This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Dupixent 300 mg solution for injection in pre-filled syringe

2. Qualitative and quantitative composition

Dupilumab 300 mg solution for injection in pre-filled syringe

Each single-use pre-filled syringe contains 300 mg of dupilumab in 2 ml solution (150 mg/ml).

Dupilumab is a fully human monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signalling, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection (injection)

Clear to slightly opalescent, colourless to pale yellow solution, which is free from visible particulates.

4. Clinical particulars
4.1 Therapeutic indications

Atopic Dermatitis

Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adult patients who are candidates for systemic therapy.

Asthma

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

4.2 Posology and method of administration

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

Posology

Atopic Dermatitis

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

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

Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Asthma

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

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

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

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

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

Missed dose

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

Special populations

Elderly patients (≥ 65 years)

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

Renal impairment

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

Hepatic impairment

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

Body weight

No dose adjustment for body weight is recommended (see section 5.2).

Paediatric patients

The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 18 years have not been established (see section 5.2). No data are available.

The safety and efficacy of dupilumab in children with severe asthma below the age of 12 years have not been established (see section 5.2). No data are available.

Method of administration

Subcutaneous use

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

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

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

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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

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

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

Traceability

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

Hypersensitivity

If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of dupilumab should be discontinued immediately and appropriate therapy initiated. Very rare cases of serum sickness/serum sickness-like reactions have been reported in the atopic dermatitis development program following the administration of dupilumab. Anaphylactic reaction has been reported very rarely in the asthma development program following the administration of dupilumab (section 4.8).

Eosinophilic conditions

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

Helminth infection

Patients with known helminth infections were excluded from participation in clinical studies. Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signaling. Patients with pre-existing helminth infections should be treated before initiating dupilumab. If patients become infected while receiving treatment with dupilumab and do not respond to anti-helminth treatment, treatment with dupilumab should be discontinued until infection resolves.

Conjunctivitis related events

Patients treated with dupilumab who develop conjunctivitis that does not resolve following standard treatment should undergo ophthalmological examination (section 4.8).

Atopic dermatitis patients with comorbid asthma

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

Vaccinations

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

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, i.e. essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

Dupilumab has no or negligible influence on the ability to drive or operate machinery.

4.8 Undesirable effects

Atopic dermatitis

Summary of the safety profile

The most common adverse reactions were injection site reactions, conjunctivitis, blepharitis, and oral herpes. Very rare cases of serum sickness/serum sickness-like reactions have been reported in the atopic dermatitis development program (see section 4.4).

In the monotherapy studies, the proportion of patients who discontinued treatment due to adverse events was 1.9 % of the placebo group, 1.9 % of the dupilumab 300 mg Q2W group, 1.5 % of the dupilumab 300 mg QW group. In the concomitant TCS study, the proportion of patients who discontinued treatment due to adverse events was 7.6 % of the placebo + TCS group, 1.8 % of the dupilumab 300 mg Q2W + TCS group, and 2.9 % of the dupilumab 300 mg QW + TCS group.

Tabulated list of adverse reactions

The safety of dupilumab was evaluated in four randomized, double-blind, placebo-controlled studies and one dose-ranging study in patients with moderate-to-severe atopic dermatitis. In these 5 trials, 1,689 subjects were treated with subcutaneous injections of dupilumab, with or without concomitant topical corticosteroids (TCS). A total of 305 patients were treated with dupilumab for at least 1 year.

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

Table 1: List of adverse reactions in atopic dermatitis

MedDRA System Organ Class

Frequency

Adverse Reaction

Infections and infestations

Common

Conjunctivitis

Oral herpes

Blood and lymphatic system disorders

Common

Eosinophilia

Immune system disorders

Very rare

Serum sickness/serum sickness-like reactions

Nervous system disorders

Common

Headache

Eye disorders

Common

Conjunctivitis allergic

Eye pruritus

Blepharitis

General disorders and administration site conditions

Very common

Injection site reactions

Asthma

Summary of the safety profile

The most common adverse reaction was injection site erythema. Anaphylactic reaction has been reported very rarely in the asthma development program (see section 4.4).

In DRI12544 and QUEST studies, the proportion of patients who discontinued treatment due to adverse events was 4.3% of the placebo group, 3.2% of the dupilumab 200 mg Q2W group, and 6.1% of the dupilumab 300 mg Q2W group.

Tabulated list of adverse reactions

A total of 2,888 adult and adolescent patients with moderate-to-severe asthma were evaluated in 3 randomised, placebo-controlled, multicentre trials of 24 to 52 weeks duration (DRI12544, QUEST, and VENTURE). Of these, 2,678 had a history of 1 or more severe exacerbations in the year prior to enrolment despite regular use of medium-to-high dose inhaled corticosteroids plus an additional controller(s) (DRI12544 and QUEST). A total of 210 patients with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (VENTURE).

Listed in Table 2 are adverse reactions observed in asthma clinical trials presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: List of adverse reactions in asthma

MedDRA System Organ Class

Frequency

Adverse Reaction

Immune system disorders

Very rare

Anaphylactic reaction

General disorders and administration site conditions

Very common

Common

Common

Common

Injection site erythema

Injection site oedema

Injection site pain

Injection site pruritus

Description of selected adverse reactions in atopic dermatitis and asthma indications

Hypersensitivity

Very rare cases of serum sickness/serum sickness-like reactions and anaphylactic reaction have been reported following administration of dupilumab (see section 4.4).

Conjunctivitis and related events

Conjunctivitis occurred more frequently in atopic dermatitis patients who received dupilumab. Most patients with conjunctivitis recovered or were recovering during the treatment period. Among asthma patients frequency of conjunctivitis was low and similar between dupilumab and placebo (see section 4.4).

Eczema herpeticum

Eczema herpeticum was reported in < 1 % of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy studies. In the 52-week atopic dermatitis dupilumab + TCS study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS group and 1.9 % of the placebo + TCS group.

Eosinophilia

Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo. Eosinophil counts declined to near baseline levels during study treatment.

Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was reported in < 2 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients.

Infections

In the 16-week atopic dermatitis monotherapy clinical studies, serious infections were reported in 1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS study, serious infections were reported in 0.6 % of patients treated with placebo and 0.2 % of patients treated with dupilumab.

Immunogenicity

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

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

Approximately 6 % of patients with atopic dermatitis or asthma who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies.

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

Approximately 5 % of patients in the placebo groups in the 52 week studies were also positive for antibodies to dupilumab; approximately 2 % exhibited persistent ADA response and approximately 1% had neutralizing antibodies.

Less than 0.4 % of patients exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers (see section 4.4).

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

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

Pharmacodynamic effects

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

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

Clinical efficacy and safety in atopic dermatitis

The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥16, and a minimum body surface area (BSA) involvement of ≥ 10 %. Eligible patients enrolled into the three studies had previous inadequate response to topical medication.

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

SOLO 1 enrolled 671 patients (224 to placebo, 224 to dupilumab 300 mg Q2W, and 223 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.

SOLO 2 enrolled 708 patients (236 to placebo, 233 to dupilumab 300 mg Q2W, and 239 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.

CHRONOS enrolled 740 patients (315 to placebo + topical corticosteroid (TCS), 106 to dupilumab 300 mg Q2W + TCS, and 319 to dupilumab 300 mg QW + TCS) and had a treatment period of 52 weeks. Patients received dupilumab or placebo with concomitant use of TCS starting at baseline using a standardized regimen. Patients were also permitted to use topical calcineurin inhibitors (TCI).

Endpoints

In all three pivotal studies, the co-primary endpoints were the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points on a 0-4 IGA scale and the proportion of patients with improvement of at least 75 % in EASI (EASI-75) from baseline to week 16. Other evaluated outcomes included the proportion of patients with improvement of at least 50 % and 90 % in EASI (EASI-50 and EASI-90, respectively), reduction in itch as measured by the peak pruritus Numerical Rating Scale (NRS), and percent change in the SCORing Atopic Dermatitis (SCORAD) scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Hospital Anxiety and Depression Scale (HADS) scores. In CHRONOS, efficacy was also evaluated at week 52.

Baseline Characteristics

In the monotherapy studies (SOLO 1 and SOLO 2), across all treatment groups, the mean age was 38.3, the mean weight was 76.9 kg, 42.1% were female, 68.1% were white, 21.8% were Asian, and 6.8% were black. In these studies, 51.6 % of patients had a baseline IGA score of 3 (moderate AD), 48.3 % of patients had a baseline IGA of 4 (severe AD) and 32.4 % of patients had received prior systemic immunosuppressants. The baseline mean EASI score was 33.0, the baseline weekly averaged pruritus NRS was 7.4, the baseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.5, the baseline mean DLQI was 15.0, and the baseline mean HADS total score was 13.3.

In the concomitant TCS study (CHRONOS), across all treatment groups, the mean age was 37.1, the mean weight was 74.5 kg, 39.7 % were female, 66.2 % were white, 27.2 % were Asian, and 4.6 % were black. In this study, 53.1 % of patients had a baseline IGA score of 3 and 46.9 % of patients had a baseline IGA of 4 and 33.6 % of patients received prior systemic immunosuppressants. The baseline mean EASI score was 32.5, the baseline weekly pruritus NRS was 7.3, the baseline mean SCORAD score was 66.4, the baseline mean POEM score was 20.1, the baseline mean DLQI was 14.5, and the baseline mean HADS total score was 12.7.

Clinical Response

16-Week Monotherapy Studies (SOLO 1 and SOLO 2)

In SOLO 1 and SOLO 2, from baseline to week 16, a significantly greater proportion of patients randomized to dupilumab achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of > 4 points on the pruritus NRS compared to placebo (see Table 3).

A significantly greater proportion of patients randomized to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 2; p < 0.01) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.

Figure 1 and Figure 2 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively up to week 16.

Table 3: Efficacy results of dupilumab monotherapy at week 16 (FAS)

SOLO 1 (FAS)a

SOLO 2 (FAS)a

Placebo

Dupilumab

300 mg Q2W

Dupilumab

300 mg QW

Placebo

Dupilumab

300 mg Q2W

Dupilumab

300 mg QW

Patients randomised

224

224

223

236

233

239

IGA 0 or 1b, % respondersc

10.3 %

37.9 %e

37.2 %e

8.5 %

36.1 %e

36.4 %e

EASI-50, % respondersc

24.6 %

68.8 %e

61.0 %e

22.0 %

65.2 %e

61.1 %e

EASI-75, % respondersc

14.7 %

51.3 %e

52.5 %e

11.9 %

44.2 %e

48.1 %e

EASI-90, % respondersc

7.6 %

35.7 %e

33.2 %e

7.2 %

30.0 %e

30.5 %e

EASI, LS mean % change from baseline (+/-SE)

-37.6 %

(3.28)

-72.3 %e

(2.63)

-72.0 %e (2.56)

-30.9 % (2.97)

-67.1 %e

(2.52)

-69.1 %e (2.49)

SCORAD, LS mean % change from baseline (+/- SE)

-29.0 % (3.21)

-57.7 %e

(2.11)

-57.0 %e

(2.11)

-19.7 %

(2.52)

-51.1 %e

(2.02)

-53.5 %e

(2.03)

Pruritus NRS, LS mean % change from baseline (+/- SE)

-26.1 % (3.02)

-51.0 %e

(2.50)

-48.9 %e

(2.60)

-15.4 %

(2.98)

-44.3 %e

(2.28)

-48.3 %e

(2.35)

Number of patients with baseline pruritus NRS score > 4

212

213

201

221

225

228

Pruritus NRS (> 4-point improvement), % respondersc, d

12.3 %

40.8 %e

40.3 %e

9.5%

36.0 %e

39.0 %e

LS = least squares; SE= standard error

a Full analysis set (FAS) includes all patients randomized.

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

c Patients who received rescue treatment or with missing data were considered as non-responders.

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

e p-value <0.0001

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

SOLO 1

SOLO 2

LS = least squares

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

b Full analysis set (FAS) includes all patients randomized.

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

SOLO 1

SOLO 2

LS = least squares

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

b Full analysis set (FAS) includes all patients randomized.

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

52-Week Concomitant TCS Study (CHRONOS)

In CHRONOS, a significantly greater proportion of patients randomized to dupilumab 300 mg Q2W + TCS achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of > 4 points on the pruritis NRS from baseline to week 16 and week 52 compared to placebo + TCS (see Table 4).

A significantly greater proportion of patients randomized to dupilumab + TCS achieved a rapid improvement in the pruritus NRS compared to placebo + TCS (defined as > 4-point improvement as early as week 2; p < 0.05) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.

Figure 3 and Figure 4 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively, up to week 52 in CHRONOS.

Table 4: Efficacy results of dupilumab with concomitant TCSa at Week 16 and Week 52 in CHRONOS

Week 16 (FAS)b

Week 52 (FAS Week 52) b

Placebo + TCS

Dupilumab

300 mg Q2W + TCS

Dupilumab

300 mg QW + TCS

Placebo +

TCS

Dupilumab

300 mg Q2W + TCS

Dupilumab

300 mg QW + TCS

Patients randomized

315

106

319

264

89

270

IGA 0 or 1c, % respondersd

12.4 %

38.7 %f

39.2 %f

12.5 %

36.0 %f

40.0 %f

EASI-50, % respondersd

37.5 %

80.2 %f

78.1 %f

29.9 %

78.7 %f

70.0 %f

EASI-75, % respondersd

23.2 %

68.9 %f

63.9 %f

21.6 %

65.2 %f

64.1 %f

EASI-90, % respondersd

11.1 %

39.6 %f

43.3 %f

15.5 %

50.6 %f

50.7 %f

EASI, LS mean % change from baseline (+/- SE)

-48.4 %

(3.82)

-80.5 %f

(6.34)

-81.5 %f

(5.78)

-60.9 %

(4.29)

-84.9 %g

(6.73)

-87.8 %h

(6.19)

SCORAD, LS mean % change from baseline (+/- SE)

-36.2 %

(1.66)

-63.9 %f

(2.52)

-65.9 %f

(1.49)

-47.3 %

(2.18)

-69.7 %f

(3.06)

-70.4 %f

(1.72)

Pruritus NRS, LS mean % change from baseline (+/- SE)

-30.3 %

(2.36)

-56.6 %f

(3.95)

-57.1 %f

(2.11)

-31.7 %

(3.95)

-57.0 %i

(6.17)

-56.5 %f

(3.26)

Number of patients with baseline pruritus NRS score 4

299

102

295

249

86

249

Pruritus NRS (4-point improvement), % respondersd, e

19.7 %

58.8 %f

50.8 %f

12.9 %

51.2 %f

39.0 %f

LS = least squares; SE = standard error

a All patients were on background topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors.

b Full analysis set (FAS) includes all patients randomized. FAS week 52 includes all patients randomized at least one year before the cutoff date of the primary analysis.

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

d Patients who received rescue treatment or with missing data were considered as non-responders.

e a significantly greater proportion of patients on dupilumab had improvement in pruritus NRS of ≥ 4 points compared to placebo at week 2 (p < 0.05).

f p-value < 0.0001

g p-value = 0.0015

h p-value = 0.0003

i p-value = 0.0005

Figure 3: Mean percent change from baseline in EASI in CHRONOSa (FAS Week 52)b

CHRONOS

LS = least squares

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

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

Figure 4: Mean percent change from baseline in NRS in CHRONOSa (FAS Week 52)b

CHRONOS

LS = least squares

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

bFAS week 52 includes all patients randomized at least one year before the cutoff date of the primary analysis.

Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in CHRONOS were consistent with the results in the overall study population.

Clinical Response in Patients Not Adequately Controlled with, Intolerant to, or for whom Ciclosporin Treatment was Inadvisable (CAFE study)

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

A total of 325 patients were enrolled, with 210 patients who were previously exposed to ciclosporin and 115 patients who have never been exposed to ciclosporin because ciclosporin treatment was medically inadvisable. The mean age was 38.4 years, 38.8 % were female, the baseline mean EASI score was 33.1, the mean BSA was 55.7, the baseline weekly average pruritis NRS was 6.4, the baseline mean SCORAD score was 67.2, and the baseline mean DLQI was 13.8.

The primary endpoint was the proportion of patients with EASI-75 at week 16.

Primary and secondary endpoints for the 16 week CAFE study are summarized in table 5.

Table 5: Results of the primary and secondary endpoints in CAFE study

Placebo + TCS

Dupilumab

300 mg Q2W + TCS

Dupilumab

300 mg QW+TCS

Patients randomised

108

107

110

EASI-75, % responders

29.6 %

62.6 %

59.1 %

EASI, LS mean % change from baseline (+/- SE)

-46.6

(2.76)

-79.8

(2.59)

-78.2

(2.55)

Pruritus NRS, LS mean % change from baseline (+/- SE)

-25.4 %

(3.39)

-53.9 %

(3.14)

-51.7 %

(3.09)

SCORAD, LS mean % change from baseline (+/- SE)

-29.5 %

(2.55)

-62.4 %

(2.48)

-58.3 %

(2.45)

DLQI, LS mean change from baseline (SE)

-4.5

(0.49)

-9.5

(0.46)

-8.8

(0.45)

(all p values <0.0001)

In the subgroup of patients resembling the CAFE study population within the 52 week CHRONOS study, 69.6 % of dupilumab 300 mg Q2W-treated patients reached EASI-75 vs 18.0 % placebo-treated patients at week 16, and 52.4 % of dupilumab 300 mg Q2W-treated vs 18.6 % placebo-treated at week 52. In this subset, the percent change of pruritus NRS from baseline was -51.4 % vs -30.2 % at week 16 and -54.8 % vs -30.9 % at week 52, for the dupilumab 300 mg Q2W and placebo groups respectively.

Maintenance and Durability of Response (SOLO CONTINUE study)

To evaluate maintenance and durability of response, subjects treated with dupilumab for 16 weeks in SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomized in SOLO CONTINUE study to an additional 36-week treatment of dupilumab or placebo, for a cumulative 52-week study treatment. Endpoints were assessed at weeks 51 or 52.

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

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

Primary and secondary endpoints for the 52 week SOLO CONTINUE study are summarized in table 6.

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

Placebo

Dupilumab 300 mg

N=83

Q8W

N=84

Q4W

N=86

Q2W/QW

N=169

Co-Primary Endpoints

LS mean change (SE) between baseline and week 36 in percent change in EASI Score from Parent Study baseline

21.7

(3.13)

6.8***

(2.43)

3.8***

(2.28)

0.1***

(1.74)

Percent of patients with EASI-75 at week 36 for patients with EASI-75 at baseline, n (%)

24/79

(30.4%)

45/82*

(54.9%)

49/84**

(58.3%)

116/162***

(71.6%)

Key Secondary Endpoints

Percent of patients whose IGA response at week 36 was maintained within 1 point of baseline in the subset of patients with IGA (0,1) at baseline, n (%)

18/63

(28.6)

32/64

(50.0)

41/66**

(62.1)

89/126***

(70.6)

Percent of patients with IGA (0,1) at week 36 in the subset of patients with IGA (0,1) at baseline, n (%)

9/63

(14.3)

21/64

(32.8)

29/66** (43.9)

68/126***

(54.0)

Percent of patients whose peak pruritus NRS increased by ≥ 3 points from baseline to week 35 in the subset of patients with peak pruritus NRS ≤ 7 at baseline, n (%)

56/80

(70.0)

45/81

(55.6)

41/83

(49.4)

57/168***

(33.9)

P< 0.05, *P< 0.01, **P< 0.001, ***P≤ 0.0001

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

Quality of Life/Patient-Reported Outcomes in Atopic Dermatitis

In both monotherapy studies (SOLO 1 and SOLO 2), both dupilumab 300 mg Q2W and 300 mg QW groups significantly improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 16 weeks compared to placebo. A significantly larger proportion of patients administered dupilumab groups had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4 points improvement) from baseline to week 16 compared to placebo group. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the dupilumab groups compared to placebo at 16 weeks. In a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥ 8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab groups achieved HADS-anxiety and HADS-depression scores < 8 at week 16 compared to placebo (See Table 7).

Table 7: Additional secondary endpoint results of dupilumab monotherapy at Week 16

Monotherapy

SOLO 1 at Week 16

SOLO 2 at Week 16

Placebo

Dupilumab

300 mg Q2W

Dupilumab

300 mg QW

Placebo

Dupilumab

300 mg Q2W

Dupilumab

300 mg QW

Patients randomized

224

224

223

236

233

239

DLQI, LS mean change from baseline (SE)

-5.3

(0.50)

-9.3a

(0.40)

-9.0a

(0.40)

-3.6

(0.50)

-9.3a

(0.38)

-9.5a

(0.39)

POEM, LS mean change from baseline (SE)

-5.1

(0.67)

-11.6a

(0.49)

-11.0a

(0.50)

-3.3

(0.55)

-10.2a

(0.49)

-11.3a

(0.52)

HADS, LS mean change from baseline (SE)

-3.0

(0.65)

-5.2b

(0.54)

-5.2b

(0.51)

-0.8

(0.44)

-5.1a

(0.39)

-5.8a

(0.38)

Number of patients with DLQI 4 at baseline

213

209

209

225

223

234

DLQI

(≥ 4-point improvement), % responders

30.5 %

64.1 %a

58.4 %a

27.6 %

73.1 %a

62.0 %a

Number of patients with POEM 4 at baseline

223

222

222

234

233

239

POEM

(≥ 4-point improvement), % responders

26.9 %

67.6 %a

63.1 %a

24.4 %

71.7 %a

64.0 %a

Number of patients with HADS-anxiety ≥ 8 or HADS-depression ≥ 8 at baseline

97

100

102

115

129

136

Patients achieving HADS-anxiety and HADS-depression score < 8, %

12.4 %

41.0 %a

36.3 %b

6.1 %

39.5 %a

41.2 %a

LS = least squares; SE = standard error

a p-value < 0.0001

b p-value < 0.001

In the concomitant TCS study (CHRONOS), dupilumab 300 mg Q2W + TCS and dupilumab 300 mg QW + TCS improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 52 weeks compared to placebo + TCS. A larger proportion of patients administered dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4-point improvement) from baseline to week 52 compared to the placebo + TCS. In addition, dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS reduced anxiety and depression as measured by the HADS total score at 52 weeks compared to placebo + TCS. In a post-hoc analysis in a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS groups achieved HADS-anxiety and HADS-depression scores < 8 at week 52 compared to placebo + TCS (See Table 8).

Table 8: Other secondary endpoint results of dupilumab with concomitant TCS at Week 16 and Week 52 in CHRONOS

Concomitant Use of TCS

CHRONOS at Week 16

CHRONOS at Week 52

Placebo

Dupilumab 300 mg Q2W + TCS

Dupilumab 300 mg QW + TCS

Placebo

+TCS

Dupilumab 300 mg Q2W + TCS

Dupilumab

300 mg QW + TCS

Patients randomized

315

106

319

264

89

270

DLQI, LS mean change from baseline (SE)

-5.8

(0.34)

-10.0a

(0.50)

-10.7a

(0.31)

-7.2

(0.40)

-11.4a

(0.57)

-11.1a

(0.36)

POEM, LS mean change from baseline (SE)

-5.3

(0.41)

-12.7a

(0.64)

-12.9a

(0.37)

-7.0

(0.57)

-14.2a

(0.78)

-13.2a

(0.45)

HADS, LS mean change from baseline (SE)

-4.0

(0.37)

-4.9

(0.58)

-5.4c

(0.35)

-3.8

(0.47)

-5.5c

(0.71)

-5.9b

(0.42)

Number of patients with DLQI 4 at baseline

300

100

311

254

85

264

DLQI

(≥ 4-point improvement), % responders

43.0 %

81.0 %a

74.3 %a

30.3 %

80.0 %a

63.3 %a

Number of patients with POEM 4 at baseline

312

106

318

261

89

269

POEM

(4-point improvement), % responders

36.9 %

77.4 %a

77.4 %a

26.1 %

76.4 %a

64.7 %a

Number of patients with HADS-anxiety 8 or HADS-depression 8 at baseline

148

59

154

133

53

138

Patients achieving HADS-anxiety and HADS-depression < 8, %

26.4 %

47.5 %c

47.4 %b

18.0 %

43.4 %b

44.9 %a

LS = least squares; SE = standard error

a p-value < 0.0001

b p-value < 0.001

c p-value < 0.05

Clinical efficacy and safety in asthma

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

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

QUEST was a 52-week confirmatory study which included 1,902 patients (12 years of age and older). Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller medication. Patients requiring a third controller were allowed to participate in this trial. Patients were randomised to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg (N = 317) or 300 mg (N= 321) every other week) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at week 12 in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils and FeNO.

VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, patients received 300 mg dupilumab (n=103) or placebo (n=107) once every other week for 24 weeks following an initial dose of 600 mg or placebo. Patients continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oral corticosteroid dose.

The demographics and baseline characteristics of these 3 studies are provided in Table 9 below.

Table 9: Demographics and Baseline Characteristics of Asthma Trials

Parameter

DRI12544

(n = 776)

QUEST

(n = 1902)

VENTURE

(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 (%)(± SD)

60.77 (10.72)

58.43 (13.52)

52.18 (15.18)

% 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

(AD %, NP %, AR %)

72.9

(8.0, 10.6, 61.7)

77.7

(10.3, 12.7, 68.6)

72.4

(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

≥ 50

 

49.9

21.6

 

49.6

20.5

 

54.3

25.2

Mean total IgE IU/mLSD)

435.05 (753.88)

432.40 (746.66)

430.58 (775.96)

Mean baseline Eosinophil count (± SD) cells/mcL

350 (430)

360 (370)

350 (310)

% patients with EOS

≥ 150 cells/mcL

≥ 300 cells/mcL

 

77.8

41.9

 

71.4

43.7

 

71.4

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 eosinophil

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

Exacerbations

In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 10 and Table 11).

Table 10: 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

%

Reduction

Exacerbations per Year

%

Reduction

N

Rate

(95% CI)

Rate

Ratio (95%CI)

N

Rate

(95% CI)

Rate

Ratio (95%CI)

All Severe Exacerbations

DRI12544 study

Dupilumab200 mg Q2W

120

0.29

(0.16, 0.53)

0.28a

(0.14, 0.55)

72%

65

0.30

(0.13, 0.68)

0.29c

(0.11, 0.76)

71%

Dupilumab300 mg Q2W

129

0.28

(0.16, 0.50)

0.27b

(0.14, 0.52)

73%

64

0.20

(0.08, 0.52)

0.19d

(0.07, 0.56)

81%

Placebo

127

1.05

(0.69, 1.60)

68

1.04

(0.57, 1.90)

QUEST study

Dupilumab200 mg Q2W

437

0.45

(0.37, 0.54)

0.44e

(0.34,0.58)

56%

264

0.37

(0.29, 0.48)

0.34e

(0.24,0.48)

66%

Placebo

232

1.01

(0.81, 1.25)

148

1.08

(0.85, 1.38)

Dupilumab300 mg Q2W

452

0.43

(0.36, 0.53)

0.40 e

(0.31,0.53)

60%

277

0.40

(0.32, 0.51)

0.33e

(0.23,0.45)

67%

Placebo

237

1.08

(0.88, 1.33)

142

1.24

(0.97, 1.57)

ap-value = 0.0003, bp-value = 0.0001, cp-value = 0.0116, dp-value = 0.0024, ep-value <0.0001

Table 11. Rate of Severe Exacerbations in QUEST Defined by Baseline FeNO Subgroups

Treatment

Exacerbations per Year

Percent Reduction

N

Rate (95% CI)

Rate Ratio (95%CI)

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)

ap-value <0.0001

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

Lung Function

Clinically significant increases in pre-bronchodilator FEV1 were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV1 in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 12 and Table 13).

Significant improvements in FEV1 were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 5).

Figure 5: Mean Change from Baseline in Pre-Bronchodilator FEV1 (L) Over Time (Baseline Eosinophils ≥ 150 and ≥ 300 cells/mcL and FeNO ≥25 ppb) in QUEST

QUEST: Blood Eosinophils

≥ 150 cells/mcL

QUEST: Blood Eosinophils

≥ 300 cells/mcL

QUEST: FeNO ≥ 25 ppb

Table 12: 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 From baseline

L (%)

LS Mean

Difference vs. placebo (95% CI)

N

LS mean Δ From baseline

L (%)

LS Mean

Difference vs. placebo (95% CI)

DRI12544 study

Dupilumab200 mg Q2W

108

0.32 (18.25)

0.19a

(0.09, 0.29)

65

0.43 (25.9)

0.26c

(0.11, 0.40)

Dupilumab300 mg Q2W

120

0.26 (17.1)

0.16b

(0.06, 0.26)

64

0.39 (25.8)

0.21d

(0.06, 0.36)

Placebo

102

0.09 (4.36)

68

0.18 (10.2)

QUEST study

Dupilumab200 mg Q2W

425

0.36 (23.6)

0.17e

(0.11, 0.23)

264

0.43 (29.0)

0.21e

(0.13, 0.29)

Placebo

224

0.18 (12.4)

148

0.21 (15.6)

Dupilumab300 mg Q2W

434

0.37 (25.3)

0.15e

(0.09, 0.21)

277

0.47 (32.5)

0.24e

(0.16, 0.32)

Placebo

229

0.22 (14.2)

142

0.22 (14.4)

ap-value <0.0001, bp-value = 0.0004, cp-vaue = 0.0008, dp-value = 0.0063, ep-value <0.0001

Table 13: Mean Change from Baseline in Pre-Bronchodilator FEV1 at Week 12 and Week 52 in QUEST by Baseline FeNO Subgroups

Treatment

At Week 12

At Week 52

N

LS Mean Δ From baseline L (%)

LS Mean Difference vs. placebo (95% CI)

LS Mean Δ From baseline L (%)

LS Mean Difference 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%)

ap-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). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)). Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study.. Similar results were observed in VENTURE. The ACQ-5 and AQLQ(S) responder rate results in patients with elevated baseline biomarkers of type 2 inflammation in QUEST at week 52 are presented in Table 14.

Table 14: ACQ-5 and AQLQ(S) Responder Rates at Week 52 in QUEST

PRO

Treatment

EOS

≥150 cells/mcL

EOS

300 cells/mcL

FeNO

≥25 ppb

N

Responder rate %

N

Responder rate (%)

N

Responder 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 6 months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab.

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

The results for VENTURE by baseline biomarkers are presented in the Table 15.

Table 15: Effect of dupilumab on OCS dose reduction, VENTURE (Baseline Blood Eosinophil Levels ≥ 150 and ≥ 300 cells/mcL and FeNO ≥ 25 ppb)

Baseline Blood EOS

≥ 150 cells/mcL

Baseline Blood EOS

≥ 300 cells/mcL

FeNO ≥ 25 ppb

Dupilumab

300 mg Q2W

N=81

Placebo

N=69

Dupilumab

300 mg Q2W

N=48

Placebo

N=41

Dupilumab

300 mg Q2W

N=57

Placebo

N=57

Primary endpoint (week 24)

Percent reduction in OCS from baseline

Mean overall percent reduction from baseline (%)

Difference (% [95% CI])

(Dupilumab vs. placebo)

75.91

29.39b

(15.67, 43.12)

46.51

79.54

36.83b

(18.94, 54.71)

42.71

77.46

34.53b

(19.08, 49.97)

42.93

Median % reduction in daily OCS dose from baseline

100

50

100

50

100

50

Percent reduction from baseline

100%

≥ 90%

≥ 75%

≥ 50%

> 0%

No reduction or any increase in OCS dose, or dropped out of study

 

54.3

58.0

72.8

82.7

87.7

12.3

 

33.3

34.8

44.9

55.1

66.7

33.3

 

60.4

66.7

77.1

85.4

85.4

14.6

 

31.7

34.1

41.5

53.7

63.4

36.6

 

52.6

54.4

73.7

86.0

89.5

10.5

 

28.1

29.8

36.8

50.9

66.7

33.3

Secondary endpoint (week 24)a

Proportion of patients achieving a reduction of OCS dose to <5 mg/day

77

44

84

40

79

34

Odds ratio (95% CI)

4.29c

(2.04, 9.04)

8.04d

(2.71, 23.82)

7.21b

(2.69, 19.28)

aModel estimates by logistic regression

bp-value <0.0001

cp-value =0.0001

dp-value =0.0002

Paediatric population

A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in

QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant improvements in FEV1 (LS mean change from baseline at eek 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. Safety and efficacy in paediatric patients (< 12 years of age) with severe asthma have not been established. The adverse event profile in adolescents was generally similar to the adults.

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

5.2 Pharmacokinetic properties

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

Absorption

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

Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 60.3±35.1 mcg/mL to 79.9±41.4 mcg/mL for 300 mg dose and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg dose administered every other week.

Distribution

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

Biotransformation

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

Elimination

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates.

After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 9 weeks for the 200 mg Q2W, 10-11 weeks for the 300 mg Q2W regimen and 13 weeks for the 300 mg QW regimen.

Linearity/non-linearity

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

Special populations

Gender

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

Elderly patients

Of the 1,472 patients with atopic dermatitis exposed to dupilumabin a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 67 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

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

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

Race

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

Hepatic impairment

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

Renal impairment

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

Body Weight

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

Paediatric population

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

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

5.3 Preclinical safety data

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

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

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

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

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

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

6. Pharmaceutical particulars
6.1 List of excipients

arginine hydrochloride

histidine

polysorbate 80

sodium acetate trihydrate

glacial acetic acid

sucrose

water for injections

6.2 Incompatibilities

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

6.3 Shelf life

30 months.

If necessary, pre-filled syringes may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. If the carton needs to be removed permanently from refrigerator, the date of removal may be recorded on the outer carton. After removal from the refrigerator, Dupixent must be used within 14 days or discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

6.5 Nature and contents of container

2 ml solution in a siliconised type-1 clear glass pre-filled syringe with or without needle shield, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.

Dupixent 300 mg solution for injection in pre-filled syringe

Pack size:

• 1 pre-filled syringe

• 2 pre-filled syringes

• Multipack containing 3 (3 packs of 1) pre-filled syringes

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The instructions for the preparation and administration of Dupixent in a pre-filled syringe are given in the package leaflet.

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

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

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

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

7. Marketing authorisation holder

sanofi-aventis groupe

54, rue La Boétie

75008 Paris

France

8. Marketing authorisation number(s)

EU/1/17/1229/001

EU/1/17/1229/002

EU/1/17/1229/003

EU/1/17/1229/004

EU/1/17/1229/005

EU/1/17/1229/006

EU/1/17/1229/007

EU/1/17/1229/008

EU/1/17/1229/009

EU/1/17/1229/010

EU/1/17/1229/011

EU/1/17/1229/012

EU/1/17/1229/013

EU/1/17/1229/014

EU/1/17/1229/015

EU/1/17/1229/016

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 26 September 2017

10. Date of revision of the text

1 August 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu