Atopic dermatitis 

Adults and adolescents  

Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy. 

Children 6 to 11 years of age 

Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 to 11 years old who are candidates for systemic therapy. 

Asthma 

Adults and adolescents  

Dupixent is indicated in adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.  

Children 6 to 11 years of age 

Dupixent is indicated in children 6 to 11 years old as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with medium to high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.  

Chronic rhinosinusitis with nasal polyposis (CRSwNP)   

Dupixent is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control. 

Eosinophilic Esophagitis 

DUPIXENT is indicated for the treatment of adult and adolescents aged 12 years and older, weighing at least 40 kg, with eosinophilic esophagitis (EoE), who are inadequately controlled by, are intolerant to, or who are not candidates for conventional medicinal therapy.

Prurigo Nodularis 

DUPIXENT is indicated for the treatment of adult patients with prurigo nodularis (PN), who are candidate for systemic therapy.

Chronic Obstructive Pulmonary Disease 

Dupixent is indicated as an add-on maintenance treatment in adult patients with uncontrolled chronic obstructive pulmonary disease (COPD) associated with type 2 inflammation. 

Chronic Spontaneous Urticaria 

Dupixent is indicated for the treatment of chronic spontaneous urticaria (CSU) in patients 12 years and older, whose disease is inadequately controlled by H1 antihistamines and who are naive to anti-IgE therapy for CSU.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of conditions for which dupilumab is indicated (see section 4.1). 

Posology 

Atopic dermatitis  

Adults 

The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week administered as subcutaneous injection. 

Children and Adolescent (6 to 17 years of age) 

The recommended dose of dupilumab for Children and adolescent patients 6 to 17 years of age is specified in Table 1. 

Table 1: Dose of dupilumab for subcutaneous administration in adolescent patients 6 to 17 years of age with atopic dermatitis

Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. 

Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. If dupilumab treatment interruption becomes necessary, patients can still be successfully re-treated. 

Asthma  

Adults and adolescents 

The recommended dose of dupilumab for adults and adolescents (12 years of age and older) is: 

•       For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, an initial dose of 600 mg (two 300 mg injections), followed by 300 mg every other week administered as subcutaneous injection. 

•       For all other patients, an initial dose of 400 mg (two 200 mg injections), followed by 200 mg every other week administered as subcutaneous injection. 

Children 6 to 11 years of age 

The recommended dose of dupilumab for paediatric patients 6 to 11 years of age is specified in Table 2. 

Table 2: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with asthma

For paediatric patients (6 to 11 years old) with asthma and co-morbid severe atopic dermatitis, as per approved indication, the recommended dose should be followed in Table 2. 

Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see section 5.1). Steroid reductions should be accomplished gradually (see section 4.4). 

Dupilumab is intended for long-term treatment. The need for continued therapy should be considered at least on an annual basis as determined by physician assessment of the patient’s level of asthma control. 

Chronic rhinosinusitis with nasal polyposis (CRSwNP)   

The recommended dose of dupilumab for adult patients is an initial dose of 300 mg followed by 300 mg given every other week. 

Dupilumab is intended for long-term treatment. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for CRSwNP. Some patients with initial partial response may subsequently improve with continued treatment beyond 24 weeks. 

Eosinophilic Esophagitis  

The recommended dosage of DUPIXENT for adult and adolescent 12 years of age and older, weighing at least 40 kg, is 300 mg given every week (QW).  

Dupilumab 300 mg QW has not been studied in patients with EoE weighing less than 40 kg.  

Dupilumab is intended for long-term treatment.Dupilumab 300 mg QW has been studied up to 52 weeks. Dosing beyond 52 weeks has not been studied. 

Chronic Obstructive Pulmonary Disease (COPD)  

The recommended dosage of DUPIXENT for adult patients is 300 mg given every other week (Q2W). 

Chronic Spontaneous Urticaria (CSU)  

Adults 

The recommended dose of Dupixent for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week. 

Pediatric patients (12 to 17 years of age) 

The recommended dose of Dupixent for pediatric patients 12 to 17 years of age is specified in Table 3. 

Table 3: Dose of Dupixent for Subcutaneous Administration in Pediatric Patients 12 to 17 Years of Age with CSU:

Prurigo Nodularis  

The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week (Q2W). 

Dupilumab can be used with or without topical corticosteroids. 

PN clinical trial data are available for patients treated up to 24 weeks. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for PN. 

Missed dose  

If a weekly dose is missed, administer the dose as soon as possible, starting a new schedule based on this date.  

If an every other week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, wait until the next dose on the original schedule.  

If every 4-week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date. 

Special populations 

Elderly (≥ 65 years) 

No dose adjustment is recommended for elderly patients (see section 5.2). 

Renal impairment  

No dose adjustment is needed in patients with mild or moderate renal impairment. Very limited data are available in patients with severe renal impairment (see section 5.2). 

Hepatic impairment 

No data are available in patients with hepatic impairment (see section 5.2). 

Body weight  

No dose adjustment for body weight is recommended for patients with asthma and EoE 12 years of age and older or in adults with atopic dermatitis, CRSwNP, PN, COPD or CSU. (see section 5.2). 

Paediatric patients  

The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 years have not been established. The safety and efficacy of dupilumab in children with a body weight < 15kg have not been established. No data are available. 

The safety and efficacy of dupilumab in children with severe asthma below the age of 6 years have not been established. No data are available. 

The safety and efficacy in children with CRSwNP below the age of 18 years have not been established. No data are available. 

The safety and efficacy of dupilumab in children with PN below the age of 18 years have not been established. No data are available. 

The safety and efficacy of dupilumab in children with EoE below the age of 12 years have not been established. 

The safety and efficacy of dupilumab in children patients with COPD younger than 18 years have not been established. COPD does not normally occur in children. 

The Safety and efficacy in pediatric patients with CSU younger than 12 years have not been established. 

Method of administration 

Subcutaneous use 

The dupilumab pre-filled pen is not intended for use in children below 6 years of age. 

Dupilumab is administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used. 

Each pre-filled pen is for single use only. 

For the initial 600 mg dose, two 300 mg injections should be administered consecutively in different injection sites. 

It is recommended to rotate the injection site with each injection. Dupilumab should not be injected into skin that is tender, damaged or has bruises or scars. 

A patient may self-inject dupilumab or the patient's caregiver may administer dupilumab if their healthcare professional determines that this is appropriate. Proper training should be provided to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section at the end of the package leaflet. 

Traceability 

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.  

Acute asthma exacerbations 

Dupilumab should not be used to treat acute asthma symptoms or acute exacerbations. Dupilumab should not be used to treat acute bronchospasm or status asthmaticus. 

Corticosteroids 

Systemic, topical, or inhaled corticosteroids should not be discontinued abruptly upon initiation of therapy with dupilumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. 

Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. This should be taken into consideration to determine type 2 status in patients taking oral corticosteroids (see section 5.1). 

Hypersensitivity 

If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of dupilumab should be discontinued immediately and appropriate therapy initiated. Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported. Anaphylactic reactions and angioedema have occurred from minutes to up to seven days after the dupilumab injection (see section 4.8). 

Eosinophilic conditions 

Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in the asthma development program. Cases of vasculitis consistent with EGPA have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP development program. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. Patients being treated for asthma may present with serious systemic eosinophilia sometimes presenting with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid therapy. These events usually, but not always, may be associated with the reduction of oral corticosteroid therapy. 

Acute Symptoms of Asthma or Chronic Obstructive Pulmonary Disease or Acute Deteriorating Disease  

Dupixent should not be used to treat acute symptoms or acute exacerbations of asthma or COPD. Do not use Dupixent to treat acute bronchospasm or status asthmaticus. 

Helminth infection 

Patients with known helminth infections were excluded from participation in clinical studies. Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signaling. Patients with pre-existing helminth infections should be treated before initiating dupilumab. If patients become infected while receiving treatment with dupilumab and do not respond to antihelminth treatment, treatment with dupilumab should be discontinued until infection resolves. Cases of enterobiasis were reported in children 6 to 11 years old who participated in the paediatric asthma development program (see section 4.8). 

Conjunctivitis and keratitis related events 

Conjunctivitis and keratitis related events have been reported with dupilumab, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis (see section 4.8).  

Patients should be advised to report new onset or worsening eye symptoms to their healthcare provider. Patients treated with dupilumab who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis should undergo ophthalmological examination, as appropriate (see section 4.8).  

Atopic dermatitis or CRSwNP patients with comorbid asthma 

Patients on dupilumab for moderate-to-severe atopic dermatitis or severe CRSwNP who also have comorbid asthma should not adjust or stop their asthma treatments without consultation with their physicians. Patients with comorbid asthma should be monitored carefully following discontinuation of dupilumab. 

Vaccinations 

Live and live attenuated vaccines should not be given concurrently with dupilumab as clinical safety and efficacy has not been established. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed (see section 4.5). It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab. 

Sodium content  

This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, that is to say essentially “sodium-free”.  

Immune responses to vaccination were assessed in a study in which patients with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab. After 12 weeks of dupilumab administration, patients were vaccinated with a Tdap vaccine (T cell-dependent), and a meningococcal polysaccharide vaccine (T cell-independent) and immune responses were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated patients. No adverse interactions between either of the non-live vaccines and dupilumab were noted in the study.  

Therefore, patients receiving dupilumab may receive concurrent inactivated or non-live vaccinations. For information on live vaccines see section 4.4. 

In a clinical study of atopic dermatitis patients, the effects of dupilumab on the pharmacokinetics (PK) of CYP substrates were evaluated. The data gathered from this study did not indicate clinically relevant effects of dupilumab on CYP1A2, CYP3A, CYP2C19, CYP2D6, or CYP2C9 activity. 

An effect of dupilumab on the PK of co-administered medicinal products is not expected. Based on the population analysis, commonly co-administered medicinal products had no effect on dupilumab pharmacokinetics on patients with moderate to severe asthma. 

Pregnancy 

There is a limited amount of data from the use of dupilumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Dupilumab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. 

Breast-feeding 

It is unknown whether dupilumab is excreted in human milk or absorbed systemically after ingestion. A decision must be made whether to discontinue breast-feeding or to discontinue dupilumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 

Fertility 

Animal studies showed no impairment of fertility (see section 5.3). 

Dupilumab has no or negligible influence on the ability to drive and use machines. 

Summary of the safety profile 

The most common adverse reactions are injection site reactions (includes erythema, oedema, pruritus, pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. An additional adverse reaction of injection site bruising was reported in EoE and COPD. Additional adverse reactions of injection site induration, injection site rash, and injection site dermatitis were reported in COPD. Rare cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4). 

Tabulated list of adverse reactions 

The dupilumab safety data presented in Table 4 were predominantly derived from 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. These studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period are representative of the overall safety profile for dupilumab. 

Listed in Table 4 are adverse reactions observed in clinical trials and/or postmarketing setting presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4: List of adverse reactions

*eye disorders and oral herpes occurred predominately in atopic dermatitis studies. 

^†the frequencies for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in atopic dermatitis studies. 

^#from postmarketing reporting. 

Description of selected adverse reactions 

Hypersensitivity 

Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported following administration of dupilumab (see section 4.4). 

Conjunctivitis and keratitis related events 

Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received dupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic dermatitis study (AD-1225) at 5 years, the respective rates of conjunctivitis and keratitis remained similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Among asthma and COPD patients frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP and Prurigo Nodularis (PN) patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients. There were no cases of keratitis reported in the CRSwNP or PN development program. Among patients with EoE, and CSU, the frequency of conjunctivitis was low and similar between dupilumab and placebo groups. There were no cases of keratitis reported in the CRSwNP, PN, EoE and CSU development program (see section 4.4). 

Eczema herpeticum  

Eczema herpeticum was reported in < 1% of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitis dupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS group and 1.9 % of the placebo + TCS group. These rates remained stable at 5 years in the long-term OLE study (AD-1225). 

Eosinophilia  

Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo in the atopic dermatitis, asthma, CSU, COPD and CRSwNP indications Eosinophil counts declined to near baseline levels during study treatment and returned to baseline during the asthma open-label extension safety study (TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was maintained up to 5 years in the long-term OLE study (AD-1225). Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2). Mean and median blood eosinophil counts declined to near baseline or remained below baseline levels in EoE (TREET Parts A and B) during study treatment. 

In COPD, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was higher in the Dupixent group than in the placebo; none of the cases were associated with clinical symptoms. Across atopic dermatitis, asthma, CRSwNP, and CSU indications, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in Dupixent and placebo groups. In EoE and PN the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was lower in Dupixent than in the placebo group.  

Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was reported in < 3 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52, PRIME, and PRIME2 studies; TREET Parts A and B; BOREAS and NOTUS, CUPID A, B and C).

In adult and pediatric subjects with CSU (CUPID Study A, B and Study C) treated with Dupilumab, an increase from baseline in blood eosinophil count was not observed compared to placebo at Week 12 and a slight increase was observed during study treatment.

Treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in 8.4% of dupilumab-treated patients and 0% in placebo-treated patients in study AD-1539, with median eosinophil counts declining below baseline at end of treatment period. 

Infections 

In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported in 1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treated with placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remained stable at 5 years in the long-term OLE study (AD-1225). 

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.4% of patients treated with placebo. 

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for CRSwNP clinical studies. In the 52-week SINUS-52 study, serious infections were reported in 1.3 % of patients treated with dupilumab and 1.3 % of patients treated with placebo. 

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for PN clinical studies. In the safety pool, serious infections were reported in 1.3% of patients treated with dupilumab and 1.3% of patients treated with placebo. 

The overall incidence of infections was numerically higher with dupilumab (32.0%) compared to placebo (24.8%) in the safety pool for EoE TREET (Parts A and B) studies. In the 24-week safety pool, serious infections were reported in 0.5% of patients treated with dupilumab and 0% of patients treated with placebo. 

No increase was observed in the overall incidence of infections with Dupilumab compared to placebo in the safety pool for CSU clinical studies. In the safety pool, serious infections were reported in 0% of patients treated with Dupilumab and 0.8% of patients treated with placebo. 

No increase was observed in the overall incidence of infections with Dupilumab compared to placebo in the safety pool for COPD clinical studies. Serious infections were reported in 4.9% of patients treated with Dupilumab and 4.8% of patients treated with placebo 

Immunogenicity 

As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab. 

Anti-Drug-Antibodies (ADA) responses were not generally associated with impact on dupilumab exposure, safety, or efficacy. 

Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 

300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies. Similar results were observed in adult patients with PN who received dupilumab 300 mg Q2W for 24 weeks, in paediatric patients (6 years to 11years of age) with atopic dermatitis who received either dupilumab 200 mg Q2W, 200 mg Q4W or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received either dupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 5 years in the long-term OLE study (AD-1225). 

Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3 % exhibited persistent ADA responses, and approximately 5 % had neutralizing antibodies. 

Approximately 9 % of patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4 % exhibited persistent ADA responses and approximately 4 % had neutralizing antibodies. 

Approximately 5% of patients with CSU who received Dupilumab 200 mg Q2W or 300 mg Q2W through 24 weeks developed antibodies to dupilumab; approximately 1% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.

Approximately 8% of patients with COPD who received Dupilumab 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses and approximately 3% had neutralizing antibodies. 

Approximately 1% of patients with EoE who received dupilumab 300 mg QW or 300 mg Q2W for 24 weeks developed antibodies to dupilumab; 0% exhibited persistent ADA responses and approximately 0.5% had neutralizing antibodies. 

Regardless of age or population, approximately 4 % of patients in the placebo groups were positive for antibodies to dupilumab; approximately 2 % exhibited persistent ADA response and approximately 1 % had neutralizing antibodies. 

Less than 1 % of patients who received dupilumab at approved dosing regimens exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers (see section 4.4). 

Approximately 8% of subjects with PN who received DUPIXENT 300 mg Q2W for 24 weeks developed antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 3% had neutralizing antibodies. 

Paediatric population 

Atopic dermatitis  

Adolescents (12 to 17 years of age) 

The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1526). The safety profile of dupilumab in these patients followed through week 16 was similar to the safety profile from studies in adults with atopic dermatitis. 

Children 6 to 11 years of age 

The safety of dupilumab was assessed in a study of 367 patients 6 to 11 years of age with severe atopic dermatitis (AD-1652). The safety profile of dupilumab with concomitant TCS in these patients through week 16 was similar to the safety profile from studies in adults and adolescents with atopic dermatitis. 

Atopic Hand and Foot Dermatitis 

The safety of dupilumab was assessed in 27 paediatric patients 12 to 17 years of age with moderatetosevere atopic hand and foot dermatitis (AD-1924). The safety profile of dupilumab in these patients through Week 16 was consistent with the safety profile from studies in adult and paediatric patients 6 years and older with moderate-to-severe AD. 

Asthma  

Adolescents (12 to 17 years of age)  

A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in the 52-week QUEST study. The safety profile observed was similar to that seen in adults. 

The long-term safety of dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.  

Children 6 to 11 years of age 

In children 6 to 11 years of age with moderate-to-severe asthma (VOYAGE), the additional adverse reaction of enterobiasis was reported in 1.8 % (5 patients) in the dupilumab groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminth treatment without dupilumab treatment discontinuation.  

In children 6 to 11 years of age with moderate-to-severe asthma, eosinophilia (blood eosinophils ≥ 3,000 cells/mcL or deemed by the investigator to be an adverse event) was reported in 6.6 % of the dupilumab groups and 0.7% in the placebo group. Most eosinophilia cases were mild to moderate and not associated with clinical symptoms. These cases were transient, decreased over time, and did not lead to dupilumab treatment discontinuation. 

The long-term safety of dupilumab was assessed in an open-label extension study (EXCURSION) in children 6 to 11 years of age with moderate-to-severe asthma who previously participated in

VOYAGE. Among 365 patients who entered EXCURSION, 350 completed 52 weeks of treatment and 228 patients completed a cumulative treatment duration of 104 weeks (VOYAGE and EXCURSION).  

The long-term safety profile of dupilumab in EXCURSION was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

Adolescents (12 to 17 years of age) 

The safety of Dupixent was assessed in 99 adolescents aged 12 to 17 years with EoE that were enrolled in the TREET (Parts A and B) studies.¹ The safety profile observed was similar to that seen in adults.  

Chronic Spontaneous Urticaria 

Adolescents (12 to 17 years of age) 

The safety of Dupilumab was assessed in 12 adolescents aged 12 to 17 years with CSU enrolled in CUPID (Study A, B and C). An adverse event was reported in one adolescent treated with Dupixent. 

Long-term safety 

Atopic dermatitis 

The safety profile of dupilumab + TCS (CHRONOS) in adult atopic dermatitis patients) through week 52 was consistent with the safety profile observed at week 16. The long-term safety of dupilumab was assessed in an open-label extension study in patients 6 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526 and AD-1652 studies. The longterm safety profile of dupilumab observed in children and adolescents was consistent with that seen in adults with atopic dermatitis. 

In a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mg weekly dosing (99.7 %), including 179 who completed at least 260 weeks of the study. The long-term safety profile observed in this study up to 5 years was generally consistent with the safety profile of dupilumab observed in controlled studies. 

Asthma 

The safety profile of dupilumab in the 96 weeks long term safety study (TRAVERSE) was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment. 

The safety profile of dupilumab in children with asthma 6 to 11 years of age who participated in the 52 weeks long-term safety study (EXCURSION) was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment. 

CRSwNP 

The safety profile of dupilumab in adults with CRSwNP through week 52 was consistent with the safety profile observed at week 24. 

Eosinophilic esophagitis

The safety profile of dupilumab through week 52 in adult and adolescent patients 12 years of age and older (TREET Part C) was generally consistent with the safety profile observed at week 24 in TREET Parts A and B  

Reporting of suspected adverse reactions 

To report any side effect(s):

There is no specific treatment for dupilumab overdose. In the event of overdose, the patient should be monitored for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. 

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH05

Mechanism of action 

Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, and CRSwNP. PN, EOE, COPD and CSU. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.  

Pharmacodynamic effects 

In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment in adults and adolescents with atopic dermatitis. 

In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin, the type 2 biomarkers evaluated in clinical trials. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. In paediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of total IgE, allergen specific IgE, and TARC, the type 2 biomarkers evaluated in clinical trials. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment. 

Similar to other Dupilumab indications and consistent with inhibition of IL-4 and IL-13 signaling, a continuous decline in total IgE was observed in CSU trials. 

In COPD patients, Dupilumab treatment decreased type 2 biomarkers including FeNO, and total IgE compared to placebo.  Decreases in FeNO were observed by Week 4. These effects on type 2 biomarkers were sustained throughout treatment with Dupilumab. 

Clinical efficacy and safety in atopic dermatitis  

Adults with atopic dermatitis 

The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥ 3, an Eczema Area and 

Severity Index (EASI) score ≥ 16, and a minimum body surface area (BSA) involvement of ≥ 10 %. 

Eligible patients enrolled into the three studies had previous inadequate response to topical medication. 

In all three studies, patients received dupilumab subcutaneous (SC) injections administered as 1) an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg once every two weeks (Q2W); or 2) an initial dose of 600 mg dupilumab on day 1, followed by 300 mg once weekly (QW); or 3) matching placebo. If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment (which included higher potency topical steroids or systemic immunosuppressants) at the discretion of the investigator. Patients who received rescue treatment were considered non-responders. 

Endpoints 

In all three pivotal studies, the co-primary endpoints were the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 IGA scale and the proportion of patients with improvement of at least 75 % in EASI (EASI-75). Key secondary and other clinically relevant secondary endpoints are presented in Table 5. 

Baseline Characteristics 

In the monotherapy studies (SOLO 1 and SOLO 2), across all treatment groups, the mean age was 

38.3, the mean weight was 76.9 kg, 42.1 % were female, 68.1 % were white, 21.8 % were Asian, and 

6.8 % were black. In these studies, 51.6 % of patients had a baseline IGA score of 3 (moderate AD), 48.3 % of patients had a baseline IGA of 4 (severe AD) and 32.4 % of patients had received prior systemic immunosuppressants. The baseline mean EASI score was 33.0, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.4, the baseline mean POEM score was 20.5, the baseline mean DLQI was 15.0, and the baseline mean HADS total score was 13.3. 

In the concomitant TCS study (CHRONOS), across all treatment groups, the mean age was 37.1, the mean weight was 74.5 kg, 39.7 % were female, 66.2 % were white, 27.2 % were Asian, and 4.6 % were black. In this study, 53.1 % of patients had a baseline IGA score of 3 and 46.9 % of patients had a baseline IGA of 4 and 33.6 % of patients received prior systemic immunosuppressants. The baseline mean EASI score was 32.5, the baseline weekly pruritus NRS was 7.3, the baseline mean POEM score was 20.1, the baseline mean DLQI was 14.5, and the baseline mean HADS total score was 12.7. 

Clinical Response  

16-week monotherapy studies (SOLO 1 and SOLO 2) and 52-week concomitant TCS study (CHRONOS) 

In SOLO 1, SOLO 2, and CHRONOS from baseline to week 16, a significantly greater proportion of patients randomised to dupilumab achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of > 4 points on the pruritus NRS (key secondary endpoint) compared to placebo (see Table 5). 

A significantly greater proportion of patients randomised to dupilumab alone or with TCS achieved a rapid improvement in the pruritus NRS compared to placebo or placebo + TCS (defined as ≥ 4-point improvement as early as week 2, p < 0.01 and p < 0.05, respectively). 

A persistent treatment effect of dupilumab was observed in the CHRONOS study up to week 52 (see Table 5). 

The efficacy results for co-primary, key secondary and other clinically relevant secondary endpoints for all three studies are presented in Table 5. 

Table 5: Efficacy results of dupilumab monotherapy at week 16 (FAS) and with concomitant TCS^a at week 16 and week 52  

LS = least squares; SE= standard error  

^aall patients were on background topical corticosteroids therapy and patients were permitted to use topical

calcineurin inhibitors.

^bfull analysis set (FAS) includes all patients randomised.  

^cresponder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of > 2 points on a 0-4 IGA scale.

^dpatients who received rescue treatment or with missing data were considered as nonresponders.

^ethe number of patients with baseline pruritus NRS ≥ 4 as denominator.  

^fa significantly greater proportion of patients on dupilumab had improvement in pruritus NRS of ≥ 4 points compared to placebo at week 2 (p < 0.01).

^gp-value < 0.0001, statistically significant vs placebo with adjustment for multiplicity.  

^hfull analysis set (FAS) includes all patients randomised. FAS week 52 includes all patients randomised at least

one year before the cutoff date of the primary analysis.

ⁱnominal p-value = 0.0005

^jnominal p-value < 0.0001  

In SOLO1, SOLO2 and CHRONOS similar results were observed in patients receiving Dupilumab 300 mg QW.  

Figure 1a and Figure 1b show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS respectively up to week 16 in SOLO1 and SOLO2. 

Figure 2a and Figure 2b show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively up to week 52 in CHRONOS. 

Figure 1: Mean percent change from baseline in EASI (Fig 1a) and in NRS (Fig 1b) in SOLO 1^a and SOLO 2^a (FAS)^b Figure 1a. SOLO 1 and SOLO 2 EASI Figure 1b. SOLO 1 and SOLO 2 NRS 

LS = least squares   

^a  In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.  

^b  Full analysis set (FAS) includes all patients randomised.  

Figure 2: Mean percent change from baseline in EASI and pruritus NRS in CHRONOS^a (FAS Week 52)^b

Figure 2a. CHRONOS EASI                                                     Figure 2b. CHRONOS NRS 

LS = least squares

^a In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.  

^b FAS week 52 includes all patients randomised at least one year before the cutoff date of the primary analysis.  

Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in SOLO 1, SOLO 2, and CHRONOS were consistent with the results in the overall study population within each of these studies. 

Clinical response in patients not adequately controlled with, intolerant to, or for whom ciclosporin treatment was inadvisable (CAFE study)  

CAFE study evaluated the efficacy of dupilumab compared to placebo during a 16-week treatment period, administered with concomitant TCS, in adult patients with AD who are not adequately controlled with, or are intolerant to, oral ciclosporin, or when this treatment is currently contraindicated or not medically advisable. 

A total of 325 patients were enrolled, with 210 patients who were previously exposed to ciclosporin and 115 patients who have never been exposed to ciclosporin because ciclosporin treatment was medically inadvisable. The mean age was 38.4 years, 38.8 % were female, the baseline mean EASI score was 33.1, the mean BSA was 55.7, the baseline weekly average pruritis NRS was 6.4, and the baseline mean DLQI was 13.8. 

Primary endpoint (proportion of patients with EASI-75) and secondary endpoints for the 16 week CAFE study are summarized in Table 6. 

Table 6: Results of the primary and secondary endpoints in CAFE study 

(all p-values < 0.0001, statistically significant vs placebo with adjustment for multiplicity.)  

In the subgroup of patients resembling the CAFE study population within the 52-week CHRONOS study, 69.6 % of dupilumab 300 mg Q2W-treated patients reached EASI-75 vs 18.0 % placebo-treated patients at week 16, and 52.4 % of dupilumab 300 mg Q2W-treated vs 18.6 % placebo-treated at week

52. In this subset, the percent change of pruritus NRS from baseline was -51.4 % vs -30.2 % at week 16 and -54.8 % vs -30.9 % at week 52, for the dupilumab 300 mg Q2W and placebo groups respectively. 

Maintenance and durability of response (SOLO CONTINUE study)  

To evaluate maintenance and durability of response, subjects treated with dupilumab for 16 weeks in 

SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomised in SOLO CONTINUE study to an additional 36-week treatment of dupilumab or placebo, for a cumulative 52week study treatment. Endpoints were assessed at weeks 51 or 52. 

The co-primary endpoints were the difference between baseline (week 0) and week 36 in percent change in EASI from SOLO 1 and SOLO 2 studies baseline and percentage of patients with EASI-75 at week 36 in patients with EASI-75 at baseline. 

Patients who continued on the same dose regimen received in the SOLO 1 and SOLO 2 studies (300 mg Q2W or 300 mg QW) showed the optimal effect in maintaining clinical response while efficacy for other dose regimens diminished in a dose-dependent manner. 

Primary and secondary endpoints for the 52-week SOLO CONTINUE study are summarized in Table 7.           

Table 7: Results of the primary and secondary endpoints in SOLO CONTINUE study 

^†p-value < 0.05, ^*p-value < 0.01, ^**p-value < 0.001, ^***p-value ≤ 0.0001 (all statistically significant vs placebo with adjustment for multiplicity.)  

In SOLO CONTINUE, a trend for increased treatment-emergent ADA positivity with increased dosing intervals was observed. Treatment-emergent ADA: QW: 1.2 %; Q2W: 4.3 %; Q4W: 6.0 %; Q8W: 11.7 %. ADA responses lasting more than 12 weeks: QW: 0.0 %; Q2W: 1.4 %; Q4W: 0.0 %; Q8W: 2.6 %. 

Quality of life/patient-reported outcomes in atopic dermatitis

In both monotherapy studies (SOLO 1 and SOLO 2), both dupilumab 300 mg Q2W and 300 mg QW groups significantly improved patient-reported symptoms and the impact of AD on sleep, anxiety and depression symptoms as measured by HADS, and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 16 weeks compared to placebo (see Table 8). 

Similarly, in the concomitant TCS study (CHRONOS), dupilumab 300 mg Q2W + TCS and dupilumab 300 mg QW + TCS improved patient-reported symptoms and the impact of AD on sleep and healthrelated quality of life as measured by POEM and DLQI total scores, respectively, at 52 weeks compared to placebo + TCS (see Table 8). 

Table 8: Additional secondary endpoint results of dupilumab monotherapy at week 16 and concomitant use of TCS at week 16 and week 52

LS = least squares; SE = standard error

^ap-value < 0.0001,^bp-value < 0.001, ^cp-value < 0.05 (all statistically significant vs placebo with adjustment for multiplicity.

^dthe number of patients with baseline pruritus DLQI, POEM, and HADS as denominator.

^enominal p-value < 0.05, ^fnominal p-value < 0.0001, ^gnominal p-value < 0.001  

In SOLO1, SOLO2 and CHRONOS similar results were observed in patients receiving Dupilumab 300 mg QW. 

Adolescents with atopic dermatitis (12 to 17 years of age)  

The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥ 3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥ 16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10 %. Eligible patients enrolled into this study had previous inadequate response to topical medication. 

Patients received dupilumab was administered by subcutaneous (SC) injections either as:1) an initial dose of 400 mg dupilumab (two 200 mg injections) on day 1, followed by 200 mg once every other week (Q2W) for patients with baseline weight of < 60 kg or an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baseline weight of ≥ 60 kg; or 2) an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or 3) matching placebo. If needed to control intolerable symptoms, patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered non-responders. 

In this study, the mean age was 14.5 years, the median weight was 59.4 kg, 41.0 % were female, 62.5 % were White, 15.1 % were Asian, and 12.0 % were Black. At baseline 46.2 % of patients had a baseline IGA score of 3 (moderate AD), 53.8 % of patients had a baseline IGA of 4 (severe AD), the mean BSA involvement was 56.5 %, and 42.4 % of patients had received prior systemic immunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) score was 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, the baseline mean Patient Oriented Eczema Measure (POEM) score was 21.0, and the baseline mean Children Dermatology Life Quality Index (CDLQI) was 13.6. Overall, 92.0 % of patients had at least one co-morbid allergic condition; 65.6 % had allergic rhinitis, 53.6 % had asthma, and 60.8 % had food allergies. 

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75 % in EASI), from baseline to week 16. 

Clinical Response  

The efficacy results at week 16 for adolescent atopic dermatitis study are presented in Table 9. 

Table 9: Efficacy results of dupilumab in the adolescent atopic dermatitis study at week 16 (FAS)

^aFull Analysis Set (FAS) includes all patients randomised.  

^bResponder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on  

a 0-4 IGA scale.  

^cPatients who received rescue treatment or with missing data were considered as non-responders (58.8 % and  

20.7 % in the placebo and dupilumab arms, respectively).

^dp–value < 0.0001 (statistically significant vs placebo with adjustment for multiplicity)

^enominal p-value < 0.0001  

A larger percentage of patients randomised to placebo needed rescue treatment (topical corticosteroids, systemic corticosteroids, or systemic non-steroidal immunosuppressants) as compared to the dupilumab group (58.8 % and 20.7 %, respectively). 

A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 4; nominal p< 0.001) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. 

The dupilumab group significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM and CDLQI scores at 16 weeks compared to placebo. 

The long-term efficacy of dupilumab in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumab was assessed in open-label extension study (AD1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustained through week 52. 

Children (6 to 11 years of age)  

The efficacy and safety of dupilumab in paediatric patients concomitantly with TCS was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1652) in 367 subjects 6 to 11 years of age, with severe AD defined by an IGA score of 4 (scale of 0 to 4), an EASI score ≥ 21 (scale of 0 to 72), and a minimum BSA involvement of ≥ 15 %. Eligible patients enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (< 30 kg; ≥ 30 kg). 

Patients in the dupilumab Q2W + TCS group with baseline weight of < 30 kg received an initial dose of 200 mg on Day 1, followed by 100 mg Q2W from week 2 to week 14, and patients with baseline weight of ≥ 30 kg received an initial dose of 400 mg on Day 1, followed by 200 mg Q2W from week 2 to week 14. Patients in the dupilumab Q4W + TCS group received an initial dose of 600 mg on Day 1, followed by 300 mg Q4W from week 4 to week 12, regardless of weight. 

In this study, the mean age was 8.5 years, the median weight was 29.8 kg, 50.1 % of patients were female, 69.2 % were White, 16.9 % were Black, and 7.6 % were Asian. At baseline, the mean BSA involvement was 57.6 %, and 16.9 % had received prior systemic non-steroidal immunosuppressants. Also, at baseline the mean EASI score was 37.9, and the weekly average of daily worst itch score was 

7.8 on a scale of 0-10, the baseline mean SCORAD score was 73.6, the baseline POEM score was 20.9, and the baseline mean CDLQI was 15.1. Overall, 91.7 % of subjects had at least one co-morbid allergic condition; 64.4 % had food allergies, 62.7 % had other allergies, 60.2 % had allergic rhinitis, and 46.7 % had asthma. 

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) at least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75 % in EASI), from baseline to week 16. 

Clinical Response  

Table 10 presents the results by baseline weight strata for the approved dose regimens. 

Table 10: Efficacy results of dupilumab with concomitant TCS in AD-1652 at week 16 (FAS)^a 

^afull Analysis Set (FAS) includes all patients randomised. ^bresponder was defined as a patient

with an IGA 0 or 1 (“clear” or “almost clear”). ^cpatients who received rescue treatment or with missing data were considered as non-responders. ^dat Day 1, patients received 600 mg of dupilumab (see section 5.2). ^eat Day 1, patients received 400 mg (baseline weight ≥ 30 kg) of dupilumab.  

^fp-value < 0.0001 (statistically significant vs placebo with adjustment for multiplicity) ^gnominal

p-values < 0.0001  

^hnominal p-value = 0.0002 

A greater proportion of patients randomised to dupilumab + TCS achieved an improvement in the peak pruritus NRS compared to placebo + TCS (defined as ≥4-point improvement at week 4).   

The dupilumab groups significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM and CDLQI scores at 16 weeks compared to placebo. 

The long-term efficacy and safety of dupilumab + TCS in paediatric patients with moderate to severe atopic dermatitis who had participated in the previous clinical trials of dupilumab + TCS was assessed in an open-label extension study (AD-1434). Efficacy data from this trial suggests that clinical benefit provided at week 16 was sustained through week 52. Some patients receiving dupilumab 300 mg Q4W + TCS showed further clinical benefit when escalated to dupilumab 200 mg Q2W + TCS. The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526 and AD-1652 studies.

Atopic Hand and Foot Dermatitis (adults and adolescents) 

The efficacy and safety of dupilumab was evaluated in a 16-week multicenter, randomized, doubleblind, parallel-group, placebo-controlled trial (AD-1924) in 133 adult and paediatric patients 12 to 17 years of age with moderate-to-severe atopic hand and foot dermatitis, defined by an IGA (hand and foot) score ≥3 (scale of 0 to 4) and a hand and foot Peak Pruritus Numeric Rating Scale (NRS) score for maximum itch intensity ≥4 (scale of 0 to 10). Eligible patients had previous inadequate response or intolerance to treatment of hand and foot dermatitis with topical AD medications. 

In AD-1924, 38% of patients were male, 80% were White, 72% of subjects had a baseline IGA (hand and foot) score of 3 (moderate atopic hand and foot dermatitis), and 28% of patients had a baseline IGA (hand and foot) score of 4 (severe atopic hand and foot dermatitis). The baseline weekly averaged hand and foot Peak Pruritus NRS score was 7.1.  

The primary endpoint was the proportion of patients with an IGA hand and foot score of 0 (clear) or 1 (almost clear) at Week 16. The key secondary endpoint was reduction of itch as measured by the hand and foot Peak Pruritus NRS (≥4-point improvement). Other patient reported outcomes included assessment of hand and foot skin pain NRS (0-10), quality of sleep NRS (0-10), quality of life in Hand Eczema Questionnaire (0-117) (QoLHEQ) and work productivity and impairment (WPAI) (0-100%).  

The proportion of patients with an IGA (hand and foot) 0 to 1 at Week 16 was 40.3% for dupilumab and 16.7% for placebo (treatment difference 23.6, 95% CI: 8.84, 38.42). The proportion of patients with improvement (reduction) of weekly averaged hand and foot Peak Pruritus NRS ≥4 at Week 16 was 52.2% for dupilumab and 13.6% for placebo (treatment difference 38.6, 95% CI: 24.06, 53.15).  Greater improvements for hand and foot skin pain NRS, quality of sleep NRS, QoLHEQ score and WPAI overall work impairment and routine activity impairment from baseline to week 16 were seen in the dupilumab group as compared to the placebo group (LS mean change of dupilumab vs placebo:

4.66 vs -1.93 [p < 0.0001], 0.88 vs -0.00 [p < 0.05], -40.28 vs -16.18 [p < 0.0001], -38.57% vs -

22.83% [nominal p<0.001] and -36.39% vs -21.26% [nominal p < 0.001] respectively). 

Clinical efficacy and safety in asthma  

The asthma development program included three randomised, double-blind, placebo-controlled, parallel-group, multi-centre studies (DRI12544, QUEST, and VENTURE) of 24 to 52 weeks in treatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients were enrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatory biomarkers (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation as eosinophilia ≥ 150 cells/mcL and/or FeNO ≥ 20 ppb. In DRI12544 and QUEST, the pre-specified subgroup analyses included blood eosinophils ≥ 150 and ≥ 300 cells/mcL, FeNO ≥ 25 and ≥ 50 ppb.  

DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupilumab compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium-to-high dose inhaled corticosteroid and a long-acting beta agonist. The primary endpoint was change from baseline to week 12 in FEV₁ (L). Annualised rate of severe asthma exacerbation events during the 24-week placebo-controlled treatment period was also determined. Results were evaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophil count. 

QUEST was a 52-week confirmatory study which included 1,902 patients (12 years of age and older). Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller medication. Patients requiring a third controller were allowed to participate in this trial. The primary endpoints were the annualised rate of severe exacerbation events during the 52-week placebo-controlled period and change from baseline in pre-bronchodilator FEV₁ at week 12 in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophil count and FeNO.  

VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. The OCS dose was optimized during the screening period. Patients continued to receive their existing asthma medicine during the study; however, their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oral corticosteroid dose. 

The demographics and baseline characteristics of these 3 studies are provided in Table 11 below. 

Table 11: Demographics and baseline characteristics of asthma trials

ICS = inhaled corticosteroid; FEV₁ = Forced expiratory volume in 1 second; ACQ-5 = Asthma Control Questionnaire-5; AQLQ = Asthma Quality of Life Questionnaire; AD = atopic dermatitis; NP = nasal polyposis; AR = allergic rhinitis; FeNO = fraction of exhaled nitric oxide; EOS = blood eosinophil ^athe population in dupilumab asthma trials included patients on medium and high dose ICS. The medium ICS dose was defined as equal to 500 mcg fluticasone or equivalent per day.  

Exacerbations  

In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 12 and Table 13 ). 

Table 12: Rate of severe exacerbations in DRI12544 and QUEST (baseline blood eosinophil levels ≥ 150 and ≥ 300 cells/mcL)

^ap-value = 0.0003, ^bp-value = 0.0001, ^cp-value = 0.0116, ^dp-value = 0.0024, ^ep-value < 0.0001 (all statistically

significant vs placebo with adjustment for multiplicity); ^fnominal p-value < 0.0001  

Table 13: Rate of severe exacerbations in QUEST defined by baseline FeNO subgroups

^anominal p-value < 0.0001  

In the pooled analysis of DRI12544 and QUEST, hospitalisations and/or emergency room visits due to severe exacerbations were reduced by 25.5 % and 46.9 % with dupilumab 200 mg or 300 mg every other week, respectively. 

Lung function  

Clinically significant increases in pre-bronchodilator FEV₁ were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV₁ in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 11 and Table 12 ). 

Significant improvements in FEV₁ were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 3). 

Figure 3: Mean change from baseline in pre-bronchodilator FEV₁ (L) over time (baseline eosinophils ≥ 150 and ≥ 300 cells/mcL and FeNO ≥ 25 ppb) in QUEST  

Table 14: Mean change from baseline in pre-bronchodilator FEV₁ at week 12 in DRI12544 and QUEST (baseline blood eosinophil Levels ≥ 150 and ≥ 300 cells/mcL)

^ap-value < 0.0001, ^bp-value = 0.0004, ^cp-value = 0.0008, ^dp-value = 0.0063, ^ep-value < 0.0001 (all statistically

significant vs placebo with adjustment for multiplicity); ^fnominal p-value < 0.0001  

Table 15: Mean change from baseline in pre-bronchodilator FEV₁ at week 12 and week 52 in QUEST by baseline FeNO subgroups

^anominal p-value < 0.0001  

Quality of life/patient-reported outcomes in asthma  

Pre-specified secondary endpoint of ACQ-5 and AQLQ(S) responder rates were analysed at 24 weeks (DRI12544 and VENTURE) and at 52 weeks (QUEST, Table 16). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)).

Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in VENTURE.

Table 16: ACQ-5 and AQLQ(S) responder rates at week 52 in QUEST

Oral corticosteroid reduction study (VENTURE)  

VENTURE evaluated the effect of dupilumab on reducing the use of maintenance oral corticosteroids.  Baseline characteristics are presented in Table 11. All patients were on oral corticosteroids for at least 6 months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab. 

In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were reduced by 59 % in subjects receiving dupilumab compared with those receiving placebo (annualised rate 0.65 and 1.60 for the dupilumab and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV₁ from baseline to week 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS mean difference for dupilumab versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function, on oral steroid and exacerbation reduction were similar irrespective of baseline levels of type 2 inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.

The results for VENTURE by baseline biomarkers are presented in the Table 17. 

Table 17: Effect of dupilumab on OCS dose reduction, VENTURE (baseline blood eosinophil levels ≥ 150 and ≥ 300 cells/mcL and FeNO ≥ 25 ppb)

 ^amodel estimates by logistic regression, ^bnominal p-value < 0.0001, ^cnominal p-value = 0.0001, ^dnominal p-value = 0.0002  

Long-term extension study (TRAVERSE)  

The long-term safety of dupilumab in 2,193 adults and 89 adolescents with moderate-to severe asthma, including 185 adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of dupilumab (DRI12544, QUEST, and VENTURE), was assessed in the open-label extension study (TRAVERSE) (see section 4.8). Efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks. In the adults with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and improvement in lung function up to 96 weeks, despite decrease or discontinuation of oral corticosteroid dose. 

Paediatric study (6 to 11 years of age; VOYAGE)  

The efficacy and safety of dupilumab in paediatric patients was evaluated in a 52-week multicentre, randomised, double-blind, placebo-controlled study (VOYAGE) in 408 patients 6 to 11 years of age, with moderate-to-severe asthma on a medium- or high- dose ICS and one controller medication or high dose ICS alone. Patients were randomised to dupilumab (N=273) or matching placebo (N=135) every other week based on body weight ≤ 30 kg or > 30 kg, respectively. The efficacy was evaluated in populations with type 2 inflammation defined as blood eosinophil levels of ≥ 150 cells/mcL or FeNO ≥ 20 ppb. 

The primary endpoint was the annualised rate of severe exacerbation events during the 52-week placebo-controlled period and the key secondary endpoint was the change from baseline in prebronchodilator FEV₁ percent predicted at week 12. Additional secondary endpoints included mean change from baseline and responder rates in the ACQ-7-IA and PAQLQ(S)-IA scores. 

The demographics and baseline characteristics for VOYAGE are provided in Table 18 below. 

Table 18. Demographics and baseline characteristics for VOYAGE

ICS = inhaled corticosteroid; FEV₁ = Forced expiratory volume in 1 second; ACQ-7-IA = Asthma Control Questionnaire-7 Interviewer Administered; PAQLQ(S)-IA = Paediatric Asthma Quality of Life Questionnaire with Standardised Activities–Interviewer Administered; AD = atopic dermatitis; AR = allergic rhinitis; EOS = blood eosinophil; FeNO = fraction of exhaled nitric oxide   

Dupilumab significantly reduced the annualised rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in the population with the type 2 inflammation and in population defined by baseline blood eosinophils ≥ 300 cells/mcL or by baseline FeNO ≥ 20 ppb. Clinically significant improvements in percent predicted pre-bronchodilator FEV₁ were observed at week 12. Improvements were also observed for ACQ-7-IA and PAQLQ(S)-IA at week 24 and were sustained at week 52. Greater responder rates were observed for ACQ-7-IA and PAQLQ(S)-IA compared to placebo at week 24. The efficacy results for VOYAGE are presented in Table 19. 

In the population with the type 2 inflammation, the LS mean change from baseline in prebronchodilator FEV₁ at week 12 was 0.22 L in the dupilumab group and 0.12 L in the placebo group, with an LS mean difference versus placebo of 0.10 L (95% CI: 0.04, 0.16). The treatment effect was sustained over the 52-week treatment period, with an LS mean difference versus placebo at week 52 of 0.17 L (95% CI:

0.09, 0.24).

In the population defined by baseline blood eosinophils ≥ 300 cells/mcL, the LS mean change from baseline in pre-bronchodilator FEV₁ at week 12 was 0.22 L in the dupilumab group and 0.12 L in the placebo group, with an LS mean difference versus placebo of 0.10 L (95% CI: 0.03, 0.17). The treatment effect was sustained over the 52-week treatment period, with an LS mean difference versus placebo at week 52 of 0.17 L (95% CI: 0.09, 0.26). 

In both primary efficacy populations, there was a rapid improvement in FEF25-75% and FEV₁/FVC (onset of a difference was observed as early as week 2) and sustained over the 52-week treatment period, see Table 19.  

Table 19: Rate of severe exacerbations, mean change from baseline in FEV₁, ACQ-7-IA and PAQLQ(S)-IA responder rates in VOYAGE

^athe responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-7-IA and 1-7 for PAQLQ(S))

^bp-value < 0.0001; ^cp-value < 0.001, ^dp-value < 0.01 (all statistically significant vs placebo with adjustment for multiplicity); ^enominal p-value < 0.0001, ^fnominal p-value < 0.01, ^gnominal p-value < 0.05

Significant improvements in percent predicted FEV1 were observed as early as week 2 and were maintained through week 52 in VOYAGE study. 

Improvements in percent predicted FEV₁ over time in VOYAGE are shown in Figure 4.   

Figure 4: Mean change from baseline in percent predicted pre-bronchodilator FEV₁ (L) over time in VOYAGE (baseline blood eosinophils ≥ 150 cells/mcL or FeNO ≥ 20 ppb, baseline eosinophils ≥ 300 cells/mcL, and baseline FeNO ≥ 20 ppb)

systemic corticosteroid courses due to asthma was reduced by 59.3% versus placebo (0.350 [95% CI:

0.256, 0.477] versus 0.860 [95% CI: 0.616, 1.200]). In the population defined by baseline blood

eosinophils ≥ 300 cells/mcL, the mean annualised total number of systemic corticosteroid courses due to asthma was reduced by 66.0% versus placebo (0.274 [95% CI: 0.188, 0.399] versus 0.806 [95% CI: 

0.563, 1.154]). 

Dupilumab improved the overall health status as measured by the European Quality of Life 5Dimension Youth Visual Analog Scale (EQ-VAS) in both the type 2 inflammation and the baseline blood eosinophil count of ≥ 300 cells/mcL populations at week 52; the LS mean difference versus placebo was 4.73 (95% CI: 1.18, 8.28), and 3.38 (95% CI: -0.66, 7.43), respectively. 

Dupilumab reduced the impact of paediatric patient’s asthma on the caregiver quality of life as measured by the Paediatric Asthma Quality of Life Questionnaire (PACQLQ) in both the type 2 inflammation and the baseline blood eosinophil count of ≥ 300 cells/mcL population at week 52; the LS mean difference versus placebo was 0.47 (95% CI: 0.22, 0.72), and 0.50 (95% CI: 0.21, 0.79), respectively. 

Long-term extension study (EXCURSION)  

The efficacy of dupilumab, measured as a secondary endpoint, was assessed in 365 paediatric asthma patients (6 to 11 years of age) in the long-term extension study (EXCURSION). There were sustained reductions in exacerbations requiring hospitalization and/or emergency room visits and a reduction in exposure to systemic oral corticosteroids. Sustained improvements in lung function were observed across multiple parameters including percent predicted FEV1, percent predicted FVC, FEV1/FVC ratio and percent predicted FEF 25-75%. Furthermore, 75% of patients achieved and/or maintained normal lung function with pre-bronchodilator percent predicted FEV1 > 80% by the end of 

EXCURSION. Efficacy was sustained for a cumulative treatment duration of up to 104 weeks (VOYAGE and EXCURSION). 

Clinical efficacy in chronic rhinosinusitis with nasal polyposis (CRSwNP) 

The chronic rhinosinusitis with nasal polyposis (CRSwNP) development program included two randomised, double-blind, parallel-group, multicentre, placebo-controlled studies (SINUS-24 and SINUS-52) in 724 patients aged 18 years and older on background intranasal corticosteroids (INCS). These studies included patients with severe CRSwNP despite prior sino-nasal surgery or treatment with, or who were ineligible to receive, systemic corticosteroids in the past 2 years. Rescue with systemic corticosteroids or surgery was allowed during the studies at the investigator’s discretion All patients had evidence of sinus opacification on the Lund MacKay (LMK) sinus CT scan and 73 % to 90 % of patients had opacification of all sinuses. Patients were stratified based on their histories of prior surgery and co-morbid asthma/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD). 

The co-primary efficacy endpoints were change from baseline to week 24 in bilateral endoscopic nasal polyps score (NPS) as graded by central blinded readers, and change from baseline to week 24 in nasal congestion/obstruction score averaged over 28 days (NC), as determined by patients using a daily diary. For NPS, polyps on each side of the nose were graded on a categorical scale (0=no polyps; 1=small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2=polyps reaching below the lower border of the middle turbinate; 3=large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; 4=large polyps causing complete obstruction of the inferior nasal cavity). The total score was the sum of the right and left scores. Nasal congestion was rated daily by the subjects on a 0 to 3 categorical severity scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms). 

The demographics and baseline characteristics of these 2 studies are provided in Table 20 below. 

Table 20: Demographics and baseline characteristics of CRSwNP studies

^ahigher scores indicate greater disease severity except UPSIT where higher scores indicate lower disease severity; SD=standard deviation; AM = morning; NPS = nasal polyps score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal Outcome Test; VAS = visual analogue scale; FEV₁ = Forced expiratory volume in 1 second; ACQ-6 = Asthma Control Questionnaire-6; NSAID-ERD= aspirin/nonsteroidal anti-inflammatory drug exacerbated respiratory disease

Clinical Response (SINUS-24 and SINUS-52)   

The results for primary and secondary endpoints in CRSwNP studies are presented in the Table 21   

Table 21: Results of the primary and secondary endpoints in CRSwNP trials

A reduction in score indicates improvement, except UPSIT where an increase indicates improvement.  

Total symptom score is a composite severity score consisting of the sum of daily symptoms of NC, loss of smell, and anterior/posterior rhinorrhoea. NC = nasal congestion, NPS = nasal polyposis score; LMK = Lund-MacKay total CT score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal  

Outcome Test; TSS = total symptom score; VAS = visual analogue scale for rhinosinusitis  

(all p-values < 0.0001 (all statistically significant vs placebo with adjustment for multiplicity); nominal for VAS)  

The results of SINUS-52 study at week 52 are presented in Table 22.  

Table 22: Results of the efficacy at week 52 in SINUS-52 study

A reduction in score indicates improvement, except UPSIT where an increase indicates improvement.  

Total symptom score is a composite severity score consisting of the sum of daily symptoms of NC, loss of smell, and anterior/posterior rhinorrhoea.

NC = nasal congestion, NPS = nasal polyposis score; LMK = Lund-MacKay total CT score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal  

Outcome Test; TSS = total symptom score; VAS = visual analogue scale for rhinosinusitis  

(^ap-value < 0.0001 (all statistically significant vs placebo with adjustment for multiplicity); ^bnominal pvalue <0.0001  

Statistically significant and clinically meaningful efficacy was observed in SINUS-24 with regard to improvement in bilateral endoscopic NPS score at week 24. In the post-treatment period when patients were off dupilumab, the treatment effect diminished over time (see Figure 5a). Similar results were also seen in SINUS-52 at both week 24 and week 52 with a progressive improvement over time (see Figure 5b). 

Figure 5. LS mean change from baseline in bilateral nasal polyps score (NPS) in SINUS-24 and SINUS-52 - ITT population.

In both studies, significant improvements in NC and daily loss of smell severity were observed as early as the first assessment at week 4. The LS mean difference for NC at week 4 in the dupilumab group versus placebo was -0.41 (95% CI: -0.52, -0.30) in SINUS-24 and -0.37 (95% CI: -0.46, -0.27) in SINUS-52. The LS mean difference for loss of smell at week 4 in the dupilumab group versus placebo was -0.34 (95% CI: -0.44, -0.25) in SINUS-24 and -0.31 (95% CI: -0.41, -0.22) in SINUS-52. A reduction in the proportion of patients with anosmia was observed in SINUS-24 and SINUS-52. At baseline, 74 % to 79 % of patients had anosmia, which was reduced to 24 % in SINUS-24 and 30 % in SINUS-52 at week 24, compared to no change in placebo. Improvement in nasal peak inspiratory flow

(NPIF) was observed in SINUS-24 and SINUS-52 at week 24. The LS mean difference in the dupilumab group versus placebo was 40.4 L/min (95% CI: 30.4, 50.4) and 36.6 L/min (95% CI: 28.0, 45.3), respectively. 

Among the patients with rhinosinusitis VAS score > 7 at baseline, a higher percentage of patients achieved VAS ≤ 7 in the dupilumab group compared with the placebo group (83.3 % versus 39.4 % in SINUS-24 and 75.0 % versus 39.3 % in SINUS-52) at week 24. 

In the pre-specified multiplicity-adjusted pooled analysis of two studies, treatment with dupilumab resulted in significant reduction of systemic corticosteroid use and need for sino-nasal surgery versus placebo (HR of 0.24; 95% CI: 0.17, 0.35) (see Figure 6). The proportion of patients who required systemic corticosteroids was reduced by 74 % (HR of 0.26; 95% CI: 0.18, 0.38). The total number of systemic corticosteroid courses per year was reduced by 75 % (RR of 0.25; 95% CI: 0.17, 0.37). The mean individual annualised prescribed total dose of systemic corticosteroids (in mg) during the treatment period was 71 % lower in the pooled dupilumab group compared with the pooled placebo group (60.5 [531.3] mg versus 209.5 [497.2] mg, respectively). The proportion of patients who required surgery was reduced by 83 % (HR of 0.17; 95% CI: 0.07, 0.46). 

Figure 6. Kaplan Meier Curve for time to first systemic corticosteroid use and/or sino-nasal surgery during treatment period - ITT population [SINUS-24 and SINUS-52 pooled] 

The effects of dupilumab on the primary endpoints of NPS and nasal congestion and the key secondary endpoint of LMK sinus CT scan score were consistent in patients with prior surgery and without prior surgery. 

In patients with co-morbid asthma, significant improvements in FEV₁ and ACQ-6 were observed at week 24 irrespective of baseline blood eosinophil levels. The pooled LS Mean change from baseline in FEV₁ at week 24 for dupilumab 300 mg Q2W was 0.14 vs -0.07 L for placebo, for a difference of 0.21 L (95% CI: 0.13, 0.29). In addition, improvements in FEV₁ were noted from the first post-baseline assessment, at week 8 in SINUS-24 and week 4 in SINUS-52. Improvements in ACQ-6 in patients with co-morbid asthma were observed in both studies. A response was defined as an improvement in score of 0.5 or more. The LS mean difference in the dupilumab group versus placebo at week 24 was -0.76 (95% CI: -1.00 to -0.51) in SINUS-24 and -0.94 (95% CI: -1.19, -0.69) in SINUS-52. 

The ACQ-6 responder rate for dupilumab 300 mg Q2W for SINUS-24 at week 24 was 56 % versus 28

% in placebo (odds ratio 3.17; 95% CI: 1.65, 6.09). The ACQ-6 responder rate for dupilumab 300 mg Q2W for SINUS-52 was 46 % versus 14 % placebo at week 52 (odds ratio 7.02; 95% CI: 3.10, 15.90). 

In patients with NSAID-ERD, the effects of dupilumab on the primary endpoints of NPS and NC and the key secondary endpoint of LMK sinus CT scan score were consistent with that observed in the overall CRSwNP population. 

Clinical efficacy in prurigo nodularis (PN) 

The prurigo nodularis (PN) development program included two 24-week randomised, double-blind, placebo-controlled, multicenter, parallel-group studies (PRIME and PRIME2) in 311 patients 18 years of age and older with moderate to severe PN, defined as severe pruritus (WI-NRS ≥ 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions, whose disease was not adequately controlled with topical prescription therapies or when those therapies were not advisable. PRIME and PRIME2 assessed the effect of dupilumab on itch improvement as well as its effect on PN lesions, Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS) and skin pain.  

In these two studies, patients received either subcutaneous dupilumab 600 mg (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W) for 24 weeks, or matching placebo. 

In these studies, the mean age was 49.5 years, the median weight was 71.3 kg, 65.3% of patients were female, 56.6% were White, 6.1% were Black, and 34.1% were Asian. At baseline, the mean WI-NRS was 8.5, 66.3% had 20 to 100 nodules (moderate), 33.7% had greater than 100 nodules (severe), 99.7% received prior topical therapies, 12.5% received prior systemic corticosteroids, 20.6% received prior systemic non-steroidal immunosuppressants, and 4.5% prior gabapentinoids. Eleven percent of patients were taking stable doses of antidepressants at baseline and were instructed to continue taking these medications during the study. 43.4 % had history of atopy (defined as having a medical history of AD, allergic rhinitis/rhinoconjunctivitis, asthma, or food allergy). 

The WI-NRS is comprised of a single item, rated on a scale from 0 (“no itch”) to 10 (“worst imaginable itch”). Participants were asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The IGA PN-S is a scale that measures the approximate number of nodules using a 5-point scale from 0 (clear) to 4 (severe).  

The primary efficacy endpoint was the proportion of patients with improvement (reduction) in WI-NRS by ≥4. Key secondary endpoints included the proportion of participants with IGA PN-S 0 or 1 (the equivalent of 0-5 nodules).  

The efficacy results for PRIME and PRIME2 are presented in Table 23 and Figures 7 and 8. 

Table 23: Results of the Primary and Secondary Endpoints in PRIME and PRIME2

^a Not adjusted for multiplicity in PRIME.

^b Subjects who received rescue treatment earlier or had missing data were considered as non-responders.

^c Subjects who received rescue treatment earlier or discontinued due to lack of efficacy were imputed using worst observation carried forward; other missing data were imputed using multiple imputation.

SE = secondary endpoint

The onset of action in change from baseline in WI-NRS, defined as the first timepoint at which difference from placebo was and remained significant (nominal p<0.05) in the weekly average of daily WI-NRS, was observed as early as Week 3 in PRIME (Figure 7a) and Week 4 in PRIME2 (Figure7b).  

Figure 7. LS mean percent change from baseline in WI-NRS in PRIME and PRIME2 up to Week 24

A greater proportion of patients experienced WI-NRS improvements of ≥4 points from baseline by Weeks 4 and 11 in the dupilumab group as compared to the placebo group in PRIME (Figure 7a nominal p<0.007) and PRIME2 (Figure 7b nominal p<0.013), respectively, and this difference remained significant throughout the treatment period.

Figure 8. Proportion of patients with WI-NRS ≥4 improvement over time in PRIME and PRIME2

Treatment effects in subgroups (age, gender, with or without medical history of atopy, and background treatment, including immunosuppressants) in PRIME and PRIME2 were consistent with the results in the overall study population. 

Once treatment was discontinued after 24 weeks, there was an indication towards recurrence of signs and symptoms within the 12-week follow-up period. 

Clinical efficacy in Chronic Obstructive Pulmonary Disease (COPD) 

The chronic obstructive pulmonary disease (COPD) program included two randomized, double-blind, multicenter, parallel-group, placebo-controlled trials (BOREAS and NOTUS) of 52 weeks in treatment duration which enrolled a total of 1874 adult patients with COPD to evaluate Dupixent as add-on maintenance therapy. 

Both trials enrolled patients with a diagnosis of COPD with moderate to severe airflow limitation (post-bronchodilator FEV₁/FVC ratio <0.7 and post-bronchodilator FEV₁ of 30% to 70% predicted), chronic productive cough for at least 3 months in the past year, and evidence of type 2 inflammation defined as a minimum blood eosinophil count of 300 cells/mcL at screening. Patients were uncontrolled with a Medical Research Council (MRC) dyspnea score ≥ 2 (range 0-4) and an exacerbation history of at least 2 moderate or 1 severe exacerbation in the previous year despite receiving maintenance triple therapy consisting of a long-acting muscarinic antagonist (LAMA), longacting beta agonist (LABA), and inhaled corticosteroid (ICS). Patients were allowed to receive maintenance therapy consisting of a LAMA and LABA if an ICS was contraindicated. Exacerbations were defined as moderate severity if treatment with systemic corticosteroids and/or antibiotics was required or severe if they resulted in hospitalization or observation for over 24 hours in an emergency department or urgent care facility. 

In both trials, patients were randomized to receive Dupixent 300 mg every two weeks (Q2W) or placebo  in addition to their background maintenance therapy for 52 weeks. 

In both trials, the primary endpoint was the annualized rate of moderate or severe COPD exacerbations during the 52-week treatment period. Secondary endpoints included change from baseline in prebronchodilator FEV₁ in the overall population and in the subgroup of patients with baseline FeNO ≥ 20 ppb at Weeks 12 and 52, change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 52, the SGRQ responder rate (defined as the proportion of patients with SGRQ improvement from baseline of at least 4 points) at Week 52, and annualized rate of moderate or severe COPD exacerbations in the subgroup of patients with baseline FeNO ≥ 20 ppb during the 52-week treatment period. Other multiplicity-adjusted endpoints included the change from baseline in Evaluating Respiratory Symptoms in COPD (E-RS: COPD) total score at Week 52. The E-RS:COPD scale is used to measure severity of respiratory symptoms in COPD, with higher scores indicating greater severity (range 0-40).   

The demographics and baseline characteristics of BOREAS and NOTUS are provided in Table 24 below.  

Table 24: Demographics and Baseline Characteristics (BOREAS and NOTUS)

ICS = inhaled corticosteroid; LAMA = long acting muscarinic antagonist; LABA = long acting beta agonist, FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; FeNO = fraction of exhaled nitric oxide; BODE = body-mass index, airflow obstruction, dyspnea, exercise capacity ^a Exacerbations treated with either systemic corticosteroids and/or antibiotics ^b Exacerbations requiring hospitalization or observation for over 24 hours in an emergency department or urgent care facility

Exacerbations 

In both trials, Dupixent demonstrated a statistically significant reduction in the annualized rate of moderate or severe COPD exacerbations compared to placebo when added to background maintenance therapy (see Table 25). 

Table 25: Annualized Rate of Moderate^a or Severe^b COPD Exacerbations in BOREAS and NOTUS

^a Exacerbations treated with either systemic corticosteroids and/or antibiotics

^b Exacerbations requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting in death

^c p value = 0.0005

^d p value = 0.0002

^e Analysis of the component of the primary endpoint was not adjusted for multiplicity

In both trials, the cumulative mean number of moderate or severe exacerbations observed over 52 weeks was lower in subjects receiving Dupixent compared to placebo (see Figure 9 and 10).   

Figure 9: Cumulative Mean Number of Moderate or Severe COPD Exacerbations Over 52

Weeks in BOREAS

Figure 10: Cumulative Mean               Number of Moderate or Severe COPD Exacerbations Over 52 Weeks in NOTUS    

The time to first moderate or severe COPD exacerbation was longer for patients receiving Dupixent compared to placebo in BOREAS (HR: 0.80; 95% CI: 0.66, 0.98) and NOTUS (HR: 0.71.; 95% CI: 

0.57, 0.889).   

In the subgroup analysis of patients with a higher baseline FeNO (≥ 20 ppb) in BOREAS (N=383), treatment with Dupixent statistically significantly reduced the annualized rate of moderate or severe COPD exacerbations compared to placebo (Rate Ratio: 0.625; 95% CI: 0.45, 0.869; p=0.005). In NOTUS, treatment with Dupixent showed a nominally significant reduction in the annualized rate of moderate or severe COPD exacerbations in the subgroup of patients with a higher baseline FeNO (≥20 ppb) (N=355) compared to placebo (Rate Ratio: 0.47; 95% CI: 0.33, 0.68).  

Reductions in the annualized rate of moderate or severe exacerbations were observed across all predefined subgroups including age, gender, race, smoking status, blood eosinophil counts, number of exacerbations in previous year (≤2, 3, and ≥4), high-dose ICS at baseline, and baseline percent predicted post-bronchodilator FEV₁ (<50%, ≥50%).In patients with emphysema, reduction in the annualized rate of moderate or severe exacerbations was consistent with the overall population.  

Lung Function 

In both trials, Dupixent demonstrated a statistically significant improvement in pre-bronchodilator 

FEV₁ at Weeks 12 and 52 compared to placebo when added to background maintenance therapy (see Table 31). Greater improvements in lung function (LS mean change from baseline in pre- bronchodilator FEV₁) were observed in patients treated with Dupixent compared to placebo as early as Week 2 (BOREAS) (first assessment) and Week 4 (NOTUS) and were sustained at Week 52 (see Figure 11  and 12 ).  

In BOREAS, rapid improvements in post-bronchodilator FEV₁, post-bronchodilator FEV₁/FVC ratio, and pre-bronchodilator FVC were observed with Dupixent treatment compared to placebo as early as Week 2 (first assessment) and were maintained through Week 52. In NOTUS, rapid improvements in post-bronchodilator FEV₁ and post-bronchodilator FEV₁/FVC ratio were observed with Dupixent treatment compared to placebo as early as week 8 and week 2, respectively, and were maintained through Week 52.  

Table 26: Mean Change from Baseline for Lung Function Endpoints in BOREAS and NOTUS  

LS = least squares, SE = standard error, FEV₁ = forced expiratory volume in 1 second, FVC = forced vital capacity ^ap-value < 0.0001, ^bp-value = 0.0003 (all statistically significant vs placebo with adjustment for multiplicity) ^cnominal p-value = 0.0010, ^dnominal p-value = 0.0016 ^enominal p-value = 0.0103 ^fpvalue=0.0001, ^gp-value=0.0182 (all statistically significant vs placebo with adjustment for multiplicity) ^hnominal p-value=0.0042 ,ⁱnominal p-value=0.0020, ^jnominal p-value=0.0327 ^k Efficacy results for mean change from baseline in pre-bronchodilator FEV₁ at Week 52 are presented for 721 out of 935 patients who completed the 52-week treatment period or had discontinued the trial at the time of data analysis.  

Figure 11: Mean Change from Baseline in Pre-Bronchodilator FEV₁ (L) Over Time in BOREAS

Figure 12: Mean Change from Baseline in Pre-Bronchodilator FEV₁ (L) Over Time in NOTUS^a

^a Efficacy results for mean change from baseline in pre-bronchodilator FEV₁ over time are presented for 721 out of 935 subjects who completed the 52-week treatment period or had discontinued the trial at the time of data analysis.  

In the subgroup analysis of patients with higher baseline FeNO (≥ 20 ppb) in BOREAS (N=383), treatment with Dupixent statistically significantly improved pre-bronchodilator FEV₁ from baseline at Week 12 (LS mean change: 0.232 Dupixent vs 0.108 placebo; LS mean difference: 0.124 [95% CI: 

0.045, 0.203]; p=0.002) and Week 52 (LS mean change: 0.247 Dupixent vs 0.120 placebo; LS mean difference: 0.127 [95% CI: 0.042, 0.212]; p=0.003) compared to placebo.³ In NOTUS, statistically significant improvement from baseline was observed in the subgroup of patients with a higher baseline FeNO (≥20 ppb) treated with Dupixent compared to placebo at Week 12 (N=355; LS mean change: 

0.221 Dupixent vs 0.081 placebo; LS mean difference: 0.141 [95% CI: 0.058, 0.223]; p=0.001). 

Treatment with Dupixent improved pre-bronchodilator FEV at Week 52 in the subgroup of patients 

0.176 Dupixent vs 0.095 placebo; LS mean difference: 0.081[95% CI: -0.019, 0.181]) but did not meet statistical significance.  

Improvements in lung function as measured by pre-bronchodilator FEV₁ were observed across all predefined subgroups including age, gender, race, smoking status, blood eosinophil counts, number of exacerbations in previous year (≤2, 3, and ≥4), high-dose ICS at baseline, and baseline predicted postbronchodilator FEV₁ (<50%, ≥50%). In patients with emphysema, improvement in lung function as measured by pre-bronchodilator FEV₁ was consistent with the overall population. 

Patient reported outcomes 

In both trials, health-related quality of life was measured by LS mean change in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 52. In BOREAS, a statistically significant improvement in SGRQ total score was observed in patients treated with Dupixent compared to placebo (LS mean change: -9.73 Dupixent vs -6.37 placebo; LS mean difference: -3.36 [95% CI: -5.46, -1.27]; p=0.002).⁴ In NOTUS, Dupixent nominally improved SGRQ total score at Week 52 compared to placebo (LS mean change: -9.82 Dupixent vs -6.44 placebo; LS mean difference: -3.37 [95% CI: 5.81, -0.93]; p=0.007). Greater improvements in SGRQ total score in patients treated with Dupixent were observed as early as Week 4 in BOREAS (first assessment) and Week 12 in NOTUS and were maintained through Week 52 (see Figure 13 and 14). The responder rate was significantly greater for patients treated with Dupixent (51%) compared to placebo (43%) in BOREAS (odds ratio: 1.44; 95% CI: 1.10, 1.89). In NOTUS, the responder rate was numerically greater for patients treated with Dupixent (51%) compared to placebo (47%) but did not meet statistical significance (odds ratio: 1.16; 95% CI: 0.86, 1.58). Improvements were observed in all individual domains of Symptoms, Activity and Impacts in patients treated with Dupixent compared to placebo. 

Figure 13: Mean Change from Baseline in SGRQ Total Score Over Time in BOREAS 

Figure 14: Mean Change from Baseline in SGRQ Total Score Over Time in NOTUS 

In BOREAS, Dupixent significantly improved overall respiratory symptoms compared to placebo as measured by LS mean change from baseline in the E-RS:COPD total score at Week 52 (LS mean change: -2.69 Dupixent vs -1.56 placebo; LS mean difference: -1.14 [95% CI: -1.82, -0.45]; p=0.001). Greater improvements in overall respiratory symptoms in patients treated with Dupixent compared to placebo as measured by average weekly change from baseline in the E-RS:COPD total score were observed as early as Week 1 and were maintained through Week 52 (See Figure 15). Consistent improvements were observed across all individual E-RS: COPD domains (cough and sputum, breathlessness, and chest-related symptoms).   

In NOTUS, Dupixent improved overall respiratory symptoms compared to placebo as measured by LS mean change from baseline in the E-RS:COPD total score at Week 52 (LS mean change: -2.39 Dupixent vs -1.77 placebo; LS mean difference: -0.62 [95% CI: -1.43, 0.19]) which was not statistically significant (See Figure 16 ).  

Figure 15: Mean Change from Baseline in E-RS: COPD Total Score Over Time in BOREAS

Figure 16 : Mean Change from Baseline in E-RS: COPD Total Score Over Time in NOTUS 

Clinical efficacy in eosinophilic esophagitis (EoE) 

The eosinophilic esophagitis (EoE) development program included a three-part protocol (TREET) consisting of two separately randomised, double-blind, parallel-group, multicentre, placebo-controlled, 24-week treatment studies (TREET Part A and TREET Part B) in adult and paediatric patients 12 to 17 years of age, excluding patients <40 kg. In TREET Parts A and B, all enrolled patients had to have failed conventional medicinal therapy (proton pump inhibitors), 74% were treated with another conventional medicinal therapy (swallowed topical corticosteroids) prior to inclusion. In TREET Part B, 49% of patients were inadequately controlled, intolerant or contraindicated to swallowed topical corticosteroid treatment. In both parts, patients were required to have ≥15 intraepithelial eosinophils per high-power field (eos/hpf) following an at least 8-week course of a high-dose proton pump inhibitor (PPI) either prior to or during the screening period and a Dysphagia Symptom Questionnaire (DSQ) score ≥10 on a scale of 0 to 84. Patients were stratified based on age at the time of the screening visit (12 to 17 years of age vs. 18 years and older) and use of PPI at randomisation. TREET Part A was conducted first. TREET Part B opened after enrollment into TREET Part A was complete. Patients completing the 24 weeks of the double-blind treatment period in Parts A or B were provided an option to enroll in a 28-week active treatment extension study (TREET Part C). 

In Part A, a total of 81 patients, of which 61 were adults and 20 were paediatric patients 12 to 17 years of age, were randomised to receive either 300 mg dupilumab every week (N=42) or placebo (N=39). In Part B, a total of 240 patients, of which 161 were adults and 79 were paediatric patients 12 to 17 years of age, were randomised to receive either 300 mg dupilumab every week (N=80), 300 mg dupilumab every other week (N=81; the 300 mg every other week dosage regimen is not approved for EoE) or placebo (N=79). In Part C, all patients who previously participated in Part A received 300 mg dupilumab (N=77) every week. Of the patients who previously participated in Part B, 111 received dupilumab 300 mg every week in Part C. Rescue with systemic and/or swallowed topical corticosteroids or emergency esophageal dilation was allowed during the study at the investigator’s discretion. 

In Part A, a total of 74.1% of patients enrolled had a history of prior use of swallowed topical corticosteroids for the treatment of EoE and 43.2% had a history of prior esophageal dilation. In Part B, a total of 73.3% of patients enrolled had a history of prior use of swallowed topical corticosteroids for the treatment of EoE and 35.4% had a history of prior esophageal dilation. 

The co-primary efficacy endpoints in both trials were the proportion of patients achieving histological remission defined as peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 and the absolute change in the patient-reported DSQ score from baseline to week 24. Secondary endpoints included change from baseline in the following: percent change in peak esophageal intraepithelial eosinophil count (eos/hpf), absolute change in Mean Grade Score from the Histology Scoring System

(EoEHSS), absolute change in Mean Stage Score from the EoEHSS, absolute change in

EoEEndoscopic Reference Score (EoE-EREFS), and proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 eos/hpf. 

The demographics and baseline characteristics of TREET Parts A and B are provided in Table 27. 

Table 27: Demographics and baseline characteristics (TREET Parts A and B)

^aHigher scores indicate greater disease severity 

SD = standard deviation 

The results for TREET Parts A and B are presented in Table 28. 

Table 28: Efficacy results of dupilumab at week 24 in patients 12 years of age and older with EoE (TREET Parts A and B)

^aTotal biweekly DSQ scores range from 0 to 84; higher scores indicate greater frequency and severity of dysphagia 

^bEoEHSS scores range from 0 to 3; higher scores indicate greater severity and extent of histological 

abnormalities 

^cEoE-EREFS overall scores range from 0 to 18; higher scores indicate worse endoscopic inflammatory 

and remodeling findings 

^dLS mean difference for continuous endpoints and absolute difference in proportions for categorical endpoints 

The efficacy results for co-primary and key secondary endpoints in prior swallowed topical corticosteroids subgroup and in patients who were inadequately controlled, intolerant or contraindicated to swallowed topical corticosteroids were consistent with the overall population. 

In Parts A and B, a greater proportion of patients randomised to dupilumab achieved histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf) compared to placebo. The proportion of patients with histological remission observed after 24 weeks of treatment in Part A and B was maintained for 52 weeks in Part C. Similarly, other histological and endoscopic improvement were maintained through 52 weeks. 

Treatment with dupilumab also resulted in a significant improvement in LS mean change in DSQ score compared to placebo as early as week 4 and were maintained through week 24. Efficacy in part C was similar to results observed in Parts A and B, with a continuous improvement for DSQ up to 52 weeks (TREET  Part A and C Figure 17  and TREET Parts B and C Figure 18 ). 

Figure 17: LS mean change from baseline in DSQ score over time in patients 12 years of age and older with EoE (TREET Part A and C) 

Figure 18: Mean change from baseline in DSQ score over time in patients 12 years of age and older with EoE (TREET Parts B and C) 

Consistent with improvement in DSQ total score in TREET Parts A and B, nominally significant improvements were observed at week 24 compared to placebo in pain related to dysphagia (DSQ pain score), health-related QoL (EoE-IQ), and the frequency of other non-dysphagia symptoms (EoE-SQ).   

Clinical efficacy in Chronic Spontaneous Urticaria (CSU)  

The chronic spontaneous urticaria (CSU) development program was conducted under a master protocol (CUPID). CUPID Study A, Study B and Study C were three randomized, double-blind, parallel-group, multicenter, placebo-controlled, 24-week treatment studies in adult and pediatric patients (Study A: 6 to 17 years of age, Study B: 12 to 17 years of age and Study C: 6 to 17 years of age). Study A and Study C enrolled patients with CSU who were symptomatic despite the use of H1 antihistamines. Study B enrolled patients with CSU who were symptomatic despite the use of H1 antihistamines and were inadequate responders or intolerant to antiIgE therapy. In all three studies, Dupixent 300 mg every two weeks, Dupixent 200 mg every two weeks, or placebo were evaluated in adults and pediatric patients (12 to 17 years of age). 

CUPID Study A and Study C

CUPID Study A and CUPID Study C enrolled 289  patients of which 274  were adults, 10 were pediatric patients 12 to 17 

years of age, and 5 were pediatric patients 6 to 11 years of age, randomized to receive either Dupixent 300 mg every two weeks (N=139 ), Dupixent 200 mg every two weeks (N=5 ), or placebo (N=145 ). 

In CUPID Study A and Study C, the mean age was 43.1  years, the median weight was 73 kg, 68.2 % of patients were female, 57.1 % were White, 1.7 % were Black, 16.6% were Hispanic or Latino and 33.6 % were Asian. The mean weekly itch and urticaria activity severity scores (ISS7, UAS7) at baseline were 15.5  and 29.8 , respectively, despite use of an H1 antihistamine. Majority of patients (64.7 %) had severe CSU disease activity at baseline with a UAS7 score of ≥28. The mean baseline UCT was 4.5 , corresponding to uncontrolled urticaria (UCT <12). The reported mean duration of CSU at enrollment across treatment groups was 6.1  years (with an overall subject-level range of 1 to 60 years).  

The primary efficacy endpoint was change from baseline in itch severity score over 7 days (ISS7) at Week 24. The ISS7 score was defined as the sum of the daily itch severity scores (ISS) recorded at the same time of the day for a 7-day period, ranging from 0 to 21. 

The key secondary endpoint was change from baseline in urticaria activity score over 7 days (UAS7) at Week 24. Disease severity was measured by a weekly urticaria activity score (UAS7, range 0–42), which is a composite of the weekly itch severity score (ISS7, range 0–21) and the weekly hive count score (HSS7 range 0–21). Additional secondary endpoints included the change from baseline in hives severity score over 7 days (HSS7) and the urticaria control test (UCT) at Week 12 and Week 24. The UCT is a measure for assessing urticaria control based on 4 assessment elements (severity of urticaria symptom, frequency of treatment being not sufficient, quality-of-life impairment, and overall urticarial control), with a score ranging from 0 to 16.  

The demographics and baseline characteristics of CUPID Study A are provided in Table 29 below.

Table 29: Demographics and Baseline Characteristics of CUPID Study A and Study C

The results for primary and secondary endpoints in CUPID Study A and Study C are presented in the Table 30. 

Dupixent treatment led to an improvement over time in ISS7 and UAS7 through the 24week treatment period (Figures 19 and 20).  

Figure 19: LS mean change from baseline in ISS7 up to Week 24 in CUPID Study A and Study C- ITT population 

Study C 

Figure 20: LS mean change from baseline in UAS7 up to Week 24 in CUPID Study A and Study C- ITT population 

Study C 

Similar improvement in HSS7 was observed over 24 weeks. 

Improvements in ISS7 and UAS7 at Week 24 were consistent regardless of the patients’ baseline IgE. 

Dupixent improved overall disease control compared to placebo as measured by UCT (higher score reflects greater disease control) at Week 24 (LS mean difference versus placebo of 2.84 [95% CI: 1.27:  4.40]) in Study A and 0.93 [95% CI: -0.48, 2.34] in Study C)  and at Week 12 (LS mean difference versus placebo of 1.86 [95% CI: 0.35: 3.36].  

Study A showed statistically significant improvement in ISS7 and UAS7 from baseline at Week 12 (LS mean difference versus placebo of -2.37 [95% CI: (-4.60, -0.13) for ISS7 and -5.02 [95% CI: (-9.32, 0.72)] for UAS7 respectively. Study C showed numerical differences in ISS7 and UAS7 from baseline at Week 12 (LS mean difference versus placebo of -1.84 [95% CI: (-3.78, 0.10)] for ISS7 and -3.36 [95% CI: (-7.07, 0.36)] for UAS7.The proportion of patients with UAS7 ≤6 at Week 12 was 34.3% and 31.1% for

Dupixent and 17.6% and 16.9% for placebo [Odds Ratio: Study A: 2.645 [95% CI: (1.154, 6.061); Study

C: 2.676 [95% CI:(1.169, 6.125)] for Study A and C respectively

CUPID Study B 

CUPID Study B evaluated the efficacy of Dupixent in patients with CSU who are inadequate responders (N=104) or intolerant (N=4) to anti-IgE therapy. This study enrolled 108 patients 12 years of age and older, and had same efficacy endpoints as Study A and Study C. Dupixent did not meet statistical significance for reduction in the primary endpoint ISS7 at Week 24 (Dupixent -7.68, placebo -4.81, treatment difference, -2.87), but demonstrated nominally significant improvements for secondary endpoints UAS7 and HSS7 at Week 24 (UAS7: Dupixent -14.37, placebo -8.54, treatment difference 5.83; HSS7: Dupixent -6.64, placebo -3.63, treatment difference -3.01).  

Paediatric population 

Atopic dermatitis  

The safety and efficacy of dupilumab have been established in 12 to 17 years old with moderatetosevere atopic dermatitis in study AD-1526 which included 251 adolescents. The safety and efficacy of dupilumab have been established in 6 to 11 years old with severe atopic dermatitis in study AD-1652 which included 367 paediatric patients. Use is supported by study AD-1434 which enrolled patients who had completed AD-1526 (136 moderate and 64 severe at the time of enrolment in study AD1434) and patients who had completed study AD-1652 (110 moderate and 72 severe at the time of enrolment in in study AD-1434). The safety and efficacy were generally consistent between children 6 to 11 years old, adolescent, and adult patients with atopic dermatitis (see section 4.8). Safety and efficacy in paediatric patients < 6 years of age with atopic dermatitis have not been established. 

Asthma 

A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant improvements in FEV₁ (LS mean change from baseline at week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults. The safety profile in adolescents was generally similar to the adults. 

A total of 89 adolescents aged 12 to 17 years with moderate-to-severe asthma were enrolled in the open label long-term study (TRAVERSE). In this study, efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks.  

A total of 408 children aged 6 to 11 years with moderate-to-severe asthma was enrolled in the

VOYAGE study, which evaluated doses of 100 mg Q2W and 200 mg Q2W. The efficacy of dupilumab

300 mg Q4W in children aged 6 to 11 years is extrapolated from the efficacy of 100 mg and 200 mg Q2W in VOYAGE and 200 mg and 300 mg Q2W in adults and adolescents (QUEST). Patients who completed the treatment period of the VOYAGE study could participate in the open label extension study (EXCURSION). Eighteen patients (≥ 15 kg to < 30 kg) out of 365 patients were exposed to 300 mg Q4W in this study, and the safety profile was similar to that seen in VOYAGE. Safety and efficacy in paediatric patients < 6 years of age with asthma have not been established. 

The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in atopic dermatitis and asthma (see section 4.2 for information on paediatric use). The European Medicines Agency has waived the obligation to submit the results of studies with dupilumab in all subsets of the paediatric population in the treatment of nasal polyposis (see section 4.2 for information on paediatric use). 

The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in paediatric patients 12 years of age and older, weighing at least 40 kg. Use of DUPIXENT in this population is supported by an adequate and well-controlled study in adults (Parts A and B) which included 72 paediatric patients 12 to 17 years of age, weighing at least 40 kg, and additional pharmacokinetic data. The safety and effectiveness in adults and paediatric patients were similar   

The safety and effectiveness of DUPIXENT for the treatment of EoE in paediatric patients less than 12 years of age and weighing less than 40 kg have not been established. 

Chronic Spontaneous Urticaria 

The safety and effectiveness of Dupixent for the treatment of CSU have been established in pediatric subjects 12 year of age and older. A total of 12 adolescents aged 12 to 17 years and 5 children aged 6 to 11 years with CSU were enrolled in CUPID Study A, B and C, who received doses of Dupilumab 200 mg Q2W (30 kg to <60 kg), 300 mg Q2W (≥60 kg) or placebo. Two children 6 to 11 years of age (both in the Dupilumab group), discontinued study treatment early (Week 4 and Week 10) and two adolescents aged 12 to 17 years of age (one in each treatment group) discontinued study treatment early (Week 12 and Week 22). An adverse event was reported in one adolescent treated with Dupilumab. No adverse events were reported in children aged 6 to 11 years treated with Dupixent. The effectiveness of Dupilumab for the treatment of CSU in pediatric patients 12 to 17 years of age is based on safety and efficacy in adults with this condition due to the similarity of pathophysiology, disease course, response to available therapies, and consistent dupilumab exposure established through PK modeling. Safety for Dupilumab in pediatric patients 12 to 17 years of age with CSU is supported by available safety information from the pediatric AD indication.  The recommended dosage in pediatric patients 12 years of age or older is based on body weight.CSU is supported by available safety information from the pediatric AD indication.  The recommended dosage in pediatric patients 12 years of age or older is based on body weight. 

Safety and effectiveness in pediatric patients younger than 12 years of age with CSU have not been established.

Prurigo Nodularis 

Safety and effectiveness in paediatric patients younger than 18 years of age with PN have not been established.

The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis, asthma, and CRSwNP. 

Absorption 

After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximum concentration in serum (t_max) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, and CRSwNP, PN, COPD, EoE and CSU patients, ranging between 61 % and 64 %, as determined by a population pharmacokinetics (PK) analysis. 

Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week or 300 mg dose every other week without a loading dose. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 

55.3±34.3 mcg/mL to 81.5±43.9 mcg/mL for 300 mg administered Q2W,from 172±76.6 to 195±71.7 mcg/mL for 300mg dose administered weekly, and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg administered Q2W. 

Distribution 

A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system. 

Biotransformation 

Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids. 

Elimination 

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates. After the last steady state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, ranged from 9-13 weeks in adults and adolescents and are approximately 1.5 times and 2.5 times longer in paediatric patients 6 to 11 years of age and paediatric patients less than 6 years of age, respectively .  

Linearity/non-linearity 

Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75600 mg. 

Special populations 

Gender  

Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. 

Elderly  

Of the 1,539 patients with atopic dermatitis including patients with atopic hand and foot dermatitis exposed to dupilumab in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 71were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. 

Age was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. However, there were only 61 patients over 65 years of age included in this analysis. 

Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population. 

There were only 79 patients older than 65 years with CRSwNP exposed to dupilumab among them 11 patients were 75 years and older. 

Of the 152 patients with PN exposed to dupilumab, a total of 37 were 65 years of age or older. A total of 8 patients were 75 years of age or older. Efficacy and safety in these age groups were similar to the overall study population. 

There were only 2 patients older than 65 years with EoE exposed to dupilumab. 

Of the 1872 patients with COPD exposed to DUPIXENT, a total of 1071 were 65 years or older including 244 subjects 75 years or older. Efficacy and safety in this age group were similar to the overall study population 

Of the 198 patients with CSU exposed to Dupixent, a total of 30 were 65 years of age and older including 7 patients 75 years of age and older. Efficacy and safety in this age group were similar to the overall study population. 

Race  

Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis. 

Hepatic impairment  

Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab. 

Renal impairment  

Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very limited data are available in patients with severe renal impairment. 

Body weight  

Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy. There were only 6 patients exposed to dupilumab with body weight ≥130 kg in CRSwNP clinical studies. 

Paediatric population  

Atopic dermatitis 

Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in paediatric patients 6 to 17 years of age.  

The pharmacokinetics of dupilumab in paediatric patients (< 6 years of age) or body weight < 15 kg with atopic dermatitis has not been studied. 

For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (< 60 kg) or 300 mg (≥ 60 kg), the mean ±SD steady state trough concentration of dupilumab was 54.5±27.0 mcg/mL. 

For children 6 to 11 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (≥ 15 kg) in AD-1652, the mean ± SD steady-state trough concentration was 76.3±37.2 mcg/mL. At week 16 in AD-1434 in children 6 to 11 years of age who initiated every four-week dosing (Q4W) with 300 mg (≥ 15 kg), and whose dose was increased to every other week dosing (Q2W) with

200 mg (≥ 15 to < 60 kg) or 300 mg (≥ 60 kg), the mean±SD steady-state trough concentration was

108±53.8 mcg/mL. For children 6 to 11 years of age receiving 300 mg Q4W, initial doses of 300 mg on Days 1 and 15 produce similar steady-state exposure as an initial dose of 600 mg on Day 1, based on PK simulations. 

Asthma  

The pharmacokinetics of dupilumab in paediatric patients (< 6 years of age) with asthma has not been studied. 

A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean ±SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight. 

In the VOYAGE study, dupilumab pharmacokinetics was investigated in 270 patients with moderatetosevere asthma following subcutaneous administration of either 100 mg Q2W (for 91 children weighing < 30 kg) or 200 mg Q2W (for 179 children weighing ≥ 30 kg). The volume of distribution for dupilumab of approximately 3.7 L was estimated by population PK analysis. Steady-state concentrations were achieved by week 12. The mean ± SD steady-state trough concentration was 58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥ 15 kg to < 30 kg and ≥ 30 kg to < 60 kg resulted in predicted steady-state trough concentrations similar to the observed trough concentrations of 200 mg Q2W (≥ 30 kg) and 100 mg Q2W (< 30 kg), respectively. In addition, simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥ 15 kg to < 60 kg resulted in predicted steady-state trough concentrations similar to those demonstrated to be efficacious in adults and adolescents. After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 14 to 18 weeks for 100 mg Q2W, 200 mg Q2W or 300 mg Q4W. 

CRSwNP 

CRSwNP does not normally occur in children. The pharmacokinetics of dupilumab in paediatric patients (< 18 years of age) with CRSwNP has not been studied. 

PN 

The pharmacokinetics of dupilumab in paediatric patients (< 18 years of age) with PN has not been studied. 

Eosinophilic Esophagitis 

In a clinical study (Parts A and B), dupilumab pharmacokinetics were investigated in 35 paediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE, receiving 300 mg QW. The mean ± SD steady-state trough concentration of dupilumab was 227 ± 95.3 mcg/mL. 

Chronic Spontaneous Urticaria 

Adolescents (12 to 17 years of age) 

A total of 12 adolescents aged 12 to 17 years with CSU were enrolled in CUPID Study A, B and C. The observed steady-state trough concentrations of 3 adolescent patients with CSU who received Dupixent 300 mg Q2W or 200 mg Q2W for 24 weeks were within the range of the steady-state trough concentrations in adult patients with CSU who received Dupixent 300 mg Q2W for 24 weeks. 

Pharmacokinetics in pediatric patients (<12 years of age) with CSU have not been established. 

Chronic Obstructive Pulmonary Disease 

COPD does not normally occur in children. The pharmacokinetics of dupilumab have not been studied in children (<18 years of age) with COPD  

Drug Interaction Studies 

An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on DUPIXENT pharmacokinetics in subjects with moderate-to-severe asthma. 

Cytochrome P450 Substrates 

The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with AD (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%. 

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development. 

The mutagenic potential of dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes. 

Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Rα inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab. 

During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Rα, no fetal abnormalities were observed at doses that saturate the IL-4Rα.  

An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth. 

Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Rα showed no impairment of fertility (see section 4.6). 

L-Arginine monohydrochloride  

L-Histidine  

L-Histidine monohydrochloride monohydrate  

Polysorbate 80 (E 433)  

Sodium acetate trihydrate  

Acetic acid, glacial (E 260)  

Sucrose  

Water for injections 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 

Store in a refrigerator (2°C - 8°C). 

Do not freeze. 

Store in the original carton in order to protect from light.  

2 mL solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.  

The pre-filled pen is available either with a round cap and oval viewing window encircled with an arrow or with a square cap with ridges and an oval viewing window without an arrow. 

Pack size:  

·         1 pre-filled pen  

·         2 pre-filled pens  

·         6 pre-filled pens 

·         Multipack containing 6 (2 packs of 3) pre-filled pens  

Not all pack sizes may be marketed. 

Comprehensive instructions for the administration of Dupixent in a pre-filled pen are given at the end of the package leaflet. 

The solution should be clear to slightly opalescent, colourless to pale yellow. If the solution is cloudy, discoloured or contains visible particulate matter, the solution should not be used. 

After removing the 300 mg pre-filled pen from the refrigerator, it should be allowed to reach room temperature up to 25°C by waiting for 45 min before injecting Dupixent. 

The pre-filled pen should not be exposed to heat or direct sunlight and should not be shaken. 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. After use, place the pre-filled pen into a puncture-resistant container and discard as required by local regulations. Do not recycle the container.