly
associated with oral JAK inhibitors were infrequently observed (Gong et al. 2021). Ruxolitinib
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cream at all doses was overall well tolerated with an acceptable safety profile. The most common
treatment emergent AEs (TEAEs) were similar between vehicle and treatment groups and included
nasopharyngitis, URTIs, headache, application site reactions and AD. Application site reactions,
such as stinging/burning, were infrequent (< 1%) and reported more in the vehicle group compared
with treatment groups. Treatment with ruxolitinib did not lead to any clinically meaningful changes
in hematologic parameters. Despite the above reassuring data, it is important to note that ruxolitinib
cream currently possesses a black box warning for serious infections, mortality, malignancy, major
adverse cardiovascular event (MACE) and thrombosis, based upon prior studies of oral JAK
inhibitors to treat inflammatory conditions.
Delgocitinib
Delgocitinib is a novel topical pan-JAK inhibitor, which acts to inhibit all JAKs (JAK1, JAK2,
JAK3 and tyrosine kinase 2). It is approved in Japan for the treatment of AD, though it remains
under investigation for the treatment of AD in the US. It was granted Fast Track Designation by
the FDA in 2020, to help expedite its development and review, for adults with moderate-to-severe
chronic hand eczema.
Efficacy Data
In a phase 2 trial (Nakagawa et al. 2018), delgocitinib led to significant improvement in EASI score
compared with the vehicle along with a percentage of body surface area (BSA) affected, nocturnal
and daytime pruritus. Notably, a significant reduction in pruritus was noted as early as the first night
of study treatment with JTE-052 at 0.5% and higher doses. IGA scores were improved at end of
treatment with JTE ointment at doses of 0.5% and higher doses.
In a phase 3 trial, QBA4-1 (Nakagawa et al. 2020a), significantly more patients with
moderate-to-severe AD treated with delgocitinib 0.5% ointment had clinically meaningful
improvements in signs and symptoms of AD, as determined by mEASI, IGA and pruritus NRS
scores with sustained improvements up to 28 weeks. These results were replicated in the pediatric
population in a similar phase 3 trial (Nakagawa et al. 2021) and for up to 52 weeks in an open-label
study, QBA4-2 (Nakagawa et al. 2020b).
Safety Data
Delgocitinib had a favorable safety profile in AD RCTs. In a pooled safety analysis (Nakagawa
et al. 2020a), most AEs were mild with the most common AEs reported as nasopharyngitis, contact
dermatitis, acne and application site folliculitis. Application site irritation symptoms were infrequent
(< 2%) and mild, with no reports of skin atrophy or telangiectasia at the sites of application. Serious
AEs were rarely attributed to the low systemic exposure to delgocitinib.
Tofacitinib
Tofacitinib is a potent JAK 1 and JAK 3 inhibitor.
Efficacy Data
In a phase 2a study (Bissonnette et al. 2016), treatment with 2% tofacitinib ointment BID showed
significantly greater efficacy in patients with mild-to-moderate AD as measured by EASI, BSA,
physician’s global assessment (PGA) scores and pruritus as measured by Itch Severity Item (ISI).
There was significant improvement in EASI and BSA by week 1 and improvement in pruritus by
day 2.
Safety Data
With regards to its safety, tofacitinib ointment had comparable safety and tolerability effects when
compared with a placebo (Bissonnette et al. 2016). The most frequently reported treatment-related
AEs were mild and included nasopharyngitis, increased blood creatine phosphokinase (CPK),
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contact dermatitis and headache. Although oral tofacitinib carries an FDA black box warning for
serious AEs, including serious infections, thrombosis and malignancies; none of these were reported
in this limited trial.
Oral JAK Inhibitors
Abrocitinib
Abrocitinib is an oral, selective JAK 1 inhibitor approved by the FDA in January 2022 for the
treatment of moderate-to-severe AD in adult patients whose disease is not controlled with other
systemic drug products, including biologics or when the use of those therapies is inadvisable.
Efficacy Data
In the JADE MONO-1 phase 3 trial, adults and adolescents with moderate-to-severe AD treated
with abrocitinib monotherapy had significant improvement in IGA and EASI75, with clinically
meaningful responses noted as early as week 2 of treatment (Simpson et al. 2020b). These results
were substantiated in a replicate phase 3 trials in adults, JADE MONO-2 (Silverberg et al.
2020c), and adolescents, JADE TEEN (Eichenfield et al. 2021). A pooled analysis of the above
trials demonstrated abrocitinib’s impact on itch, sleep disturbance, health-related QoL and work
productivity (Silverberg et al. 2021b). In the JADE REGIMEN phase 3 trial, investigators found that
reinitiation of abrocitinib effectively recaptured response after disease flare (Blauvelt et al. 2022).
In the JADE COMPARE phase 3 trial, adults with AD were randomized to receive, in addition
to standard topical therapy, 100 mg or 200 mg abrocitinib once daily, 300 mg dupilumab SC Q2W or
placebo (Bieber et al. 2021a). Compared with placebo, patients treated with either dose of abrocitinib
had significant improvement in IGA and EASI75 responses at weeks 12 and 16. The 200 mg dose of
abrocitinib had a superior itch response at week 2 compared with dupilumab. However, there were
no significant differences in IGA and EASI75 responses between the groups at week 16.
Safety Data
In an integrated safety analysis, abrocitinib was deemed to have an acceptable safety and tolerability
profile (Simpson et al. 2021). Most AEs reported were mild and self-limited. The most common
dose-related, drug-related AEs were nausea, headache and acne. There was no dose-response
relationship for serious infections, which was similar across placebo and treatment groups. The
most frequent serious infections (0.2% or less for each type) in abrocitinib-treated patients included
pneumonia, herpes simplex, and herpes zoster. There were three serious AEs determined as MACE
as well as five events of venous thromboembolism (VTE) that occurred in the 200 mg group. There
were three deaths due to gastric carcinoma (diagnosed on day 43), sudden death and COVID-19.
With regards to lab evaluation, there was an asymptomatic, dose-dependent decrease in platelets,
with nadir around week 4 with subsequent increase and plateau around week 12. Additionally, there
was a dose-related, asymptomatic increase in CPK, which began at week 4 and plateaued at week 8,
as well as a dose-dependent effect on low- or high-density lipoprotein (LDL; HDL) from baseline
to week 16.
Updacitinib
Upadacitinib is an oral, reversible small-molecule JAK 1 inhibitor approved in January 2022 for
the treatment of moderate-to-severe AD for ages 12 and older whose disease is not controlled with
other systemic drug products, including biologics or when the use of those therapies is inadvisable.
Efficacy Data
In the dual Measure Up 1 and Measure Up 2 phase 3 RCTs (Guttman-Yassky et al. 2021), significantly
more patients with moderate-to-severe AD treated with upadacitinib achieved an EASI75 and an
IGA 0/1, with improvements noted as early as week 2. Additionally, significantly more patients had
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improvements in itch by day 2 and 3 with upadacitinib 30 and 15 mg, respectively, compared with
placebo. These results were corroborated in the phase 3 AD Up trial, where adults and adolescents
with moderate-to-severe AD were treated with upadacitinib in combination with TCS for 16 weeks
(Reich et al. 2021). Upadacitinb’s efficacy was sustained for up to 52 weeks with a clear dose
response observed from week 2 onwards (Silverberg et al. 2021c).
In a head-to-head comparator phase 3 trial, Heads Up, investigators analyzed the efficacy of
upadacitinib compared with dupilumab in adult patients with moderate-to-severe AD (Blauvelt
et al. 2021). Significantly more patients receiving upadacitinib compared with dupilumab achieved
an EASI75. Additionally, upadacitinib demonstrated superiority over dupilumab in all secondary
endpoints analyzed, including significant improvement in the worst pruritus NRS as early as
week 1, achievement of EASI75 as early as week 2 and achievement of EASI100.
Safety Data
Upadacitinib carries an FDA black box warning for treatment in RA including serious infections,
malignancy and thrombosis. In the above RCTs, upadacitinib was overall well tolerated with an
acceptable safety profile. Most AEs were reported as mild, with the most frequently reported
AEs in the trials including acne, URTIs, nasopharyngitis, AD and headache. Acne was reported
more frequently in the upadacitinib groups compared with placebo, as high as 17% in one trial
(Guttman-Yassky et al. 2021). With regards to laboratory parameters, patients treated with
upadacitinib infrequently developed abnormal liver function, cytopenias and/or elevated CPK. With
regards to liver function, most were transaminitis elevations, which were mild to moderate and
transient. Similarly, most cytopenias were transient in nature and mild to moderate in severity.
Baricitinib
Baricitinib is an oral, reversible, synthetic and selective JAK 1 and JAK 2 inhibitor. Although
baricitinib has been approved for the treatment of moderate-to-severe AD in adult patients in the
European Union (EU) and Japan, it remains under FDA review for this indication.
Efficacy Data
In dual-phase 3 monotherapy trails, BREEZE-AD1 and BREEZE-AD2 (Simpson et al. 2020c),
significantly more patients with moderate-to-severe AD achieved the primary end point of a
vIGA-AD 0/1 following treatment with baricitinib 4 mg or 2 mg groups compared with placebo.
Additionally, improvements in sleep disturbance, skin pain and QoL measures were observed by
week 1 in these groups. Baricitinib’s efficacy was sustained over 68 weeks (Silverberg et al. 2021d).
In the BREEZE-AD7 phase 3 trial, baricitinib 4 mg combination therapy with TCS significantly
improved the signs and symptoms of moderate-to-severe AD (Reich et al. 2020). Additionally,
baricitinib plus TCS led to significant improvement in PROs, including health-related QoL and
work productivity (Wollenberg et al. 2021c). Notably, in posthoc analyses of the above trials,
treatment with baricitinib produced significant and rapid improvements in symptoms of skin pain
(Thyssen et al. 2021), itch and sleep disturbance, typically starting one day after taking the first dose
of baricitinib (Buhl et al. 2021).
Safety Data
In a pooled safety analysis (Bieber et al. 2021b), baracitinib’s safety profile was deemed acceptable,
with the most common TEAEs reported as nasopharyngitis, headache, CPK elevations and diarrhea.
The frequency of serious infections, opportunistic infections and conjunctival disorders was low and
similar between treatment groups. The most common serious infections were eczema herpeticum,
cellulitis and pneumonia. In this analysis, herpes zoster infections were infrequent, did not show
dose-dependent increases and were lower than previously reported for RA patients treated with
baricitinib. Alternatively, herpes simplex infections were reported more frequently in the AD trials
compared to RA and were reported more frequently for baricitinib 4-mg as compared with 2-mg
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and placebo. The incidence rate of herpes simplex infections decreased with extended treatment,
suggesting continued treatment with baricitinib does not lead to an increased incidence of herpes
simplex infections.
Based on RA trials, baricitinib carries an FDA black box warning for serious infections,
malignancy and thrombosis. However, in the AD trials, no malignancies, gastrointestinal perforations,
CV events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated
patients, although in the extended data set, there were two positively adjudicated MACEs (2-mg
group), two VTEs (4-mg group) and one death. With regards to laboratory changes, an increase
in CPK was the most common laboratory change, which was mostly asymptomatic. Additionally,
baricitinib was associated with increases in both LDL and HDL as well as small reversible increases
in serum creatinine.
JAK Inhibitors Key Points
• There are currently three JAK inhibitors approved for the treatment of AD, including topical
ruxolinitib, oral abrocitinib and upadacitinib, with several other JAK inhibitors under
investigation.
• There are no head-to-head comparator trials between JAK inhibitors in the treatment of AD and
as such, the approach to treatment must be individualized for each patient with consideration
of comorbidities, available safety data and patient preferences. See Table 3 for a comparison of
available trial data.
• Although approved JAK inhibitors have overall acceptable safety profiles, it is important to note
they carry a black box warning, typically based upon prior outcomes in rheumatologic diseases.
In the above trials, most AEs were mild and self-limited, although more serious AEs were
reported in a few patients, including serious infections, MACE, VTE and death. Additionally,
given derangements in laboratory parameters reported in trials, it is important to monitor while
on treatment in these agents.
Chronic Rhinosinusitis With Nasal Polyps
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic inflammation of
nasal mucosa and paranasal sinuses. It is often associated with impaired QoL along with a substantial
economic burden (Wu et al. 2021). Several biologics are currently indicated for the management of
CRSwNP or nasal polyps (see Table 4).
Anti-IgE Therapy
Omalizumab
Omalizumab is indicated as an add-on maintenance treatment for nasal polyps in adult patients with
inadequate response to intranasal corticosteroids (INCS). The recommended dosing is based on
body weight and serum total IgE.
Efficacy Data
In dual-phase 3 studies, POLYP 1 and POLYP 2, omalizumab therapy in patients with severe
CRSwNP with prior inadequate response to INCS led to significant improvement in endoscopic,
clinical and PROs (Gevaert et al. 2020). Furthermore, patients with comorbid asthma and
NSAID-exacerbated respiratory disease (NERD) had similar improvements compared to patients
without NERD. In a subgroup analysis (Damask et al. 2021), omalizumab was consistently favored
over placebo independent of underlying patient factors, including patients with BEC > 300 and
≤ 300 cells/μL with or without previous sinonasal surgery, asthma and aspirin sensitivity.
Table 4. Biologics for treatment in CRSwNP.
https://t.me/medicina_free
Biologic Target FDA
Approval
for
CRSwNP
Dupilumab
Omalizumab
Mepolizumab
Benralizumab
IL-4Rα
(impacts IL-4
and IL-13)
IgE
IL-5
IL-5Rα 30 mg Q4W (x3) →
ü
ü
ü
Age Approved
for CRSwNP
> 18 years 300 mg Q2W SC
> 18 years 75–600 mg
> 18 years 100 mg Q4W SC
Dosing and Frequency for CRSwNP Route Phase 3 Clinical Trial results
Q2W or Q4W SC
(Dosing based on
serum total IgE and
Bodyweight)
SC
Q8W
Nasal Polyp
Burden
ü ü ü ü
ü ü ü
ü ü ü ü
ü ü ü
Nasal
Congestion
Sense of
Smell
Reduced Need
for Surgery
Targeted and Biologic Therapeutics for Allergic and Immunologic Diseases 239
(Not Evaluated)
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Other Disease Considerations
Omalizumab has also been investigated in the management of AR as well as aeroallergen
immunotherapy with promising results thus far; however, further studies are warranted (Verbruggen
et al. 2009; Kopp et al. 2009).
Safety Data
Overall, omalizumab is well tolerated with an acceptable safety profile in the management of
CRSwNP with no new or unexpected safety concerns identified compared with earlier trials in
asthma and CSU. The most common AEs observed were similar to prior trials, including headache,
nasopharyngitis, injection-site reactions and asthma exacerbation; all of which have been previously
reported with omalizumab. There were no confirmed events of anaphylaxis in these trials.
Anti-IL 4/13 Therapeutics
Dupilumab
Dupilumab is FDA-approved as an add-on maintenance treatment in adult patients with inadequately
controlled CRSwNP.
Efficacy Data
In dual-phase 3 trials, LIBERTY NP SINUS-24 and SINUS-52, adult patients with symptomatic
CRSwNP, despite previous treatment with OCS, surgery or both, treated with dupilumab had
significant improvement in Nasal Polyp Score (NPS), nasal congestion or obstruction and the sinus
Lund-Mackay CT scores. Additionally, there was a significant improvement in the University of
Pennsylvania Smell Identification Test (UPSIT), loss-of-smell and SNOT-22 total scores. In a
prespecified pooled analysis, compared with the placebo, the dupilumab group had 74% fewer who
needed treatment with OCS and 83% fewer who needed surgery. In patients with comorbid asthma,
dupilumab significantly improved lung function and asthma control. In a subsequent analysis of
the SINUS-24 and SINUS-52 (Mullol et al. 2021) dupilumab produced rapid, as soon as day 3, and
sustained improvement in sense of smell, regardless of CRSwNP duration, prior sinonasal surgery,
comorbid asthma or AERD.
In an analysis of patients with CRSwNP and comorbid AERD (Laidlaw et al. 2019), treatment
with dupilumab led to a significant reduction in mean NPS compared with placebo. AERD and
aspirin-tolerant patients both experienced significant improvements in the Lund-Mackay total,
SNOT-22 total, UPSIT and ACQ scores compared with placebo.
Real-World Studies
As discussed previously in the asthma section, a real-world, retrospective analysis (Bavaro et al.
2021) evaluated the response to dupilumab in patients with AERD, who were previously treated
with anti-IL-5 therapy for the management of asthma or CRSwNP. Following the transition to
dupilumab, total SNOT-22, smell/taste and congestion scores significantly improved compared to
baseline and after anti-IL-5 treatment with ACT score significantly improving from baseline.
Safety Data
Dupilumab was found to have a favorable safety profile in the treatment of CRSwNP, with no new
or unexpected safety concerns identified in prior trials for asthma or AD. The most common AEs
were nasopharyngitis, nasal polyps, headache, asthma, epistaxis and injection-site erythema.
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Anti-IL-5/5R
Mepolizumab
Mepolizumab is also indicated in the treatment of CRSwNP.
Efficacy Data
In the phase 3 SYNAPSE trial, patients treated with mepolizumab had significant improvement in
both total endoscopic NPS and nasal obstruction VAS compared to placebo (Han et al. 2021).
Real-World Studies
A 12-month real-world study (Detoraki et al. 2021) confirmed the above findings, noting the
significant improvement of SNOT-22 scores in asthma patients receiving mepolizumab therapy
with concomitant CRSwNP.
Safety Data
Mepolizumab’s safety profile for the treatment of CRSwNP is favorable, echoing safety data from
asthma RCTs. The most frequently reported AEs were nasopharyngitis, headache, epistaxis and
sinusitis (Han et al. 2021).
Benralizumab
Benralizumab is being investigated for the treatment of CRSwNP, although it does not possess FDA
approval for this indication currently.
Efficacy Data
In the phase 3 OSTRO study, patients with CRSwNP treated with benralizumab had a significant
median reduction in NPS and patients reported Mean Nasal Blockage Score; however, no significant
effect was seen in SNOT-22 scores, time to the first surgery, or need for OCS (Bachert et al. 2021).
Real-World Studies
In a real-world study (Bagnasco et al. 2020), treatment of patients with uncontrolled asthma and
concomitant nasal polyps with benralizumab led to improvement in asthma-related outcomes as
well as various sinonasal parameters, including resolution of anosmia. In another small real-world
observational study, treatment benralizumab led to significant improvement in various clinical
outcomes in patients with SEA and CRSwNP, including SNOT-22, subjective pain via the Numerical
Rating Scale (NRS), Endoscopic NPS, Lund-Mackay CT score and BEC (Lombardo et al. 2020).
CRSwNP Key Points
• There are currently three biologics approved for CRSwNP, omalizumab, dupilumab and
mepolizumab, with an overall acceptable safety profile and no new safety signals from earlier
trials for alternative indications.
• There are no head-to-head comparator trials and as such, the approach to treatment in CRSwNP
must be individualized for each patient with consideration of comorbidities, available safety
data and patient preferences. See Table 4 for a comparison between available trial data.
Chronic Spontaneous Urticaria
Chronic Spontaneous Urticaria (CSU) is defined by the presence of recurrent hives and/or
angioedema for greater than 6 weeks. It is estimated to affect up to 1% of the general population
and is associated with a significant impact on QoL in affected patients. There is only one biologic
currently approved for treatment in CSU (Johal et al. 2021).
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