Dupilumab

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306

J. K. Han and D. G. Milk

FDA- andEMA-Approved Biological Medications forCRSwNP

A summary of the FDA- and EMA-approved biologics are available in Table25.1 [7–12]. Three biologics—dupilumab, omalizumab, and mepolizumab—are currently approved by the FDA and the EMA for the treatment of patients with CRSwNP.The drugs’ major clinical trials are summarized in Table25.2. In all the clinical trials, the efcacy of these biologics was tested, while study participants continued the use of intranasal topical steroid spray. Consequently, biologics are considered add-on treatments to intranasal corticosteroids.

For patients with steroid-dependent CRS and/or asthma starting biological treatment, gradual and careful corticosteroid cessation is advised because an abrupt reduction in corticosteroid dosage may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy (e.g., eosinophilic granulomatosis with polyangiitis) [7–12].

Type 2 inammation plays a signicant role in the immune system’s defense mechanism against parasitic (helminth) infection. As a result, patients who take biologics might be at an increased risk of acquiring parasitic infection or being unable to clear parasitic infections [10–14]. Further studies are needed to gather additional information. The FDA addressed this issue and summarized that preexisting parasitic (helminth) infection should be treated before initiating biologics. If patients become infected while receiving dupilumab and do not respond to antihelminth treatment, consider discontinuing the treatment until the infection resolves [10–12].

Table 25.1 Summary of the FDA- and EMA-approved biologicals

Brand

Name Dupilumab Dupixent

Omalizumab Xolair Anti-IgE S.C 75–600mg

Mepolizumab Nucala Anti-IL-5 S.C 750mg

name Mechanism

Anti-IL-4Rα (anti-IL-4, IL-13)

Administration route Dose

S.C 300mg

every 2weeks

every 2 or 4weeks

every 4weeks

Common adverse reactions [7–12]

(Incidence ≥1%) Injection site reactions, temporary eosinophilia, insomnia, toothache, gastritis, arthralgia, and conjunctivitis

(Incidence ≥3%) Headache, injection site reaction, arthralgia, upper abdominal pain, and dizziness

(Incidence ≥5%) Headache, injection site reaction, back pain, and fatigue

25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis

NPS: −2.06 (−2.43 to −1.69)

NCS: −0.89 (−1.07 to −0.71)

UPSIT: 10.56 (8.79–12.34)

LMS: −7.44 (−8.35 to −6.53)

SNOT-22: −30.43 (1.54)

NPS: −1.80 (−2.10 to −1.51)

NCS: −0.87 (−1.03 to −0.71)

UPSIT: 10.52 (8.98–12.07)

LMS: −5.13 (−5.80 to −4.46)

Reported outcome

Least squares mean difference vs placebo (95% CI) at week 24:

Least squares mean change from baseline at week 24 (SE):

Least squares mean difference vs placebo (95% CI) at week 52:

SNOT-22: −29.84 (1.63)

Least squares mean change from baseline at week 24 (SE):

Asthma outcomes (pooled SINUS-24

and SINUS-52 [95% CI]):

(continued)

FEV1: 0.21 (0.13–0.29)

ACQ-6: −0.82 (−0.98 to −0.67)

307

Dupilumab every

2weeks for 52weeks

(n=150)

Placebo (n=153)

Dupilumab every

2weeks for 24weeks

and then every

4weeks until week

Dupilumab (n=143)

placebo (n=133)

Patients were randomly

assigned (1:1:1):

dupilumab 300mg every

2weeks for 52weeks/

placebo for 52weeks/

Patients were randomly

assigned (1:1) to

dupilumab 300mg or

placebo every 2weeks

for 24weeks

Type of study Medical intervention Number of patients

Multicenter,

randomized,

double-blind,

placebo-

controlled,

Study

Dupilumab

LIBERTY NP

Table 25.2 Summary of the major studies on biologicals for CRSwNP

SINUS 24 [15]

Multicenter,

randomized,

parallel-group

phase 3 trial

double-blind,

LIBERTY NP

SINUS 52 [15]

dupilumab every 2weeks

placebo-

controlled,

parallel-group

52 (n=145)

for 24weeks and every

4weeks until week 52

phase 3 trial

308

NPS: −1.6 (−2.4 to −0.7)

UPSIT: 14.8 (10.9–18.7)

LMS: −8.8 (−11.1 to −6.6)

Reported outcome

Least squares mean difference vs placebo (95% CI) at week 16:

Least squares mean change from baseline at week 16 (SE):

(VAS > 3–10) decreased from 86.2% to 21.4% with dupilumab

SNOT-22: −27.3 (2.7)

The proportion of patients with moderate-to-severe CRSwNP

SNOT-22, SF-36, and EQ-5D VAS scores

and 88.0% to 84.2% with placebo

Signicantly greater improvement in HRQoL, based on

J. K. Han and D. G. Milk

leave days (0.09, vs 4.18 with placebo) and signicantly greater

improvement (vs placebo) in the SNOT-22 item “reduced

productivity”

Signicantly lower adjusted annualized mean number of sick

NPS: −1.14 (−1.59 to −0.69)

NCS: −0.55 (−0.84 to −0.25)

UPSIT: 3.81 (1.38–6.24)

TNSS: –1.91 (–2.85 to –0.96)

Loss of smell score: –0.33 (–0.60 to –0.06)

Postnasal drip score: –0.56 (–0.84 to –0.28)

Runny nose score: –0.43 (–0.70 to –0.16)

AQLQ: OR 3.71 (1.0–13.71) of achieving MCID

Treatment arm mean differences (95%CI) at week 24:

Adjusted mean change from baseline at week 24 (SE):

SNOT-22: −24.7 (2.01)

Dupilumab (n=30)

placebo (n=30)

Patients were randomly

assigned: (1:1):

Type of study Medical intervention Number of patients

Multicenter,

randomized,

Study

NCT01920893

Table 25.2 (continued)

[25, 26]

dupilumab (a 600mg

loading dose followed by

300mg)

Weekly or placebo for

16weeks

double-blind,

placebo-

controlled,

parallel-group

phase IIa trial

Omalizumab (n=72)

Placebo (n=66)

75–600mg omalizumab

every 2–4weeks (with

dose and frequency

determined by serum

total IgE level and body

weight using a dosing

multicenter,

parallel-group

randomized

controlled,

phase III trial

Omalizumab

POLYP 1 [21] Double-blind,

table) or placebo for

24weeks and 4weeks of

follow-up

25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis

(continued)

NPS: −0.59 (−1.05 to −0.12)

NCS: −0.50 (−0.80 to −0.19)

UPSIT: 3.86 (1.57–6.15)

TNSS: –2.09 (–3.00 to –1.18)

Loss of smell score: –0.45 (–0.73 to –0.16)

Postnasal drip score: –0.54 (–0.81 to –0.27)

Runny nose score: –0.63 (–0.90 to –0.35)

Adjusted mean change from baseline at week 24 (SE):

SNOT-22: −21.59 (2.25)

AQLQ: OR 4.04 (1.07–15.25) of achieving MCID

Patients who continued omalizumab experienced further

improvements in NPS, NCS, SNOT-22, TNSS, and UPSIT scores

through 52weeks

Patients who switched from placebo to omalizumab experienced

favorable responses across end points through week 52 that were

similar to POLYP 1 and 2 at week 24

After omalizumab discontinuation, scores gradually worsened over

the 24-week follow-up but remained improved from pretreatment

Reported outcome

Treatment arm mean differences

(95%CI) at week 24:

levels for both groups

309

Omalizumab (n=62)

Placebo (n=65)

75–600mg omalizumab

every 2–4weeks (with

dose and frequency

determined by serum

total IgE level and body

weight using a dosing

Type of study Medical intervention Number of patients

Double-blind,

multicenter,

parallel-group

randomized

controlled,

phase III trial

Study

(POLYP 2)

[21]

(n=249)

table) or placebo for

24weeks and 4weeks of

follow-up

After 24weeks of

Open-label

Open label

omalizumab or placebo

in POLYP 1 and 2,

patients received

omalizumab for

28weeks and followed

for another 24weeks

extension

study of

POLYP 1

and 2

extension of

Polyp 1,2 [27]

310

NPS: −0.73 (−1.11 to −0.34)

Nasal obstruction VAS score: −3.14 (−4.09 to −2.18)

Adjusted difference in median (95% CI) at Week 52

Loss of smell VAS score: −0.37 (−0.65 to −0.08)

Reported outcome

J. K. Han and D. G. Milk

(time-to-rst nasal surgery): 0·43 (0·25–0·76)

SNOT-22: −29·4 (24·67)

Mean (SD) change from baseline at week 52:

course) for nasal polyps until week 52: 0·58 (0·36–0·92)

The proportion of patients having nasal surgery up to week 52

The proportion of patients requiring systemic corticosteroids (≥1

Changes in UPSIT were not statistically signicant

Signicantly greater proportion of patients no longer required

surgery at week 25 (16[30%]) compared to placebo (5[10%])

Signicant improvement in nasal polyposis severity VAS score,

endoscopic nasal polyp score, VAS symptom scores, and sino-nasal

outcome test [SNOT]-22 PRO score

No improvement in olfaction testing and lung function tests

Dupilumab reduces the need for surgery or OCS use (moderate

certainty, improves smell and quality of life (high certainty))

Omalizumab reduces the need for surgery (high certainty),

improves smell and quality of life (high certainty)

Mepolizumab reduces the need for surgery (low certainty),

improving smell and quality of life

Mepolizumab

Patients were randomly

Type of study Medical intervention Number of patients

Randomized,

Study

Mepolizumab

Table 25.2 (continued)

SYNAPSE

(n=206)

Placebo (n=201)

assigned (1:1), to receive

either 100mg

mepolizumab

subcutaneously or

multicenter,

double-blind,

placebo-

controlled,

[28]

placebo once every

4weeks for 52weeks

parallel-group,

phase 3 trial

Mepolizumab

(n=54)

Placebo (n=51)

Patients received

intravenous

mepolizumab 750mg or

placebo every 4weeks

for a total of six doses

(24weeks)

Randomized,

double-blind,

placebo-

controlled trial

NCT01362244

[29]

Included in the SR:

9 RCTs on dupilumab,

omalizumab,

mepolizumab, and

reslizumab. Overall 1236

adults, with follow-up of

20–64weeks

review

Comparison among biologics

[30] Systematic

25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis

Reported outcome

Dupilumab improves disease-specic HRQOL compared to

placebo. It likely results in a reduction in disease severity (on a 0-

to 10-point VAS) and may result in a reduction in the number of

serious adverse events

Mepolizumab improves disease-specic HRQL.It likely results in

the reduction difference of disease severity and the number of

serious adverse events

Omalizumab probably improves disease-specic HRQOL

compared to placebo. It is uncertain if there is a difference in the

number of serious adverse events

Dupilumab, omalizumab, mepolizumab, benralizumab, and ASA-D

improved patient-important outcomes with clinically important

differences in effects and ranking among agents, with dupilumab

uniquely ranking among the most benecial for all outcomes

studied

311

10 studies. Of 1262 adult

participants

Type of study Medical intervention Number of patients

Library

Intervention

Review,

systematic

review

Study

[31] Cochrane

Twenty-nine randomized

controlled trials

(n=3461) were included

in the network

meta-analysis

review and

network

meta-analysis

[32] Systematic

NPS nasal polyp score, NCS nasal congestion score, SNOT-22 sinonasal outcome test-22, UPSIT University of Pennsylvania Smell Identication Test, LMS

Lund-Mackay score, FEV1 forced expiratory volume in 1s, ACQ asthma control questionnaire, SF-36 short-form health survey, TNSS total nasal symptom

score, AQLQ asthma quality of life questionnaire, EQ-5D 5-dimension EuroQoL general health status VAS, CI condence interval

312

J. K. Han and D. G. Milk

Dupilumab

Dupilumab is a fully human monoclonal antibody that binds to the IL-4Ra subunit and thereby inhibits the signaling of IL-4 and IL-13 (Fig.25.1). The effectiveness and safety of dupilumab vs. placebo have been evaluated in several studies. The phase III studies were LIBERTY NP SINUS-24 and SINUS-52 [15] (Table25.2). These studies found that:

• Dupilumab was found to induce signicant improvement in nasal symptoms

(nasal congestion, sense of smell), disease-related QOL, nasal polyp score

(NPS), sense of smell, and radiologic sinus opacication (LMS).

• Dupilumab also reduced the need for systemic corticosteroids and ESS.

• Stopping the medication after 24weeks of treatment led to a gradual exacerba-

tion of symptoms, which might indicate that prolonged and even life-long treat-

ment is required.

*Special Considerations

Transient eosinophilia is a common side effect of dupilumab treatment. The exact pathogenesis is unclear. One hypothesis is that dupilumab blocks eosinophil tissue migration by inhibiting the production of eotaxins mediated by IL-13, thereby increasing circulating blood eosinophils [15]. Another explanation is that the corticosteroid- sparing effect of dupilumab can expose existing cases of eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) that were masked by prolonged treatment with systemic corticosteroids which is eventually weaned when taking the biologic [16]. This eosinophilia is typically transient and asymptomatic, occurring within 2–6months of treatment. However, a growing number of publications have highlighted a possible correlation between dupilumab treatment and eosinophilic complications such as EGPA and HES [17–20]. An unpublished postmarketing analysis of the FDA Adverse Event Reporting System Public Dashboard found 218 reports of eosinophilic complications of dupilumab treatment, including 92 reports of EGPA and 92 reports of eosinophilic complications of the respiratory tract. The recent EUFOREA guideline addressed this issue and suggested the following algorithm to monitor eosinophil levels during dupilumab treatment [5]. Figure25.3 details a proposed algorithm for monitoring blood eosinophil levels during dupilumab treatment.

25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis

Fig. 25.3 Proposed algorithm to monitor blood eosinophil levels during dupilumab treatment [5]

313

Omalizumab

Omalizumab is an anti-IgE monoclonal antibody, approved by the FDA in 2020 for the treatment of CRSwNP. POLYP 1 and POLYP 2 were phase III clinical trials (Table25.2) that studied the effectiveness and safety of omalizumab vs. placebo in participants with CRSwNP [21]. These studies found that:

• Omalizumab improved nasal symptoms, NPS, disease-related QOL, and sense of

smell and reduced the need for ESS.

• There was no signicant change in the need for rescue treatment with systemic

corticosteroids.

*Special Considerations

IgE is thought to play a vital role in cancer immune surveillance. Some studies have reported a possible link between absent or very low serum IgE levels and malig-

23]. A recent literature review by the World Allergy Organization addressed this

question and summarized that there is no evidence of an increased risk of malignancy in omalizumab-treated patients. They concluded that there was no increase in the number of tumor cases in omalizumab patients compared to the general

314

population based on systematic studies and meta-analyses performed on more than 40,000 patients [24].

Anaphylaxis and other hypersensitivity reactions, such as serum sickness, were described. The FDA advises administering the drug only in a healthcare setting prepared to manage anaphylaxis and stopping treatment in the case of fever, arthralgia, and rash [11].

J. K. Han and D. G. Milk

Mepolizumab

Mepolizumab is an anti-IL-5 monoclonal antibody, and its binding to IL-5 reduces the production and survival of eosinophils. The FDA has approved mepolizumab for treating CRSwNP since 2021. SYNAPSE (summarized in Table25.2) was the main phase III clinical trial evaluating mepolizumab vs. placebo over a 52-week period [28]. This study found that:

• Mepolizumab demonstrated efcacy in improving nasal symptoms, disease-

related QOL, NPS, sense of smell, and sinus opacication.

• It reduced the need for ESS and systemic corticosteroids and reduced the levels

of blood eosinophils.

• Half of the patients in the mepolizumab group had an improvement of 1 point or

more in nasal polyp scores.

*Special Considerations

Herpes zoster infections have occurred in patients receiving mepolizumab. Consider vaccination if medically appropriate [12].

Matching theBiologic tothePatient

Thus far, nostudy has directly compared the efcacy of one biologic to another in treatment of CRSwNP. In addition,no biomarkers have been identied to dene a certain group of type 2 CRS patients that will respond best to a certain biological medication. However, indirect treatment analyses have suggested that dupilumab may have a better response than mepolizumab and omalizumab in CRSwNP patients [32–34]. Further studies are required to establish a denitive preference for one biologic over another.

Deciding on the appropriate biologic should be tailored to the individual patient,be based on a multidisciplinary approach, and take into account several factors, includingcomorbidities (e.g., allergic asthma, atopic dermatitis, and eosinophilic diseases), the option of home administration, cost, local health economics, and patient compliance and preference. One other factor to consider is the duration of treatment response with various biologics. For instance, one study showed that mepolizumab may have a possible sustained effect for a duration of 6months [35]. Some evidence suggests benets of switching biological medications or even combining biologics for patients with type 2 comorbidities (e.g., asthma). It is

25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis

Fig. 25.4 Suggested algorithm to monitor and assess patient’s response to treatment

315

alsoreasonable to consider transitioning to an alternative biologic when the response is suboptimal or an adverse reaction is encountered. However, further studies are required to establish denitive recommendations. Figure25.4 is a suggested algorithm to monitor treatment response. It is important to note that the time until medication response is observed can vary signicantly from days to months.

Biological Treatment forAspirin-Exacerbated Respiratory Disease (AERD)

AERD or NERD (nonsteroidal anti-inammatory drug-exacerbated respiratory disease) is a subgroup of CRSwNP, that is characterized by CRSwNP, asthma, and hypersensitivity reactions to aspirin and NSAIDs. It is also known as “Samter’s triad.” [36]. Its prevalence is approximately 10% in CRSwNP and 15% in severe asthma [37]. This entity is driven by type 2 inammation, is associated with severe and difcult-to-treat asthma and rhinosinusitis, and often presents with aggressive and rapid recurrence of nasal polyps following ESS [38]. The integration of biologics into the management of asthma and CRSwNP gave new hope to patients with these frustrating diseases. The current evidence supports the use of biologics in AERD; however, more high-quality studies are needed to furtherassess the impact of biologics on this specic subgroup of patients and to determine what is the best biological medication for them. The major studies evaluating the role ofbiological treatment in AERD are summarized in Table25.3.

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