DUPIXENT 200mg 175mg / ml injection solution in pre-filled syringe medication leaflet

Dupixent 200 mg solution for injection in pre-filled syringe

Dupixent 200 mg solution for injection in pre-filled pen

Dupilumab 200 mg solution for injection in pre-filled syringe

Each single-use pre-filled syringe contains 200 mg of dupilumab in 1.14 mL solution (175 mg/mL).

Dupilumab 200 mg solution for injection in pre-filled pen

Each single-use pre-filled pen contains 200 mg of dupilumab in 1.14 mL solution (175 mg/mL).

Dupilumab is a fully human monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells byrecombinant DNA technology.

This medicine contains 2.28 mg of polysorbate 80 in each 200 mg dose (1.14mL). Polysorbates maycause allergic reactions.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to slightly opalescent, colourless to pale yellow sterile solution, which is free from visibleparticulates, with a pH of approximately 5.9.

Adults and adolescents

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

Children 6 months to 11 years of age

Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 months to 11 years oldwho 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 forsevere asthma with type 2 inflammation characterised by raised blood eosinophils and/or raisedfraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with highdose 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 asthmawith type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhalednitric oxide (FeNO), see section 5.1, who are inadequately controlled with medium to high doseinhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Eosinophilic esophagitis (EoE)

Dupixent is indicated for the treatment of eosinophilic esophagitis in adults, adolescents and childrenaged 1 year and older, weighing at least 15 kg, who are inadequately controlled by, are intolerant to, orwho are not candidates for conventional medicinal therapy (see section 5.1).Error! No documentvariable supplied.

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

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

Adolescents (12 to 17 years of age)

The recommended dose of dupilumab for adolescent patients 12 to 17 years of age is specified in

Table 1.

Table 1: Dose of dupilumab for subcutaneous administration in adolescent patients 12 to 17years of age with atopic dermatitis

Body weight of patient Initial dose Subsequent doses(every other week)less than 60 kg 400 mg (two 200 mg injections) 200 mg60 kg or more 600 mg (two 300 mg injections) 300 mg

Children 6 to 11 years of age

The recommended dose of dupilumab for children 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 withatopic dermatitis

Body weight of Initial dose Subsequent dosespatient15 kg to 300 mg (one 300 mg injection) on Day 1, 300 mg every 4 weeks (Q4W)*,less than 60 kg followed by 300 mg on Day 15 starting 4 weeks a fter Day 15 dose60 kg or more 600 mg (two 300 mg injections) 300 mg every other week (Q2W)

*the dose may be increased to 200 mg Q2W in patients with body weight of 15 kg to less than 60 kgbased on physician’s assessment.

Children 6 months to 5 years of age

The recommended dose of dupilumab for children 6 months to 5 years of age is specified in Table 3.

Table 3: Dose of dupilumab for subcutaneous administration in children 6 months to 5 years ofage with atopic dermatitis

Body Weight of Patient Initial Dose Subsequent Doses5 kg to less than 15 kg 200 mg (one 200 mg injection) 200 mg every 4 weeks (Q4W)15 kg to less than 30 kg 300 mg (one 300 mg injection) 300 mg every 4 weeks (Q4W)

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

Consideration should be given to discontinuing treatment in patients who have shown no responseafter 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response maysubsequently improve with continued treatment beyond 16 weeks. If dupilumab treatment interruptionbecomes 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:

* An initial dose of 400 mg (two 200 mg injections), followed by 200 mg given every other weekadministered as subcutaneous injection.

* For patients with severe asthma and who are on oral corticosteroids or for patients with severeasthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severechronic 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.

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 4.

Table 4: Dose of dupilumab for subcutaneous administration in children 6 to 11 years ofage with asthma

Body weight Initial and subsequent doses15 to less than 30 kg 300 mg every four weeks (Q4W)30 kg to less than 60 kg 200 mg every other week (Q2W)or300 mg every four weeks (Q4W)60 kg or more 200 mg every other week (Q2W)

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

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

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

Eosinophilic esophagitis (EoE)

The recommended dose of dupilumab for adults, adolescents and children 1 year of age and older,weighing at least 15 kg, is specified in Table 5.

Table 5: Dose of dupilumab for subcutaneous administration in adults, adolescents and children1 year of age and older with EoE

Body Weight Dose15 to less than 30 kg 200 mg every other week (Q2W)30 to less than 40 kg 300 mg every other week (Q2W)40 kg or more 300 mg every week (QW)

Dupilumab is intended for long-term treatment.

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

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

If an every 4 week dose is missed, administer the injection within 7 days from the missed dose andthen 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.

No dose adjustment is recommended for elderly (≥ 65 years) patients (see section 5.2).

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

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

No dose adjustment for body weight is recommended for patients with asthma 12 years of age andolder or in adults with atopic dermatitis (see section 5.2).

The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 monthshave not been established. The safety and efficacy of dupilumab in children with a body weight < 5 kghave 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 notbeen established. No data are available.

The safety and efficacy of dupilumab in children with EoE below the age of 1 year, or with a bodyweight < 15 kg have not been established.

Subcutaneous use

The dupilumab pre-filled pen is for use in adult and paediatric patients aged 2 years and older.

The dupilumab pre-filled syringe is for use in adult and paediatric patients aged 6 months andolder. The dupilumab pre-filled pen is not intended for use in children below 2 years of age.

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

Each pre-filled syringe or pre-filled pen is for single use only.

For indications that require an initial dose of 400 mg (see Posology in section 4.2), two 200 mginjections should be administered consecutively in different injection sites.

It is recommended to rotate the injection site with each injection. Dupilumab should not be injectedinto 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 theirhealthcare professional determines that this is appropriate. Proper training should be provided topatients and/or caregivers on the preparation and administration of dupilumab prior to use according tothe Instructions for Use (IFU) section at the end of the package leaflet. In children 12 years of age andolder, it is recommended that dupilumab is administered by or under supervision of an adult. Inchildren 6 months to less than 12 years of age, dupilumab should be given by a caregiver.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Acute exacerbations of Asthma or COPD

Dupilumab should not be used to treat acute symptoms or acute exacerbations of asthma or COPD.

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

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

Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. This should betaken into consideration to determine type 2 status in patients taking oral corticosteroids (see section5.1).

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

Eosinophilic conditions

Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosiswith polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in theasthma development program. Cases of vasculitis consistent with EGPA have been reported withdupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP developmentprogram. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiaccomplications, and/or neuropathy presenting in their patients with eosinophilia. Patients being treatedfor asthma may present with serious systemic eosinophilia sometimes presenting with clinical featuresof eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis,conditions which are often treated with systemic corticosteroid therapy. These events usually, but notalways, may be associated with the reduction of oral corticosteroid therapy.

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-13signalling. 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 anti-helminth treatment, treatment with dupilumab should be discontinued until infection resolves. Cases ofenterobiasis were reported in children 6 to 11 years old who participated in the paediatric asthmadevelopment program (see section 4.8).

Conjunctivitis and keratitis related events

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

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

Patients with comorbid asthma

Patients on dupilumab who also have comorbid asthma should not adjust or stop their asthmatreatments without consultation with their physicians. Patients with comorbid asthma should bemonitored carefully following discontinuation of dupilumab.

Concurrent use of live and live attenuated vaccines with dupilumab should be avoided as clinicalsafety and efficacy have not been established. It is recommended that patients should be brought up todate with live and live attenuated immunisations in agreement with current immunisation guidelinesprior to treatment with dupilumab. Clinical data are not available to support more specific guidance forlive or live attenuated vaccines administration in patients treated with dupilumab. Immune responsesto TdaP vaccine and meningococcal polysaccharide vaccine were assessed (see section 4.5).

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, that is to sayessentially ‘sodium-free’.

Polysorbate 80 (E433)

This medicine contains 2.28 mg of polysorbate 80 in each 200 mg dose (1.14 mL). Polysorbates maycause allergic reactions.

Immune responses to vaccination were assessed in a study in which patients with atopic dermatitiswere treated once weekly for 16 weeks with 300 mg of dupilumab. After 12 weeks of dupilumabadministration, patients were vaccinated with a Tdap vaccine (T cell-dependent), and a meningococcalpolysaccharide vaccine (T cell-independent) and immune responses were assessed 4 weeks later.

Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar indupilumab-treated and placebo-treated patients. No adverse interactions between either of the non-livevaccines 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 clinicallyrelevant 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 thepopulation analysis, commonly co-administered medicinal products had no effect on dupilumabpharmacokinetics on patients with moderate to severe asthma.

There is a limited amount of data from the use of dupilumab in pregnant women. Animal studies donot 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 tothe foetus.

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 therapytaking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

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.

The most common adverse reactions in atopic dermatitis, asthma, and CRSwNP are injection sitereactions (includes erythema, oedema, pruritus, pain and swelling), conjunctivitis, conjunctivitisallergic, arthralgia, oral herpes, and eosinophilia. An additional adverse reaction of injection sitebruising 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 (seesection 4.4).

The dupilumab safety data presented in Table 6 were predominantly derived from 12 randomised,placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. These studiesinvolved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during thecontrolled period are representative of the overall safety profile for dupilumab.

Listed in Table 6 are adverse reactions observed in clinical trials and/or postmarketing settingpresented 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); veryrare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 6: List of adverse reactions

MedDRA System Frequency Adverse Reaction

Organ Class

Infections and Common Conjunctivitis*infestations Oral herpes*

Blood and lymphatic Common Eosinophiliasystem disorders

Immune system Uncommon Angioedema#disorders Rare Anaphylactic reaction

Serum sickness reaction

Serum sickness-like reaction

Eye disorders Common Conjunctivitis allergic*

Uncommon Keratitis*#

Blepharitis*†

Eye pruritus*†

Dry eye*†

Rare Ulcerative keratitis*†#

Skin and Uncommon Facial rash#subcutaneous tissuedisorders

Musculoskeletal and Common Arthralgia#connective tissuedisorders

General disorders Common Injection site reactions (includes erythema, oedema,and administration pruritus, pain, swelling, and bruising)site conditions

*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 wasuncommon in atopic dermatitis studies.#from postmarketing reporting.

Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction havebeen 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 receiveddupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis orkeratitis recovered or were recovering during the treatment period. In the long-term OLE atopicdermatitis study (AD-1225) at 5 years, the respective rates of conjunctivitis and keratitis remainedsimilar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Amongasthma and COPD patients, the frequency of conjunctivitis and keratitis was low and similar betweendupilumab and placebo. Among CRSwNP and Prurigo Nodularis (PN) patients the frequency ofconjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopicdermatitis patients. There were no cases of keratitis reported in the CRSwNP or PN developmentprogram. Among patients with EoE, the frequency of conjunctivitis was low and similar betweendupilumab and placebo groups. There were no cases of keratitis in the EoE development program (seesection 4.4).

Eczema herpeticum

Eczema herpeticum was reported in < 1 % of the dupilumab groups and in < 1 % of the placebo groupin the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitisdupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCSgroup 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 countcompared to patients treated with placebo in the atopic dermatitis, asthma, CRSwNP, and COPDindications. Eosinophil counts declined to near baseline levels during study treatment and returned tobaseline during the asthma open-label extension safety study (TRAVERSE). The mean bloodeosinophil levels decreased to below baseline by week 20 and was maintained up to 5 years in thelong-term OLE study (AD-1225). Compared to placebo, no increase in mean blood eosinophil countswas observed in PN (PRIME and PRIME2). Mean and median blood eosinophil counts declined tonear baseline or remained below baseline levels in EoE and COPD (BOREAS and NOTUS) duringstudy treatment.

Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was reported in < 3 % of dupilumab-treatedpatients 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; BOREASand NOTUS).

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

In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported in1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-weekatopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treatedwith placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remainedstable 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 placeboin the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections werereported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumaband 1.4% of patients treated with placebo.

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

The overall incidence of infections was numerically higher with dupilumab (32.0%) compared toplacebo (24.8%) in the 24-week safety pool for the EoE TREET (Parts A and B) studies. The overallincidence of infections was numerically higher in placebo (41.2%) compared to dupilumab (35.8%) inthe EoE KIDS (Part A) study. In the 24-week safety pool for the EoE TREET (Parts A and B) studiesserious infections were reported in 0.5% of patients treated with dupilumab and 0% of patients treatedwith placebo. No serious infections were reported in EoE KIDS (Part A) study. Upper respiratory tractinfections composed of several terms, including, but not limited to, COVID-19, sinusitis, and upperrespiratory tract infection was numerically higher with dupilumab (17.2%) compared to placebo (10.3%)in EoE TREET (Parts A and B), and with dupilumab (26.9%) compared to placebo (20.6%) in EoE

KIDS (Part A) study.

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

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

Antidrug Antibodies (ADA) responses were not generally associated with impact on dupilumabexposure, safety, or efficacy.

Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab300 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 inadult patients with PN who received dupilumab 300 mg Q2W for 24 weeks, paediatric patients (6months to 11 years of age) with atopic dermatitis who received either dupilumab 200 mg Q2W, 200mg Q4W or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who receiveddupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed inadult patients with atopic dermatitis treated with dupilumab for up to 5 years in the long-term OLEstudy (AD-1225).

Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 300 mg or200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3 % exhibitedpersistent ADA responses, and approximately 5 % had neutralizing antibodies.

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

Approximately 1% of patients 1 year of age and older with EoE who received dupilumab 300 mg QW(≥40 kg), 300 mg Q2W (≥30 to <60 kg), 200 mg Q2W (≥15 to <30 kg), or 100 mg Q2W (≥5 to <15kg) for 52 weeks developed antibodies to dupilumab; the ADA responses were neither persistent norneutralizing.

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

Regardless of age or population, up to 7 % of patients in the placebo groups were positive forantibodies to dupilumab; up to 3 % exhibited persistent ADA response and up to 2 % had neutralizingantibodies.

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 withserum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers(see section 4.4).

Adolescents (12 t o17 years of age)

The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age withmoderate-to-severe atopic dermatitis (AD-1526). The safety profile of dupilumab in thesepatients followed through week 16 was similar to the safety profile from studies in adults withatopic 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 severeatopic dermatitis (AD-1652). The safety profile of dupilumab with concomitant TCS in thesepatients through week 16 was similar to the safety profile from studies in adults and adolescentswith atopic dermatitis.

Children 6 months to 5 years of age

The safety of dupilumab with concomitant TCS was assessed in a study of 161 patients 6 months to5 years of age with moderate-to-severe atopic dermatitis, which included a subgroup of 124 patientswith severe atopic dermatitis (AD-1539). The safety profile of dupilumab with concomitant TCS inthese patients, through week 16 was similar to the safety profile from studies in adults and paediatricpatients 6 to 17 years of age 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 moderate-to-severe atopic hand and foot dermatitis (AD-1924). The safety profile of dupilumab in these patientsthrough Week 16 was consistent with the safety profile from studies in adult and paediatric patients 6months of age and older with moderate-to-severe AD.

Asthma

Adolescents (12 t o17 years of age)

A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in the 52 week QUESTstudy. 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 anopen-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients werefollowed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with thesafety 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 adversereaction of enterobiasis was reported in 1.8 % (5 patients) in the dupilumab groups and none in theplacebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminthtreatment 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 thedupilumab groups and 0.7% in the placebo group. Most eosinophilia cases were mild to moderate andnot associated with clinical symptoms. These cases were transient, decreased over time, and did notlead to dupilumab treatment discontinuation.

The long-term safety of dupilumab was assessed in an open-label extension study (EXCURSION) inchildren 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 and228 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 profileobserved in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

EoE

Adolescents (12 to 17 years of age)

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

Children 1 to 11 years of age

The safety of dupilumab was assessed in a trial of 101 children 1 to 11 years of age with EoE (EoE

KIDS Part A). The safety profile of dupilumab in these patients through Week 16 was similar with thesafety profile seen in adult and adolescent patients 12 to 17 years of age with EoE.

A total of 98 patients completing Part A were provided an option to enrol in a 36-week activetreatment extension period (EoE-KIDS Part B). The safety profile of dupilumab through Week 52 wassimilar to the safety profile observed at Week 16.

The safety profile of dupilumab + TCS (CHRONOS) in adult atopic dermatitis patients) through week52 was consistent with the safety profile observed at week 16. The long-term safety of dupilumab wasassessed in an open-label extension study in patients 6 months to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed throughweek 52 was similar to the safety profile observed at week 16 in the AD-1526, AD-1652, and AD-1539 studies. The long-term safety profile of dupilumab observed in children and adolescents wasconsistent 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 repeatdoses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mgweekly dosing (99.7 %), including 179 who completed at least 260 weeks of the study. The long-termsafety profile observed in this study up to 5 years was generally consistent with the safety profile ofdupilumab observed in controlled studies.

Asthma

The safety profile of dupilumab in the 96 weeks long term safety study (TRAVERSE) was consistentwith 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 52weeks long-term safety study (EXCURSION) was consistent with the safety profile observed in thepivotal asthma study (VOYAGE) for 52 weeks of treatment.

CRSwNP

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

Eosinophilic esophagitis

The safety profile of dupilumab through week 52 in adult and adolescent patients 12 years of age andolder (TREET Part C) and in children 1 to 11 years of age (EoE KIDS Part B) was generally consistentwith the safety profile observed at week 24 in TREET Parts A and B and at Week 16 in EoE KIDS

Part A.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 andinterleukin-13 signalling. Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), andboth IL-4 and IL-13 signalling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 aremajor drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, and EoE.

Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type2 inflammation.

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

In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedlydecreased 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 2inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. Inpaediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebomarkedly 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 maximalsuppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects weresustained throughout treatment.

Clinical efficacy and safety in atopic dermatitis

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

The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in amulticentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescentpatients 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 aseverity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥ 16 on a scale of 0 to72, and a minimum body surface area (BSA) involvement of ≥10 %. Eligible patients enrolledinto this study had previous inadequate response to topical medication.

Patients received dupilumab was administered by subcutaneous (SC) injections either as: 1) aninitial dose of 400 mg dupilumab (two 200 mg injections) on day 1, followed by 200 mg onceevery other week (Q2W) for patients with baseline weight of < 60 kg or an initial dose of 600 mgdupilumab (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baselineweight 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) matchingplacebo. If needed to control intolerable symptoms, patients were permitted to receive rescuetreatment at the discretion of the investigator. Patients who received rescue treatment wereconsidered 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 patientshad 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 systemicimmunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) scorewas 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, thebaseline 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 atleast one co-morbid allergic condition; 65.6 % had allergic rhinitis, 53.6 % had asthma, and60.8 % had food allergies.

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almostclear”) least a 2-point improvement and the proportion of patients with EASI-75 (improvementof 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 7.

Table 7: Efficacy results of dupilumab in the adolescent atopic dermatitis study at week 16 (FAS)

AD-1526(FAS)a

Placebo Dupilumab200 mg (< 60 kg) and300 mg (≥ 60 kg)

Q2W

Patients randomised 85a 82a

IGA 0 or 1b, % respondersc 2.4 % 24.4 %d

EASI-50, % respondersc 12.9 % 61.0 %d

EASI-75, % respondersc 8.2 % 41.5 %d

EASI-90, % respondersc 2.4 % 23.2 %d

EASI, LS mean % change from baseline (+/-SE) -23.6 % -65.9 %d(5.49) (3.99)

Pruritus NRS, LS mean % change from baseline (+/- -19.0 % -47.9 %d

SE) (4.09) (3.43)

Pruritus NRS (≥ 4-point improvement), % 4.8 % 36.6 %drespondersc

CDLQI, LS mean change from baseline -5.1 -8.5d(+/-SE) (0.62) (0.50)

CDLQI, (≥ 6-point improvement), % responders 19.7 % 60.6 %e

POEM, LS mean change from baseline -3.8 -10.1d(+/- SE) (0.96) (0.76)

POEM, (≥ 6-point improvement), % responders 9.5 % 63.4 %eafull 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 ona 0-4 IGA scale.

cpatients who received rescue treatment or with missing data were considered as non-responders (58.8 % and20.7 % 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 thedupilumab group (58.8 % and 20.7 %, respectively).

A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvementin 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 increasethrough the treatment period.

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

The long-term efficacy of dupilumab in adolescent patients with moderate-to-severe AD who hadparticipated in previous clinical trials of dupilumab was assessed in open-label extension study (AD-1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustainedthrough week 52.

Paediatrics (6 to 11 years of age)

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

Patients in the dupilumab Q2W + TCS group with baseline weight of < 30 kg received an initial doseof 200 mg on Day 1, followed by 100 mg Q2W from week 2 to week 14, and patients with baselineweight of ≥ 30 kg received an initial dose of 400 mg on Day 1, followed by 200 mg Q2W from week 2to 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 werefemale, 69.2 % were White, 16.9 % were Black, and 7.6 % were Asian. At baseline, the mean BSAinvolvement 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 was7.8 on a scale of 0-10, the baseline mean SCORAD score was 73.6, the baseline POEM score was20.9, and the baseline mean CDLQI was 15.1. Overall, 91.7 % of subjects had at least one co-morbidallergic 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”) atleast a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least75 % in EASI), from baseline to week 16.

Clinical Response

Table 8 presents the results by baseline weight strata for the approved dose regimens.

Table 8: Efficacy results of dupilumab with concomitant TCS in AD-1652 at week 16 (FAS)a

Dupilumab Placebo Dupilumab Placebo300 mg Q4Wd +TCS 200 mg Q2We + TCS+ TCS + TCS(N=122) (N=123) (N=59) (N=62)≥ 15 kg ≥ 15 kg ≥ 30 kg ≥ 30 kg

IGA 0 or 1b, % respondersc32.8 %f 11.4 % 39.0 %h 9.7 %

EASI-50, % respondersc 91.0 %f 43.1 % 86.4 %g 43.5 %

EASI-75, % respondersc 69.7 %f 26.8 % 74.6 %g 25.8 %

EASI-90, % respondersc 41.8 %f 7.3 % 35.6 %h 8.1 %

EASI, LS mean % change from -82.1 %f -48.6 % -80.4 %g -48.3 %baseline (+/-SE) (2.37) (2.46) (3.61) (3.63)

Pruritus NRS, LS mean % change -54.6 %f -25.9 % -58.2 %g -25.0 %from baseline (+/- SE) (2.89) (2.90) (4.01) (3.95)

Pruritus NRS (≥ 4-pointf gimprovement), % respondersc 50.8 % 12.3 % 61.4 % 12.9 %

CDLQI, LS mean change from -10.6f -6.4 -9.8g -5.6baseline (+/-SE) (0.47) (0.51) (0.63) (0.66)

CDLQI, (≥ 6-point improvement), %77.3 %gresponders 38.8 % 80.8 %g 35.8 %

POEM, LS mean change from -13.6f -5.3 -13.6g -4.7baseline (+/- SE) (0.65) (0.69) (0.90) (0.91)

POEM, (≥ 6-point improvement), %gresponders 81.7 % 32.0 % 79.3 %g 31.1 %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 < 0.0001hnominal p-value = 0.0002

A greater proportion of patients randomised to dupilumab + TCS achieved an improvement in the peakpruritus 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 sleepand health-related quality of life as measured by POEM and CDLQI scores at 16 weeks compared toplacebo.

The long-term efficacy and safety of dupilumab + TCS in paediatric patients with moderate to severeatopic dermatitis who had participated in the previous clinical trials of dupilumab + TCS was assessedin an open-label extension study (AD-1434). Efficacy data from this trial suggests that clinical benefitprovided 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 safetyprofile of dupilumab in patients followed through week 52 was similar to the safety profile observed atweek 16 in the AD-1526 and AD-1652 studies.

Paediatrics (6 Months to 5 years of age)

The efficacy and safety of dupilumab + TCS in paediatric patients was evaluated in a multicentre,randomised, double-blind, placebo-controlled study (AD-1539) in 162 patients 6 months to 5 years ofage, with moderate-to-severe AD (ITT population) defined by an IGA score ≥ 3 (scale of 0 to 4), an

EASI score ≥ 16 (scale of 0 to 72), and a minimum BSA involvement of ≥ 10. Of the 162 patients, 125patients had severe AD defined by an IGA score of 4. Eligible patients enrolled into this study hadprevious inadequate response to topical medication. Enrolment was stratified by baseline weight (≥ 5to < 15 kg and ≥ 15 to < 30 kg).

Patients in the dupilumab Q4W + TCS group with baseline weight of ≥ 5 to < 15 kg received an initialdose of 200 mg on Day 1, followed by 200 mg Q4W from week 4 to week 12, and patients withbaseline weight of ≥ 15 to < 30 kg received an initial dose of 300 mg on Day 1, followed by 300 mg

Q4W from week 4 to week 12. Patients were permitted to receive rescue treatment at the discretion ofthe investigator. Patients who received rescue treatment were considered non-responders.

In AD-1539, the mean age was 3.8 years, the median weight was 16.5 kg, 38.9% of patients werefemale, 68.5% were White, 18.5% were Black, and 6.2% were Asian. At baseline, the mean BSAinvolvement was 58.4%, and 15.5% had received prior systemic non-steroidal immunosuppressants.

Also, at baseline the mean EASI score was 34.1, and the weekly average of daily worst itch score was7.6 on a scale of 0-10. Overall, 81.4% of patients had at least one co-morbid allergic condition; 68.3%had food allergies, 52.8% had other allergies, 44.1% had allergic rhinitis, and 25.5% had asthma.

These baseline disease characteristics were comparable between moderate-to-severe and severe ADpopulations.

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) atleast a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least75 % in EASI), from baseline to week 16. The primary endpoint was the proportion of patients with an

IGA 0 (clear) or 1 (almost clear) at week 16.

Clinical Response

The efficacy results at week 16 for AD-1539 are presented in Table 9.

Table 9: Efficacy results of dupilumab with concomitant TCS in AD-1539 at Week 16 (FAS)a

Dupilumab Placebo Dupilumab Placebo200 mg (5 to < 15kg) or + TCS 200 mg (5 to < 15kg) or + TCS300 mg (15 to < 30 kg) (ITT 300 mg (15 to < 30 kg) (severe AD

Q4Wd+ TCS population) Q4Wd+ TCS population)(ITT (N=79) (severe AD population) (N=62)population)(N=83)a (N=63)

IGA 0 or 1b,c 27.7%e 3.9% 14.3%f 1.7%

EASI-50, % respondersc 68.7%e 20.2% 60.3%g 19.2%

EASI-75c 53.0%e 10.7% 46.0%g 7.2%

EASI-90c 25.3%e 2.8% 15.9%h 0%

EASI, LS mean % change from -70.0%e -19.6% -55.4%g -10.3%baseline (+/-SE) (4.85) (5.13) (5.01) (5.16)

Worst scratch/itch NRS, LS -49.4%e -2.2% -41.8g 0.5mean % change from baseline (5.03) (5.22) (5.35) (5.40)(+/-SE) *

Worst Scratch/Itch NRS (≥4- 48.1%e 8.9% 42.3%i 8.8%point improvement)c *

Patient’s sleep quality NRS, LS 2.0e 0.3 1.7g 0.2mean change from baseline (+/- (0.25) (0.26) (0.25) (0.25)

SE)*

Patient’s skin pain NRS, LS -3.9e -0.6 -3.4g -0.3mean change from baseline (+/- (0.30) (0.30) (0.29) (0.29)

SE)*

POEM, LS mean change from -12.9e -3.8 -10.6g -2.5baseline (+/- SE)* (0.89) (0.92) (0.93) (0.95)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 (62% and 19% in the placebo and dupilumab arms, respectively) or withmissing data were considered as non-responders.dAt Day 1, patients received 200 mg (5 to <15kg) or 300 mg (15 to <30 kg) of dupilumab.ep-values < 0.0001,fnominal p-value < 0.05, gnominal p-value < 0.0001, hnominal p-value < 0.005, inominal p-value < 0.001

*Caregiver reported outcome

A significantly greater proportion of patients randomised to dupilumab + TCS achieved a rapidimprovement in the Worst Scratch/Itch NRS compared to placebo + TCS (defined as ≥ 4-pointimprovement as early as week 3, nominal p< 0.005) and the proportion of patients responding on the

Worst Scratch/Itch NRS continued to increase through the treatment period.

In this study, dupilumab significantly improved health-related quality of life as measured by the

CDLQI (in 85 patients 4 to 5 years old) and IDQOL (in 77 patients 6 months to 3 years old). In the

ITT population, greater LS mean changes in CDLQI and IDQOL scores from baseline to week 16were observed in the dupilumab + TCS (-10.0 and -10.9) group compared to the placebo + TCS group(-2.5 and -2.0), respectively (p< 0.0001). Similar improvements in both CDLQI and IDQOL wereobserved in the severe AD population.

The long-term efficacy and safety of dupilumab + TCS in paediatric patients with moderate to severeatopic dermatitis who had participated in the previous clinical trials of dupilumab + TCS wereassessed in an open-label extension study (AD-1434). Efficacy data from this trial suggest that clinicalbenefit provided at week 16 was sustained through week 52. The safety profile of dupilumab inpatients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1539 study.

Atopic Hand and Foot Dermatitis (adults and adolescents)

The efficacy and safety of dupilumab was evaluated in a 16-week multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (AD-1924) in 133 adult and paediatric patients 12 to 17years of age with moderate-to-severe atopic hand and foot dermatitis, defined by an IGA (hand andfoot) score ≥3 (scale of 0 to 4) and a hand and foot Peak Pruritus Numeric Rating Scale (NRS) scorefor maximum itch intensity ≥4 (scale of 0 to 10). Eligible patients had previous inadequate response orintolerance 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 (handand 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 averagedhand 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 handand foot Peak Pruritus NRS (≥4-point improvement). Other patient reported outcomes includedassessment 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 dupilumaband 16.7% for placebo (treatment difference 23.6, 95% CI: 8.84, 38.42). The proportion of patientswith improvement (reduction) of weekly averaged hand and foot Peak Pruritus NRS ≥4 at Week 16was 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 inthe 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).

Adults with atopic dermatitis

For clinical data in adults with atopic dermatitis please refer to the dupilumab 300 mg Summary of

Product Characteristics.

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 intreatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients wereenrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatorybiomarkers (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation aseosinophilia ≥ 150 cells/mcL and/or FeNO ≥ 20 ppb. In DRI12544 and QUEST, the pre-specifiedsubgroup 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 ona medium-to-high dose inhaled corticosteroid and a long acting beta agonist. The primary endpointwas change from baseline to week 12 in FEV1 (L). Annualised rate of severe asthma exacerbationevents during the 24-week placebo controlled treatment period was also determined. Results wereevaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2inflammatory 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 withpersistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controllermedication. Patients requiring a third controller were allowed to participate in this trial. The primaryendpoints were the annualised rate of severe exacerbation events during the 52-week placebocontrolled period and change from baseline in pre-bronchodilator FEV1 at week 12 in the overallpopulation (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 unrestrictedby baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use ofhigh dose inhaled corticosteroids plus an additional controller. The OCS dose was optimized duringthe 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), aslong as asthma control was maintained. The primary endpoint was the percent reduction in oralcorticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroiddose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oralcorticosteroid dose.

The demographics and baseline characteristics of these 3 studies are provided in Table 10 below.

Table 10: Demographics and baseline characteristics of asthma trials

Parameter DRI12544 QUEST VENTURE(n = 776) (n = 1902) (n=210)

Mean age (years) (SD) 48.6 (13.0) 47.9 (15.3) 51.3 (12.6)% Female 63.1 62.9 60.5% White 78.2 82.9 93.8

Duration of Asthma (years), mean ± SD 22.03 (15.42) 20.94 (15.36) 19.95 (13.90)

Never smoked, (%) 77.4 80.7 80.5

Mean exacerbations in previous year ± SD 2.17 (2.14) 2.09 (2.15) 2.09 (2.16)

High dose ICS use (%)a 49.5 51.5 88.6

Pre-dose FEV1 (L) at baseline ± SD 1.84 (0.54) 1.78 (0.60) 1.58 (0.57)

Mean percent predicted FEV1 at baseline 60.77 (10.72) 58.43 (13.52) 52.18 (15.18)(%)(± SD)% Reversibility (± SD) 26.85 (15.43) 26.29 (21.73) 19.47 (23.25)

Mean ACQ-5 score (± SD) 2.74 (0.81) 2.76 (0.77) 2.50 (1.16)

Mean AQLQ score (± SD) 4.02 (1.09) 4.29 (1.05) 4.35 (1.17)

Atopic Medical History % Overall 72.9 77.7 72.4(AD %, NP %, AR %) (8.0, 10.6, 61.7) (10.3, 12.7, 68.6) (7.6, 21.0, 55.7)

Mean FeNO ppb (± SD) 39.10 (35.09) 34.97 (32.85) 37.61 (31.38)% patients with FeNO ppb≥ 25 49.9 49.6 54.3≥ 50 21.6 20.5 25.2

Mean total IgE IU/mL (± SD) 435.05 (753.88) 432.40 (746.66) 430.58 (775.96)

Mean baseline Eosinophil count (± SD) 350 (430) 360 (370) 350 (310)cells/mcL% patients with EOS≥ 150 cells/mcL 77.8 71.4 71.4≥ 300 cells/mcL 41.9 43.7 42.4

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 eosinophilathe population in dupilumab asthma trials included patients on medium and high dose ICS. The medium ICSdose was defined as equal to 500 mcg fluticasone or equivalent per day.

In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or300 mg every other week had significant reductions in the rate of severe asthma exacerbationscompared to placebo. There were greater reductions in exacerbations in subjects with higher baselinelevels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 11 and Table 12).

Table 11: Rate of severe exacerbations in DRI12544 and QUEST (baseline blood eosinophil levels≥ 150 and ≥ 300 cells/mcL)

Treatment Baseline blood EOS≥150 cells/mcL ≥300 cells/mcL

Exacerbations per Year % Exacerbations per Year %

N Rate Rate reduction N Rate Rate reduction(95% CI) ratio (95% CI) ratio(95%CI) (95%CI)

All Severe Exacerbations

DRI12544 study

Dupilumab 120 0.29 0.28a 72 % 65 0.30 0.29c 71 %200 mg Q2W (0.16, 0.53) (0.14, 0.55) (0.13, 0.68) (0.11, 0.76)

Dupilumab 129 0.28 0.27b 73 % 64 0.20 0.19d 81 %300 mg Q2W (0.16, 0.50) (0.14, 0.52) (0.08, 0.52) (0.07, 0.56)

Placebo 127 1.05 68 1.04(0.69, 1.60) (0.57, 1.90)

QUEST study

Dupilumab 437 0.45 0.44f 56 % 264 0.37 0.34f 66 %200 mg Q2W (0.37, 0.54) (0.34,0.58) (0.29, 0.48) (0.24,0.48)

Placebo 232 1.01 148 1.08(0.81, 1.25) (0.85, 1.38)

Dupilumab 452 0.43 0.40 e 60 % 277 0.40 0.33e 67 %300 mg Q2W (0.36, 0.53) (0.31,0.53) (0.32, 0.51) (0.23,0.45)

Placebo 237 1.08 142 1.24(0.88, 1.33) (0.97, 1.57)ap-value = 0.0003, bp-value = 0.0001, cp-value = 0.0116, dp-value = 0.0024, ep-value < 0.0001 (all statisticallysignificant vs placebo with adjustment for multiplicity); fnominal p-value < 0.0001

Table 12: Rate of severe exacerbations in QUEST defined by baseline FeNO subgroups

Treatment Exacerbations per Year %

N Rate (95% CI) Rate ratio (95%CI) reduction

FeNO ≥ 25 ppb

Dupilumab 200 mg Q2W 299 0.35 (0.27, 0.45) 0.35 (0.25, 0.50)a 65 %

Placebo 162 1.00 (0.78, 1.30)

Dupilumab 300 mg Q2W 310 0.43 (0.35, 0.54) 0.39 (0.28, 0.54) a 61 %

Placebo 172 1.12 (0.88, 1.43)

FeNO ≥ 50 ppb

Dupilumab 200 mg Q2W 119 0.33 (0.22, 0.48) 0.31 (0.18, 0.52) a 69 %

Placebo 71 1.057 (0.72, 1.55)

Dupilumab 300 mg Q2W 124 0.39 (0.27, 0.558) 0.31 (0.19, 0.49) a 69 %

Placebo 75 1.27 (0.90, 1.80)anominal p-value < 0.0001

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

Clinically significant increases in pre-bronchodilator FEV1 were observed at week 12 for DRI12544and QUEST. There were greater improvements in FEV1 in the subjects with higher baseline levels oftype 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 13 and Table 14).

Significant improvements in FEV1 were observed as early as week 2 following the first dose ofdupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24(DRI12544) and week 52 in QUEST (see Figure 1).

Figure 1: Mean change from baseline in pre-bronchodilator FEV1 (L) over time (baselineeosinophils ≥ 150 and ≥ 300 cells/mcL and FeNO ≥25 ppb) in QUEST

QUEST: blood eosinophils QUEST: blood eosinophils QUEST: FeNO ≥ 25 ppb≥ 150 cells/mcL ≥ 300 cells/mcL

Table 13: Mean change from baseline in pre-bronchodilator FEV1 at week 12 in DRI12544 and QUEST(baseline blood eosinophil Levels ≥ 150 and ≥ 300 cells/mcL)

Treatment Baseline blood EOS≥ 150 cells/mcL ≥ 300 cells/mcL

N LS mean Δ LS mean N LS mean Δ LS meanfrom baseline difference vs. from baseline difference vs.

L (%) placebo (95% CI) L (%) placebo (95% CI)

DRI12544 study

Dupilumab 200 mg Q2W 120 0.32 (18.25) 0.23a 65 0.43 (25.9) 0.26c(0.13, 0.33) (0.11, 0.40)

Dupilumab 300 mg Q2W 129 0.26 (17.1) 0.18b 64 0.39 (25.8) 0.21d(0.08, 0.27) (0.06, 0.36)

Placebo 127 0.09 (4.36) 68 0.18 (10.2)

QUEST study

Dupilumab 200 mg Q2W 437 0.36 (23.6) 0.17f 264 0.43 (29.0) 0.21f(0.11, 0.23) (0.13, 0.29)

Placebo 232 0.18 (12.4) 148 0.21 (15.6)

Dupilumab 300 mg Q2W 452 0.37 (25.3) 0.15e 277 0.47 (32.5) 0.24e(0.09, 0.21) (0.16, 0.32)

Placebo 237 0.22 (14.2) 142 0.22 (14.4)ap-value < 0.0001, bp-value = 0.0004, cp-value = 0.0008, dp-value = 0.0063, ep-value < 0.0001 (all statisticallysignificant vs placebo with adjustment for multiplicity); fnominal p-value < 0.0001

Table 14: Mean change from baseline in pre-bronchodilator FEV1 at week 12 and week 52 in QUEST bybaseline FeNO subgroups

Treatment At week 12 At week 52

N LS mean Δ from LS mean difference LS mean Δ from LS mean differencebaseline L (%) vs. placebo (95% CI) baseline L (%) vs. placebo (95% CI)

FeNO ≥ 25 ppb

Dupilumab 200 mg Q2W 288 0.44 (29.0 %) 0.23 (0.15, 0.31)a 0.49 (31.6 %) 0.30 (0.22, 0.39)a

Placebo 157 0.21 (14.1 %) 0.18 (13.2 %)

Dupilumab 300 mg Q2W 295 0.45 (29.8 %) 0.24 (0.16, 0.31)a 0.45 (30.5 %) 0.23 (0.15, 0.31)a

Placebo 167 0.21 (13.7 %) 0.22 (13.6 %)

FeNO ≥ 50 ppb

Dupilumab 200 mg Q2W 114 0.53 (33.5 %) 0.30 (0.17, 0.44)a 0.59 (36.4 %) 0.38 (0.24, 0.53)a

Placebo 69 0.23 (14.9 %) 0.21 (14.6 %)

Dupilumab 300 mg Q2W 113 0.59 (37.6 %) 0.39 (0.26, 0.52)a 0.55 (35.8 %) 0.30 (0.16, 0.44)a

Placebo 73 0.19 (13.0 %) 0.25 (13.6 %)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 15). The responder rate was defined asan 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 24weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in

VENTURE.

Table 15: ACQ-5 and AQLQ(S) responder rates at week 52 in QUEST

PRO Treatment EOS EOS FeNO≥ 150 cells/mcL ≥ 300 cells/mcL ≥ 25 ppb

N Responder N Responder N Responderrate % rate (%) rate (%)

ACQ-5 Dupilumab 200 mg Q2W 395 72.9 239 74.5 262 74.4

Placebo 201 64.2 124 66.9 141 65.2

Dupilumab 300 mg Q2W 408 70.1 248 71.0 277 75.8

Placebo 217 64.5 129 64.3 159 64.2

AQLQ(S) Dupilumab 200 mg Q2W 395 66.6 239 71.1 262 67.6

Placebo 201 53.2 124 54.8 141 54.6

Dupilumab 300 mg Q2W 408 62.0 248 64.5 277 65.3

Placebo 217 53.9 129 55.0 159 58.5

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 9. All patients were on oral corticosteroids for at least 6months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in theplacebo 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 dosefor at least 3 days) were reduced by 59 % in subjects receiving dupilumab compared with thosereceiving 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 toweek 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS meandifference 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 2inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were alsoassessed in VENTURE and showed improvements similar to those in QUEST.

The results for VENTURE by baseline biomarkers are presented in the Table 16.

Table 16: Effect of dupilumab on OCS dose reduction, VENTURE (baseline blood eosinophil levels ≥ 150and ≥ 300 cells/mcL and FeNO ≥ 25 ppb)

Baseline blood EOS Baseline blood EOS FeNO ≥ 25 ppb≥ 150 cells/mcL ≥ 300 cells/mcL

Dupilumab Placebo Dupilumab Placebo Dupilumab Placebo300 mg Q2W N=69 300 mg Q2W N=41 300 mg Q2W N=57

N=81 N=48 N=57

Primary endpoint (week 24)

Percent reduction in OCS from baseline

Mean overall percentreduction from baseline (%) 75.91 46.51 79.54 42.71 77.46 42.93

Difference (% [95% CI])(Dupilumab vs. placebo) 29.39b 36.83b 34.53b(15.67, 43.12) (18.94, 54.71) (19.08, 49.97)

Median % reduction in daily 100 50 100 50 100 50

OCS dose from baseline

Percent reduction frombaseline100% % 54.3 33.3 60.4 31.7 52.6 28.1≥ 90 % 58.0 34.8 66.7 34.1 54.4 29.8≥ 75 % 72.8 44.9 77.1 41.5 73.7 36.8≥ 50 % 82.7 55.1 85.4 53.7 86.0 50.9> 0 % 87.7 66.7 85.4 63.4 89.5 66.7

No reduction or any 12.3 33.3 14.6 36.6 10.5 33.3increase in OCS dose, ordropped out of study

Secondary endpoint (week 24)a

Proportion of patients 77 44 84 40 79 34achieving a reduction of

OCS dose to < 5 mg/day

Odds ratio (95% CI) 4.29c 8.04d 7.21b(2.04, 9.04) (2.71, 23.82) (2.69, 19.28)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 previousclinical trials of dupilumab (DRI12544, QUEST, and VENTURE), was assessed in the open-labelextension study (TRAVERSE) (see section 4.8). Efficacy was measured as a secondary endpoint, wassimilar to results observed in the pivotal studies and was sustained up to 96 weeks. In the adults withoral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and improvementin 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 highdose ICS alone. Patients were randomised to dupilumab (N=273) or matching placebo (N=135) everyother week based on body weight ≤ 30 kg or > 30 kg, respectively. The efficacy was evaluated inpopulations 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-weekplacebo-controlled period and the key secondary endpoint was the change from baseline in pre-bronchodilator FEV1 percent predicted at week 12. Additional secondary endpoints included meanchange 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 17 below.

Table 17. Demographics and baseline characteristics for VOYAGE

Parameter EOS ≥ 150 EOScells/mcL or ≥ 300 cells/mcL

FeNO ≥ 20 ppb (N = 259)(N = 350)

Mean age (years) (SD) 8.9 (1.6) 9.0 (1.6)% Female 34.3 32.8% White 88.6 87.3

Mean body weight (kg) 36.09 35.94

Mean exacerbations in previous year (± SD) 2.47 (2.30) 2.64 (2.58)

ICS dose (%)

Medium 55.7 54.4

High 43.4 44.4

Pre-dose FEV1 (L) at baseline (± SD) 1.49 (0.41) 1.47 (0.42)

Mean percent predicted FEV1 (%) (±SD) 77.89 (14.40) 76.85 (14.78)

Mean % Reversibility (± SD) 27.79 (19.34) 22.59 (20.78)

Mean ACQ-7-IA score (± SD) 2.14 (0.72) 2.16 (0.75)

Mean PAQLQ(S)-IA score (± SD) 4.94 (1.10) 4.93 (1.12)

Atopic Medical History % Overall 94 96.5(AD %, AR %) (38.9, 82.6) (44.4, 85.7)

Median total IgE IU/mL (± SD) 905.52 (1140.41) 1077.00 (1230.83)

Mean FeNO ppb (± SD) 30.71 (24.42) 33.50 (25.11)% patients with FeNO≥ 20 ppb 58 64.1

Mean baseline Eosinophil count (± SD) cells/mcL 570 (380) 710 (360)% patients with EOS≥ 150 cells/mcL 94.6 0≥ 300 cells/mcL 74 100

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 Questionnairewith 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 the52-week treatment period compared to placebo in the population with the type 2 inflammation and inpopulation 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 atweek 12. Improvements were also observed for ACQ-7-IA and PAQLQ(S)-IA at week 24 and weresustained at week 52. Greater responder rates were observed for ACQ-7-IA and PAQLQ(S)-IAcompared to placebo at week 24. The efficacy results for VOYAGE are presented in Table 18.

In the population with the type 2 inflammation, 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: 0.04, 0.16). The treatment effect wassustained over the 52-week treatment period, with an LS mean difference versus placebo at week 52 of0.17 L (95% CI: 0.09, 0.24).

In the population defined by baseline blood eosinophils ≥ 300 cells/mcL, the LS mean change frombaseline in pre-bronchodilator FEV1 at week 12 was 0.22 L in the dupilumab group and 0.12 L in theplacebo group, with an LS mean difference versus placebo of 0.10 L (95% CI: 0.03, 0.17). Thetreatment effect was sustained over the 52-week treatment period, with an LS mean difference versusplacebo 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 treatmentperiod, see Table 18.

Table 18: Rate of severe exacerbations, mean change from baseline in FEV1, ACQ-7-IA and PAQLQ(S)-IAresponder rates in VOYAGE

Treatment EOS ≥ 150 cells/mcL EOS FeNOor FeNO ≥ 20 ppb ≥ 300 cells/mcL ≥20 ppb

Annualised severe exacerbations rate over 52 weeks

N Rate Rate ratio N Rate Rate ratio N Rate Rate ratio(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

Dupilumab 236 0.305 0.407b 175 0.235 0.353b 141 0.271 0.384c100 mg Q2W (0.223, 0.416) (0.274, 0.605) (0.160, 0.345) (0.222, 0.562) (0.170, 0.432) (0.227, 0.649)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 114 0.748 84 0.665 62 0.705(0.542, 1.034) (0.467, 0.949) (0.421, 1.180)

Mean change from baseline in percent predicted FEV1 at week 12

N LS mean Δ LS mean N LS mean Δ LS mean N LS mean Δ LS meanfrom difference from difference from difference vs.baseline vs. placebo baseline vs. placebo baseline placebo(95% CI) (95% CI) (95% CI)

Dupilumab 229 10.53 5.21c 168 10.15 5.32d141 11.36 6.74d100 mg Q2W (2.14, 8.27) (1.76, 8.88) (2.54, 10.93)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 110 5.32 80 4.83 62 4.62

Mean change from baseline in percent predicted FEF 25-75% at week 12

N LS mean Δ LS mean N LS mean Δ LS mean N LS mean Δ LS meanfrom baseline difference from baseline difference from baseline difference vs.

vs. placebo vs. placebo placebo(95% CI) (95% CI) (95% CI)

Dupilumab 229 16.70 11.93e 168 16.91 13.92e 141 17.96 13.97e100 mg Q2W (7.44, 16.43) (8.89, 18.95) (8.30, 19.65)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 110 4.76 80 2.99 62 3.98

Mean change from baseline in FEV1/FVC % at week 12

N LS mean Δ LS mean N LS mean Δ LS mean N LS mean Δ LS meanfrom baseline difference from baseline difference from baseline difference vs.

vs. placebo vs. placebo placebo(95% CI) (95% CI) (95% CI)

Dupilumab 229 5.67 3.73e 168 6.10 4.63e 141 6.84 4.95e100 mg Q2W (2.25, pct. 5.21) (2.97, 6.29) (3.08, 6.81)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 110 1.94 80 1.47 62 1.89

ACQ-7-IA at week 24a

N Responder OR vs. N Responder OR vs. N Responder OR vs.

placebo placebo placeborate % rate % rate %(95% CI) (95% CI) (95% CI)

Dupilumab 236 79.2 1.82g 175 80.6 2.79f 141 80.9 2.60g100 mg Q2W (1.02, 3.24) (1.43, 5.44) (1.21, 5.59)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 114 69.3 84 64.3 62 66.1

PAQLQ(S)-IA at week 24a

N Responder OR vs. N Responder OR vs. N Responder OR vs.

rate % placebo placebo placeborate % rate %(95% CI) (95% CI) (95% CI)

Dupilumab 211 73.0 1.57 158 72.8 1.84 131 75.6 2.09100 mg Q2W (0.87, 2.84)(0.92, 3.65) (0.95, pct. 4.61)(<30 kg)/200 mg Q2W(≥30 kg)

Placebo 107 65.4 81 63.0 61 67.2athe 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 weremaintained through week 52 in VOYAGE study.

Improvements in percent predicted FEV1 over time in VOYAGE are shown in Figure 2.

Figure 2: Mean change from baseline in percent predicted pre-bronchodilator FEV1 (L) overtime in VOYAGE (baseline blood eosinophils ≥ 150 cells/mcL or FeNO ≥ 20 ppb, baselineeosinophils ≥ 300 cells/mcL, and baseline FeNO ≥ 20 ppb)

Baseline blood eosinophils ≥ 150 Baseline blood eosinophils Baselinecells/mcL or FeNO ≥ 20 ppb ≥ 300 cells/mcL FeNO ≥ 20 ppb

In VOYAGE, in the population with the type 2 inflammation, the mean annualised total number ofsystemic 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 bloodeosinophils ≥ 300 cells/mcL, the mean annualised total number of systemic corticosteroid courses dueto 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 5-

Dimension Youth Visual Analog Scale (EQ-VAS) in both the type 2 inflammation and the baselineblood eosinophil count of ≥ 300 cells/mcL populations at week 52; the LS mean difference versusplacebo 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 asmeasured by the Paediatric Asthma Quality of Life Questionnaire (PACQLQ) in both the type 2inflammation 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 asthmapatients (6 to 11 years of age) in the long-term extension study (EXCURSION). There were sustainedreductions in exacerbations requiring hospitalization and/or emergency room visits and a reduction inexposure to systemic oral corticosteroids. Sustained improvements in lung function were observedacross multiple parameters including percent predicted FEV1, percent predicted FVC, FEV1/FVC ratioand percent predicted FEF 25-75%. Furthermore, 75% of patients achieved and/or maintained normallung 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 and safety in eosinophilic esophagitis

Paediatric Patients 1 to 11 Years of Age with EoE

The efficacy and safety of dupilumab was evaluated in paediatric patients 1 to 11 years of age with

EoE in a two-part study up to 52-weeks (EoE KIDS Part A & Part B). All enrolled patients had to havefailed conventional medicinal therapy (proton pump inhibitors), 77.5% were treated with anotherconventional medicinal therapy (swallowed topical corticosteroids) prior to inclusion, and 53.5% ofpatients were inadequately controlled, intolerant or contraindicated to swallowed topical corticosteroidtreatment. Eligible patients had ≥15 intraepithelial eosinophils per high-power field (eos/hpf) despite atreatment course of a proton pump inhibitor (PPI) either prior to or during the screening period and ahistory of EoE signs and symptoms. Part A was a 16-week randomized, double-blind, parallel-group,multicenter, placebo-controlled trial. Part B was an active treatment extension period evaluating thedupilumab regimens for an additional 36 weeks.

Part A evaluated dupilumab versus matching placebo at dosing regimens based on body weight (≥5 to<15 kg (100 mg Q2W), ≥15 to <30 kg (200 mg Q2W), and ≥30 to <60 kg (300 mg Q2W). Therecommended dosing regimen of dupilumab was selected for paediatric patients 1 to 11 years of ageweighing ≥40 kg (300 mg QW) based upon simulations with a population pharmacokinetic model tomatch exposures of adult and paediatric patients 12 to 17 years of age with EoE receiving 300mg QWfor whom histologic and symptomatic efficacy were observed [see section 5.1 and section 5.2].

A total of 71 patients were enrolled in Part A. The mean age was 7 years (range 1 to 11 years), themedian weight was 24.8 kg, 74.6% of patients were male, 87.3% were White, 9.9% were Black, and1.4% were Asian. A total of 55 patients from Part A continued in Part B.

The primary efficacy endpoint in Part A was the proportion of patients achieving histologicalremission defined as peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at Week 16.

Secondary endpoints included the proportion of patients achieving peak esophageal intraepithelialeosinophil count of <15 eos/hpf and the change from baseline in the following: peak esophagealintraepithelial 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, and absolutechange in EoE-Endoscopic Reference Score (EoE-EREFS). The impact on signs of EoE was measuredusing observer reported outcomes; Paediatric EoE Sign/Symptom Questionnaire-Caregiver (PESQ-C)assessed the proportion of days with one or more EoE signs and Paediatric Eosinophilic Esophagitis

Symptom Score (PEESS) assessed the frequency and severity of EoE signs.

Efficacy results for Part A are presented in Table 19 and below.

Table 19: Efficacy Results of dupilumab at Week 16 in Subjects 1 to 11 Years of Age with EoE(EoE KIDS Part A)

Placebo Difference vs

Dupilumab a

N=34 Placebo

N=37(95% CI)

Primary Endpoint

Proportion of subjects achievinghistological remission (peak25 1 64.5esophageal intraepithelial(67.6) (2.9) (48.19, 80.85)eosinophil count ≤6 eos/hpf), n(%)b

Secondary Endpoints

Proportion of subjects achievingpeak esophageal intraepithelial 31 1 81eosinophil count of <15 eos/hpf, n (83.8) (2.9) (68.07, 94.10)(%)b

Percent change from baseline inpeak esophageal intraepithelial -86.09 20.98 -107.07eosinophil count (eos/hpf), LS (11.84) (12.23) (-139.25, -74.90)mean (SE)c

Absolute change in Mean Grade

Score (0-3d) from the Histology -0.879 0.023 -0.902

Scoring System (EoEHSS) from (0.05) (0.05) (-1.03, -0.77)baseline, LS mean (SE)

Absolute change in Mean Stage

- 0.835 0.048 -0.883

Score (0-3d) from the EoEHSS(0.05) (0.05) (-1.01, -0.76)from baseline, LS mean (SE)

Absolute change in EoE-

Endoscopic Reference -3.5 0.3 -3.8

Score(EoE-EREFS) (0-18e) from (0.42) (0.45) (-4.94, -2.63)baseline, LS mean (SE)a DUPIXENT was evaluated at tiered dosing regimens based on body weight: ≥5 to <15 kg (100 mg Q2W), ≥15to <30 kg (200 mg Q2W), and ≥30 to <60 kg (300 mg Q2W).b For histological remission, the difference in percentages is estimated using the Mantel-Haenszel method,adjusting for baseline weight group (≥5 to <15 kg, ≥15 to <30 kg, and ≥30 to <60 kg).c The difference in absolute change or percent change is estimated using ANCOVA model with baselinemeasurement as covariate and the treatment, baseline weight group (≥5 to <15 kg, ≥15 to <30 kg, and ≥30 to<60 kg) strata as fixed factors.

d EoEHSS scores range from 0 to 3; higher scores indicate greater severity and extent of histologicalabnormalities.e EoE-EREFS overall scores range from 0 to 18; higher scores indicate worse endoscopic inflammatory andremodeling findings.

In Part A, a greater proportion of patients randomized to dupilumab achieved histological remission(peak esophageal intraepithelial eosinophil count ≤6 eos/hpf) compared to placebo. The proportion ofsubjects with histological remission observed after 16 weeks of treatment in Part A was maintained for52 weeks in Part B.

Numerical improvement in the proportion of days with 1 or more EoE signs (PESQ-C) was observedafter 16 weeks of treatment in Part A and was maintained for 52 weeks in Part B.

Nominally significant improvement in the frequency and severity of EoE signs (PEESS-Caregiver)was observed after 16 weeks of treatment in Part A. PEESS-Caregiver was not measured in Part B.

Adults and Adolescents with eosinophilic esophagitis

For clinical data in adults and adolescents with eosinophilic esophagitis please refer to the dupilumab300 mg Summary of Product Characteristics.

The safety and efficacy of dupilumab have been established in paediatric patients 6 months of age andolder with atopic dermatitis. Use of dupilumab in this age group is supported by study AD-1526 whichincluded 251 adolescents aged 12 to 17 years old with moderate-to-severe atopic dermatitis, in study

AD-1652 which included 367 paediatric patients aged 6 to 11 years old with severe atopic dermatitis,and study AD-1539 which included 162 children ages 6 months to 5 years old with moderate-to-severeatopic dermatitis (125 of whom had severe atopic dermatitis). Long term use is supported by study

AD-1434 which enrolled 823 paediatric patients aged 6 months to 17 years of age; this included 275adolescents, 368 children 6 to 11 years of age, and 180 children 6 months to 5 years of age. The safetyand efficacy were generally consistent between children 6 months to 5 years old, 6 to 11 years old,adolescent (12 to 17 years old), and adult patients with atopic dermatitis (see section 4.8). Safety andefficacy in paediatric patients < 6 months 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 placeboeither 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthmaexacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and300 mg every other week doses, significant improvements in FEV1 (LS mean change from baseline atweek 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 safetyprofile 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 theopen label long-term study (TRAVERSE). In this study, efficacy was measured as a secondaryendpoint, 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 ofdupilumab 300 mg Q4W in children aged 6 to 11 years is extrapolated from the efficacy of 100 mgand 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 labelextension study (EXCURSION). Eighteen patients (≥ 15 kg to < 30 kg) out of 365 patients wereexposed 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.

Eosinophilic Esophagitis

The safety and efficacy of dupilumab for the treatment of EoE have been established in paediatricpatients 1 to 17 years of age. Use of dupilumab in this population is supported by adequate and well-controlled studies and additional pharmacokinetic data. A total of 72 paediatric patients 12 to 17 yearsof age received dupilumab 300 mg QW or placebo for 24 weeks (TREET Parts A and B). Of these,there were 37 dupilumab treated patients in Parts A and B; 34 continued treatment with 300 mg QWfor an additional 28 weeks (TREET Part C). A total of 71 paediatric patients 1 to 11 years of agereceived dupilumab 100 mg Q2W, 200 mg Q2W, 300 mg Q2W, or placebo for 16 weeks (EoE KIDS

Part A). Of these, there were 37 dupilumab treated patients in Part A all of whom continued treatmentwith these dupilumab regimens for an additional 36 weeks (EoE KIDS Part B). The use of dupilumab300 mg QW in patients 1 to 11 years of age with EoE with a body weight 40 ≥ kg is also supported bya population pharmacokinetic analysis [see section 5.1]. The safety and efficacy of dupilumab inadults and paediatric patients were similar [see section 4.8 and section 5.1].

The European Medicines Agency has deferred the obligation to submit the results of studies withdupilumab in one or more subset of the paediatric population in asthma (see section 4.2 forinformation on paediatric use). Obligations related to the paediatric investigation plans for atopicdermatitis and EoE have been fulfilled.

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

After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximumconcentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SCdose is similar between AD and asthma patients, ranging between 61 % and 64 %, as determined by apopulation pharmacokinetics (PK) analysis.

Steady-state concentrations were achieved by week 16 following the administration of 600 mg startingdose and 300 mg dose every other week. Across clinical trials, the mean ±SD steady-state troughconcentrations ranged from 69.2±36.9 mcg/mL to 80.2±35.3 mcg/mL for 300 mg dose and from29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg dose administered every other week to adults.

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

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

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higherconcentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, whileat 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 times to decrease below the lower limit of detection, estimated bypopulation PK analysis, ranged from 9-13 weeks in adults and adolescents and are approximately 1.5times and 2.5 times longer in paediatric patients 6 to 11 years of age and paediatric subjects less than 6years of age, respectively.

Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-timecurve, increases with dose in a greater than proportional manner following single SC doses from 75-600 mg.

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

Of the 1539 patients with atopic dermatitis, including patients with atopic hand and foot dermatitisexposed to dupilumab in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of71 were 65 years or older. Although no differences in safety or efficacy were observed between olderand younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficientto determine whether they respond differently from younger patients.

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

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

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

Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. Noclinical studies have been conducted to evaluate the effect of hepatic impairment on thepharmacokinetics of dupilumab.

Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. Noclinical studies have been conducted to evaluate the effect of renal impairment on thepharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renalimpairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Verylimited data are available in patients with severe renal impairment.

Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningfulimpact on efficacy.

Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and inpaediatric patients 6 to 17 years of age. In paediatric patients from 6 months to 5 years of age,clearance increased with age but is accommodated in the recommended dose regimen.

The pharmacokinetics of dupilumab in paediatric patients (< 6 months of age) or body weight < 5 kgwith 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 ofdupilumab was 54.5±27.0 mcg/mL.

For children 6 to 11 years of age with atopic dermatitis receiving every four week dosing (Q4W) with300 mg (≥ 15 kg) in AD-1652, the mean ± SD steady-state trough concentration was 76.3±37.2mcg/mL. At week 16 in AD-1434 in children 6 to 11 years of age who initiated every four weekdosing (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 troughconcentration was 108±53.8 mcg/mL. For children 6 to 11 years of age receiving 300 mg Q4W, initialdoses of 300 mg on Days 1 and 15 produce similar steady-state exposure as an initial dose of 600 mgon Day 1, based on PK simulations.

For children 6 months to 5 years of age with atopic dermatitis receiving every four week dosing(Q4W) with 300 mg (≥ 15 to < 30 kg) or 200 mg (≥ 5 to < 15 kg) mean ± SD steady-state troughconcentration was 110±42.8 mcg/mL and 109±50.8 mcg/mL, respectively.

Asthma

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

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 pharmacokineticdifference was observed in adolescent patients after correction for body weight.

In the VOYAGE study, dupilumab pharmacokinetics was investigated in 270 patients with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 childrenweighing < 30 kg) or 200 mg Q2W (for 179 children weighing ≥ 30 kg). The volume of distributionfor dupilumab of approximately 3.7 L was estimated by population PK analysis. Steady-stateconcentrations were achieved by week 12. The mean ± SD steady-state trough concentration was58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneousdose in children aged 6 to 11 years with body weight of ≥ 15 kg to < 30 kg and ≥ 30 kg to < 60 kgresulted in predicted steady-state trough concentrations similar to the observed trough concentrationsof 200 mg Q2W (≥ 30 kg) and 100 mg Q2W (< 30 kg), respectively. In addition, simulation of a 300mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥ 15 kg to < 60 kgresulted in predicted steady-state trough concentrations similar to those demonstrated to be efficaciousin adults and adolescents. After the last steady state dose, the median time for dupilumabconcentrations 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.

Eosinophilic esophagitis

In a clinical study (EoE KIDS Part A), dupilumab pharmacokinetics were investigated in 36 children 1to 11 years of age with EoE receiving dupilumab [≥5 to <15 kg (100 mg Q2W), ≥15 to <30 kg (200mg Q2W), and ≥30 to <60 kg (300 mg Q2W)], the mean ± SD steady-state trough concentration ofdupilumab was 163±60.8 mcg/mL.

Simulations for paediatric patients 1 to 11 years of age were conducted with a populationpharmacokinetic model to predict trough concentrations of dupilumab at steady-state as follows: ≥15to <30 kg receiving 200 mg Q2W (170±78 mcg/mL); ≥30 to <40 kg receiving 300 mg Q2W (158±63mcg/mL); or ≥40 kg receiving 300 mg QW (276±99 mcg/mL). Steady-state trough concentrationswere also simulated for adult and paediatric patients 12 to 17 years of age and patients from ≥30 to<40 kg receiving 300 mg Q2W (159±61 mcg/mL).

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

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

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

During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific tothe 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 animalsor their offspring up to 6 months post-partum/post-birth.

Fertility studies conducted in male and female mice using a surrogate antibody against IL-4R showedno 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 medicinalproducts.

3 years.

If necessary, the pre-filled syringe or pre-filled pen can be removed from the refrigerator and kept inthe pack for up to 14 days at room temperature up to 25 °C, while protected from light. The date ofremoval from the refrigerator shall be recorded in the space provided on the outer carton. The packmust be discarded if left out of the refrigerator for more than 14 days or if the expiry date has passed.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

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

Dupixent 200 mg solution for injection in pre-filled syringe1.14 mL solution in a siliconised type-1 clear glass pre-filled syringe with needle shield, with a fixed27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.

* 1 pre-filled syringe

* 2 pre-filled syringes

* Multipack containing 6 (3 packs of 2) pre-filled syringes

Dupixent 200 mg solution for injection in pre-filled pen1.14 mL solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a fixed 27 gauge12.7 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 anarrow or with a square cap with ridges and an oval viewing window without an arrow.

* 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 syringe or in a pre-filledpen 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 200 mg pre-filled syringe or pre-filled pen from the refrigerator, it should beallowed to reach room temperature up to 25 °C by waiting for 30 min before injecting Dupixent.

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

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

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/17/1229/009

EU/1/17/1229/010

EU/1/17/1229/012

EU/1/17/1229/013

EU/1/17/1229/014

EU/1/17/1229/016

EU/1/17/1229/023

EU/1/17/1229/024

EU/1/17/1229/025

Date of first authorisation: 26 September 2017

Date of latest renewal: 02 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu