Review of Dupilumab Dose and Efficacy for Adolescent and Pediatric Atopic Dermatitis, Exercises of Pharmacokinetics

Download Review of Dupilumab Dose and Efficacy for Adolescent and Pediatric Atopic Dermatitis and more Exercises Pharmacokinetics in PDF only on Docsity!

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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 Dupixent 300 mg solution for injection in pre-filled pen

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 300 mg solution for injection in pre-filled pen

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

Dupilumab is a fully human monoclonal antibody 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 sterile solution, which is free from visible particulates, with a pH of approximately 5.9.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Atopic dermatitis

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

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

Asthma

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

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

Asthma

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

• For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, an initial dose of 600 mg (two 300 mg injections), followed by 300 mg every other week administered as subcutaneous injection.
• For all other patients, an initial dose of 400 mg (two 200 mg injections), followed by 200 mg every other week administered as subcutaneous injection.

Children 6 to 11 years of age The recommended dose of dupilumab for paediatric patients 6 to 11 years of age is specified in Table 3.

Table 3: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with asthma Body weight Initial and subsequent doses 15 to less than 30 kg 100 mg every other week (Q2W) or 300 mg every four weeks (Q4W) 30 kg to less than 60 kg 200 mg every other week (Q2W) or 300 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 per approved indication, the recommended dose should be followed in Table 2.

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

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

Chronic rhinosinusitis with nasal polyposis (CRSwNP)

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

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

Missed dose

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

Special populations

Elderly ( ≥ 65 years)

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

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

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

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

Paediatric patients The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 years have not been established. The safety and efficacy of dupilumab in children with a body weight < 15 kg 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 6 years have not been established (see section 5.2). No data are available.

CRSwNP does not normally occur in children. The safety and efficacy in children with CRSwNP below the age of 18 years have not been established (see section 5.2). No data are available.

Method of administration

Subcutaneous use

The dupilumab pre-filled pen is not intended for use in children below 12 years of age. For children 6 to 11 years of age with atopic dermatitis and asthma, the dupilumab pre-filled syringe is the presentation appropriate for administration to this population.

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 at the end of 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

Traceability

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

Atopic dermatitis or CRSwNP patients with comorbid asthma

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

Vaccinations

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

Sodium content

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

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

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

The most common adverse reactions are injection site reactions (includes erythema, oedema, pruritus, pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. Rare cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4).

Tabulated list of adverse reactions

Dupilumab was studied in 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. The pivotal controlled studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period.

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

Table 4 : List of adverse reactions MedDRA System Organ Class

Frequency Adverse Reaction

Infections and infestations

Common Conjunctivitis* Oral herpes* Blood and lymphatic system disorders

Common Eosinophilia

Immune system disorders

Uncommon Rare

Angioedema # Anaphylactic reaction Serum sickness reaction Serum sickness-like reaction Eye disorders Common Uncommon

Rare

Conjunctivitis allergic* Keratitis# Blepharitis† Eye pruritus* † Dry eye† Ulcerative keratitis†# Skin and subcutaneous tissue disorders

Uncommon Facial rash#

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

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

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

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

Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies. Similar results were observed in paediatric patients (6 to 11 years of age) with atopic dermatitis who received dupilumab 200 mg Q2W or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received dupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 3 years in the long-term OLE study (AD- 1225).

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

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

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

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

Paediatric population

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

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

The long-term safety of dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were

followed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.

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

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

Long-term safety

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

In a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mg weekly dosing (99.7 %), including 347 who completed at least 148 weeks of the study. The long-term safety profile observed in this study up to 3 years was generally consistent with the safety profile of dupilumab observed in controlled studies.

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

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

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 in Appendix V.

4.9 Overdose

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

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 randomised 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 5).

A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 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 5: 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

IGA 0 or 1b, % respondersc

10.3 % 37.9 % e^ 37.2 % e^ 8.5 % 36.1 % e^ 36.4 % e

EASI-50, % responders c

24.6 % 68.8 % e^ 61.0 % e^ 22.0 % 65.2 % e^ 61.1 % e

EASI-75, % responders c

14.7 % 51.3 % e^ 52.5 % e^ 11.9 % 44.2 % e^ 48.1 % e

EASI-90, % responders c

7.6 % 35.7 % e^ 33.2 % e^ 7.2 % 30.0 % e^ 30.5 % e

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

-72.3 % e (2.63)

-72.0 % e (2.56)

-67.1 % e (2.52)

-69.1 % e (2.49)

SCORAD, LS

mean % change from baseline (+/- SE)

-57.7 % e (2.11)

-57.0 % e (2.11)

-51.1 % e (2.02)

-53.5 % e (2.03)

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

-51.0 % e (2.50)

-48.9 % e (2.60)

-44.3 % e (2.28)

-48.3 % e (2.35)

Number of patients with baseline pruritus NRS score > 4

Pruritus NRS (> 4-point improvement), % responders c, 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 randomised. 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.

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

SOLO 1 SOLO 2

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

LS = least squares a (^) In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with

missing data were considered non-responders b (^) Full analysis set (FAS) includes all patients randomised.

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 randomised 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 6).

A significantly greater proportion of patients randomised 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 6: 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 randomised

IGA 0 or 1c, % respondersd

12.4 % 38.7 % f^ 39.2 % f^ 12.5 % 36.0 % f^ 40.0 % f

SOLO 1 SOLO 2

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 randomised. FAS week 52 includes all patients

randomised 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. g (^) p-value = 0. h (^) p-value = 0. i (^) p-value = 0.

EASI-50,

% responders d

37.5 % 80.2 % f^ 78.1 % f^ 29.9 % 78.7 % f^ 70.0 % f

EASI-75, % responders d

23.2 % 68.9 % f^ 63.9 % f^ 21.6 % 65.2 % f^ 64.1 % f

EASI-90, % responders d

11.1 % 39.6 % f^ 43.3 % f^ 15.5 % 50.6 % f^ 50.7 % f

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

-80.5 % f (6.34)

-81.5 % f (5.78)

-84.9 % g (6.73)

-87.8 % h (6.19)

SCORAD, LS

mean % change from baseline (+/- SE)

-63.9 % f (2.52)

-65.9 % f (1.49)

-69.7 % f (3.06)

-70.4 % f (1.72)

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

-56.6 % f (3.95)

-57.1 % f (2.11)

-57.0 % i (6.17)

-56.5 % f (3.26)

Number of patients with baseline pruritus NRS score ≥ 4

Pruritus NRS ( ≥ 4-point improvement), % responders d, e

19.7 % 58.8 % f^ 50.8 % f^ 12.9 % 51.2 % f^ 39.0 % f

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 7.

Table 7: 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)

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

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

DLQI, LS mean change from baseline (SE)

(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-randomised 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- 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 ( 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 8.

Table 8: Results of the primary and secondary endpoints in SOLO CONTINUE study Placebo Dupilumab 300 mg

N=

Q8W

N=

Q4W

N=

Q2W/QW

N=

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

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

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 (%)

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

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 (%)

†P< 0.05, *P< 0.01, ** P< 0.001, ***P≤ 0.

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 9).

Table 9: 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 randomised^224 224 223 236 233