ADTRALZA 150mg 150mg / ml injection solution in pre-filled syringe medication leaflet

Adtralza 150 mg solution for injection in pre-filled syringe

Adtralza 300 mg solution for injection in pre-filled pen

Adtralza 150 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 150 mg of tralokinumab in 1 mL solution (150 mg/mL).

Adtralza 300 mg solution for injection in pre-filled pen

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

Tralokinumab is produced in mouse myeloma cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colourless to pale yellow solution, pH 5.5 and osmolarity approximately280 mOsm/L.

Adtralza is indicated for the treatment of moderate-to-severe atopic dermatitis in adult and adolescentpatients 12 years and older who are candidates for systemic therapy.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatmentof atopic dermatitis.

The recommended dose of tralokinumab for adult and adolescent patients 12 years and older is aninitial dose of 600 mg administered either as:

- four 150 mg injections given by pre-filled syringesor

- two 300 mg injections given by pre-filled pens

This initial dose is followed by a 300 mg injection administered every other week either as:

- two 150 mg injections given by pre-filled syringesor

- one 300 mg injection given by pre-filled pen.

At prescriber’s discretion, every fourth week dosing may be considered for patients who achieve clearor almost clear skin after 16 weeks of treatment. The probability of maintaining clear or almost clearskin may be lower with every fourth week dosing (see section 5.1).

Consideration should be given to discontinuing treatment in patients who have shown no responseafter 16 weeks of treatment. Some patients with initial partial response may subsequently improvefurther with continued treatment every other week beyond 16 weeks.

Tralokinumab can be used with or without topical corticosteroids. The use of topical corticosteroids,when appropriate, may provide an additional effect to the overall efficacy of tralokinumab (seesection 5.1). Topical calcineurin inhibitors may be used, but should be reserved for problem areasonly, such as the face, neck, intertriginous and genital areas.

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

No dose adjustment is recommended for elderly patients (see section 5.2). Limited data are availablein patients > 75 years of age.

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

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

High body weight

For patients with high body weight (> 100 kg), who achieve clear or almost clear skin after 16 weeksof treatment, reducing the dose to every fourth week might not be appropriate (see section 5.2).

The safety and efficacy of tralokinumab in children below the age of 12 years have not yet beenestablished. No data are available.

For subcutaneous use.

The pre-filled syringe or pre-filled pen should not be shaken. After removing the pre-filled syringes orpre-filled pen from the refrigerator, they should be allowed to reach room temperature by waiting for:

- 30 minutes before injecting the pre-filled syringe

- 45 minutes before injecting the pre-filled pen.

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

For the initial 600 mg dose, four 150 mg pre-filled syringes or two 300 mg pre-filled pens should beadministered consecutively in different injection sites within the same body area.

It is recommended to rotate the injection site with each dose. Tralokinumab should not be injected intoskin that is tender, damaged or has bruises or scars.

A patient may self-inject tralokinumab or the patient's caregiver may administer tralokinumab if theirhealthcare professional determines that this is appropriate. Proper training should be provided topatients and/or caregivers on the administration of tralokinumab prior to use. Detailed instructions foruse are included at the end of the package leaflet.

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

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

If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of tralokinumabshould be discontinued and appropriate therapy initiated.

Conjunctivitis

Patients treated with tralokinumab who develop conjunctivitis that does not resolve following standardtreatment should undergo ophthalmological examination (see section 4.8).

Helminth infection

Patients with known helminth infections were excluded from participation in clinical studies. It isunknown if tralokinumab will influence the immune response against helminth infections by inhibiting

IL-13 signalling.

Patients with pre-existing helminth infections should be treated before initiating treatment withtralokinumab. If patients become infected while receiving tralokinumab and do not respond toantihelminth treatment, treatment with tralokinumab should be discontinued until infection resolves.

Live and live attenuated vaccines should not be given concurrently with tralokinumab as clinicalsafety and efficacy have not been established. Immune responses to the non-live tetanus andmeningococcal vaccines were assessed (see section 4.5). It is recommended that patients should bebrought up to date with live and live attenuated immunisations in agreement with currentimmunisation guidelines prior to treatment with tralokinumab.

This medicinal product contains less than 1 mmol sodium (23 mg) per 150 mg dose, that is to sayessentially “sodium-free”.

The safety and efficacy of concurrent use of tralokinumab with live and live attenuated vaccines hasnot been studied.

Immune responses to non-live vaccines were assessed in a study in which adult patients with atopicdermatitis were treated with an initial dose of 600 mg (four 150 mg injections) followed by 300 mgevery second (other) week administered as subcutaneous injection. After 12 weeks of tralokinumabadministration, patients were vaccinated with a combined tetanus, diphtheria, and acellular pertussisvaccine, and a meningococcal vaccine and immune responses were assessed 4 weeks later. Antibodyresponses to both tetanus vaccine and meningococcal vaccine were similar in tralokinumab-treated andplacebo-treated patients. No adverse interactions between either of the non-live vaccines ortralokinumab were noted in the study. Therefore, patients receiving tralokinumab may receiveconcurrent inactivated or non-live vaccinations.

For information on live and live attenuated vaccines, see section 4.4.

Interactions with cytochrome P450

Tralokinumab is not expected to undergo metabolism by hepatic enzymes or renal elimination.

Clinically relevant interactions between tralokinumab and inhibitors, inducers, or substrates ofmetabolising enzymes are not expected, and no dose adjustment is needed.

The effects of tralokinumab on the pharmacokinetics (PK) of CYP substrates, caffeine (CYP1A2),warfarin (CYP2C9), metoprolol (CYP2D6), omeprazole (CYP2C19) and midazolam (CYP3A), wereevaluated in atopic dermatitis patients after repeated administration. No effects were observed forcaffeine and warfarin. Small numerical changes, which were not clinically significant, were observedfor Cmax of omeprazole, AUC of metoprolol and AUC and Cmax of midazolam (the largest differencebeing for midazolam Cmax with a decrease of 22%). Therefore, clinically relevant impact oftralokinumab on the pharmacokinetics of concomitant medicinal products metabolised by the CYPenzymes is not expected.

There is limited amount of data from the use of tralokinumab in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

As a precautionary measure, it is preferable to avoid the use of tralokinumab during pregnancy.

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

Animal studies did not show any effects on male and female reproductive organs and on sperm count,motility and morphology (see section 5.3).

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

The most common adverse reactions are upper respiratory tract infections (23.4%; mainly reported ascommon cold), injection site reactions (7.2%), conjunctivitis (5.4%) and conjunctivitis allergic (2.0%).

Adverse reactions observed from clinical trials are presented in Table 1 by system organ class andfrequency, 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 eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness. Thefrequencies are based on the initial treatment period of up to 16 weeks in the pool of 5 studies in theatopic dermatitis population.

Table 1: List of adverse reactions

MedDRA System Frequency Adverse reaction

Organ Class

Infections and Very common Upper respiratory tract infectionsinfestations Common Conjunctivitis

Blood and lymphatic Common Eosinophiliasystem disorders

Eye disorders Common Conjunctivitis allergic

Uncommon Keratitis

General disorders and Common Injection site reactionsadministration siteconditions

The long-term safety of tralokinumab was assessed in 2 monotherapy studies up to 52 weeks, and ina combination study with topical corticosteroids up to 32 weeks. The long-term safety of tralokinumabis further assessed in an open-label extension study (ECZTEND) for up to 5 years of treatment inadults and adolescents with moderate-to-severe AD (atopic dermatitis) receiving 300 mg oftralokinumab every two weeks (Q2W). Interim safety data up to 39 months were generally consistentwith the safety profile observed up to week 16 in the pool of 5 adult studies.

Conjunctivitis and related events

Conjunctivitis occurred more frequently in atopic dermatitis patients who received tralokinumab(5.4%) compared to placebo (1.9%) in the initial treatment period of up to 16 weeks in the pool of5 studies. Conjunctivitis was reported at a higher frequency in patients with severe atopic dermatitiscompared to subjects with moderate atopic dermatitis in both the tralokinumab group (6.0 vs 3.3%;initial treatment period) and placebo group (2.2 vs 0.8%; initial treatment period). Most patientsrecovered or were recovering during the treatment period.

The rate of conjunctivitis in the interim safety data from the long-term open-label extension study(ECZTEND) was 3.37 events/100 patient years of exposure, compared with 22.0 events/100 patientyears of exposure in the initial 16 weeks treatment period.

Keratitis was reported in 0.5% of subjects treated with tralokinumab during the initial treatmentperiod. Of these, half were classified as keratoconjunctivitis, all were non-serious and mild ormoderate in severity, and none led to treatment discontinuation.

The rate of keratitis in the interim safety data from the long-term open-label extension study(ECZTEND) was 0.15 events/100 patient years of exposure, compared with 1.7 events/100 patientyears of exposure in the initial 16 weeks treatment period.

Eosinophilia

Adverse reactions of eosinophilia were reported in 1.3% of patients treated with tralokinumab and0.3% of patients treated with placebo during the initial treatment period of up to 16 weeks in the poolof 5 studies. Tralokinumab-treated patients had a greater mean initial increase from baseline ineosinophil count compared to patients treated with placebo. Eosinophilia (≥ 5 000 cells/mcL) wasmeasured in 1.2% of tralokinumab-treated patients and 0.3% of placebo-treated patients in the initialtreatment period. However, the increase in the tralokinumab-treated patients was transient, and meaneosinophil counts returned to baseline during continued treatment. The safety profile for subjects witheosinophilia was comparable to the safety profile for all subjects.

Eczema herpeticum

Eczema herpeticum was reported in 0.3% of the subjects treated with tralokinumab and in 1.5% ofsubjects in the placebo group in the initial treatment period of up to 16 weeks in the pool of 5 studiesin atopic dermatitis. The rate of eczema herpeticum in the initial 16 weeks treatment period was1.2 events/100 years of exposure. The rate of eczema herpeticum in the interim safety data from thelong-term open-label extension study (ECZTEND) was 0.60 events/100 years of exposure.

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

Anti-drug-antibody (ADA) responses were not associated with any impact on tralokinumab exposure,safety, or efficacy.

In ECZTRA 1, ECZTRA 2, ECZTRA 3, and the vaccine-response study, the incidence of ADA up to16 weeks was 1.4% for patients treated with tralokinumab and 1.3% for patients treated with placebo;neutralising antibodies were seen in 0.1% of patients treated with tralokinumab and 0.2% of patientstreated with placebo.

The ADA incidence for subjects who received tralokinumab up to 52 weeks was 4.6%; 0.9% hadpersistent ADA and 1.0% had neutralising antibodies.

Injection site reactions (including pain and redness) occurred more frequently in patients who receivedtralokinumab (7.2%) compared to placebo (3.0%) in the initial treatment period of up to 16 weeks inthe pool of 5 studies. Across all treatment periods in the 5 studies in atopic dermatitis, the vastmajority (99%) of injection site reactions were mild or moderate in severity, and few patients (< 1%)discontinued tralokinumab treatment. Most injections site reactions reported had a short duration withapproximately 76% of the events resolving within 1 to 5 days.

The rate of injection site reactions in the interim safety data from the long-term open-label extensionstudy (ECZTEND) was 5.8 events/100 patient years of exposure, compared with51.5 events/100 patient years of exposure in the initial 16 weeks treatment period.

The safety of tralokinumab was assessed in patients 12 to 17 years of age (adolescents) withmoderate-to-severe atopic dermatitis in a monotherapy study of 289 adolescents (ECZTRA 6) and in along-term open-label extension study (ECZTEND) including 127 adolescents transferred from

ECZTRA 6. The safety profile of tralokinumab in these patients followed through the initial treatmentperiod of 16 weeks and the long-term treatment period of 52 weeks (ECZTRA 6), as well as in theinterim safety data from the long-term open-label extension study up to 21 months (ECZTEND) weresimilar to the safety profile from studies in adults. However, a lower frequency of subjects withconjunctivitis was observed with tralokinumab in adolescents (1.0%) than in adults (5.4%), and, unlikein adults, the frequency of conjunctivitis allergic was similar for tralokinumab and placebo inadolescent patients.

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

There is no specific treatment for tralokinumab overdose. In clinical studies with tralokinumab, singleintravenous doses of up to 30 mg/kg and multiple subcutaneous doses of 600 mg every 2 weeks for12 weeks were found to be well tolerated.

Pharmacotherapeutic group: Other dermatological preparations, Agents for dermatitis, excludingcorticosteroids, ATC code: D11AH07.

Tralokinumab is a fully human IgG4 monoclonal antibody that specifically binds to the type 2cytokine interleukin-13 (IL-13) and inhibits its interaction with the IL-13 receptors. Tralokinumabneutralises the biological activity of IL-13 by blocking its interaction with the IL-13Rα1/IL-4Rαreceptor complex. IL-13 is a major driver of human type 2 inflammatory disease, such as atopicdermatitis and inhibiting the IL-13 pathway with tralokinumab in patients decreases many of themediators of type 2 inflammation.

In clinical trials, treatment with tralokinumab resulted in reduced levels of type 2 inflammationbiomarkers in both lesional skin (CCL17, CCL18 and CCL26) and in blood (CCL17, periostin and

IgE). In lesional skin, treatment with tralokinumab led also to reductions in epidermal thickness and toincrease in marker of epithelial barrier integrity (loricrin). Skin colonization with

Staphylococcus aureus was reduced more than 10-fold in patients treated with tralokinumab.

Treatment with tralokinumab also resulted in a shift of the stratum corneum lipid profile from alesional to that of non-lesional skin, indicating improvement of the skin barrier integrity.

The efficacy and safety of tralokinumab as monotherapy and with concomitant topical corticosteroids(TCS) were evaluated in three pivotal randomised, double-blind, placebo-controlled studies(ECZTRA 1, ECZTRA 2 and ECZTRA 3) in 1 976 patients 18 years of age and older with moderate-to-severe atopic dermatitis defined by Investigator’s Global Assessment (IGA) score of 3 or 4(moderate or severe), an Eczema Area and Severity Index (EASI) score of ≥ 16 at baseline, and aminimum body surface area (BSA) involvement of ≥ 10%. Eligible patients enrolled into the threestudies had previous inadequate response to topical medicinal products.

In all three studies, patients received 1) an initial dose of 600 mg tralokinumab (four 150 mginjections) on day 1, followed by 300 mg every two weeks (Q2W) up to week 16 or 2) matchingplacebo. In ECZTRA 3, patients received concomitant topical corticosteroids on active lesions asneeded. Tralokinumab was administered by subcutaneous (SC) injection in all studies.

In ECZTRA 1 and ECZTRA 2, to evaluate the maintenance of response, patients responding to theinitial 16-week treatment with tralokinumab (i.e. achieved IGA 0 or 1, or EASI-75) werere-randomised to 1) tralokinumab 300 mg Q2W or 2) tralokinumab 300 mg Q4W (alternatingtralokinumab 300 mg and placebo Q2W) or 3) placebo Q2W up to 52 weeks. The main endpoints forevaluating maintenance of response were IGA 0 or 1 and EASI-75 at week 52. Patients responding tothe initial 16-week treatment with placebo continued on placebo. Subjects not achieving IGA 0 or 1 or

EASI-75 at week 16 and subjects who did not maintain the response during the maintenance periodwere transferred to open-label treatment with tralokinumab 300 mg Q2W with optional use of topicalcorticosteroids. The studies had a treatment period of 52 weeks.

In ECZTRA 3, patients responding to the initial 16-week treatment with tralokinumab + TCS (i.e.achieved IGA 0 or 1, or EASI-75) were re-randomised to 1) tralokinumab 300 mg Q2W + TCS or 2)tralokinumab 300 mg Q4W + TCS (alternating tralokinumab 300 mg and placebo Q2W) up to32 weeks. The main endpoints for evaluating maintenance of response were IGA 0 or 1 and EASI-75at week 32. Patients responding to the initial 16-week treatment with placebo + TCS continued onplacebo + TCS. Patients who at week 16 did not achieve IGA 0 or 1 or EASI-75 continued ontralokinumab 300 mg Q2W + TCS treatment, irrespectively of their initial treatment. The study had atreatment period of 32 weeks.

In ECZTRA 1, 802 patients were enrolled (199 to placebo, 603 to tralokinumab 300 mg Q2W).

In ECZTRA 2, 794 patients were enrolled (201 to placebo, 593 to tralokinumab 300 mg Q2W).

In ECZTRA 3, 380 patients were enrolled (127 to placebo + TCS, 253 to tralokinumab300 mg Q2W + TCS).

Endpoints

In all three pivotal studies, the primary endpoints were achievement of IGA 0 or 1 (“clear” or “almostclear”) and a reduction of at least 75% in EASI (EASI-75) from baseline to week 16. Secondaryendpoints included the reduction of itch as defined by at least a 4-point improvement in the Worst

Daily Pruritus Numeric Rating Scale (NRS) from baseline to week 16, reduction in the SCORing

Atopic Dermatitis (SCORAD) scale from baseline to week 16, and change from baseline to week 16 inthe Dermatology Life Quality Index (DLQI). Additional secondary endpoints included reduction of atleast 50% and 90% in EASI (EASI-50 and EASI-90, respectively) and reduction in Worst Daily

Pruritus NRS (weekly average) from baseline to week 16. Other endpoints included change frombaseline to week 16 in the Patient Oriented Eczema Measure (POEM), at least 4-point improvement in

POEM, and Eczema-related Sleep NRS.

Baseline characteristics

In the monotherapy studies (ECZTRA 1 and ECZTRA 2), across all treatment groups, the mean agewas 37.8 years, 5.0% of the patients were 65 years of age or older, the mean weight was 76.0 kg,40.7% were female, 66.5% were White, 22.9% were Asian, and 7.5% were Black. In these studies,49.9% of patients had a baseline IGA score of 3 (moderate atopic dermatitis, 49.7% of patients had abaseline IGA of 4 (severe atopic dermatitis), and 42.5% of patients had received prior systemicimmunosuppressants (cyclosporine, methotrexate, azathioprine and mycophenolate). The meanbaseline EASI score was 32.3, mean baseline Worst Daily Pruritus NRS was 7.8, mean baseline DLQIwas 17.3, the baseline mean SCORAD score was 70.4, the baseline mean POEM score was 22.8, andthe baseline mean physical and mental components of SF-36 were 43.4 and 44.3, respectively.

In the concomitant topical corticosteroids study (ECZTRA 3), across both treatment groups, the meanage was 39.1 years, 6.3% of the patients were 65 years of age or older, the mean weight was 79.4 kg,45.0% were female, 75.8% were white, 10.8% were Asian, and 9.2% were black. In this study, 53.2%of patients had a baseline IGA score of 3, 46.3% of patients had a baseline IGA of 4, and 39.2 % ofpatients received prior systemic immunosuppressants. The baseline mean EASI score was 29.4, thebaseline Worst Daily Pruritus NRS was 7.7, the baseline mean DLQI was 17.5, the baseline mean

SCORAD score was 67.6, the baseline mean POEM score was 22.3.

Monotherapy studies (ECZTRA 1 and ECZTRA 2) - initial treatment period 0-16 weeks

In ECZTRA 1 and ECZTRA 2, from baseline to week 16, a significantly greater proportion of patientsrandomised to and dosed with tralokinumab achieved IGA 0 or 1, EASI-75, and/or an improvement of≥ 4 points on the Worst Daily Pruritus NRS compared to placebo (see Table 2).

Table 2: Efficacy results of tralokinumab monotherapy at week 16 in ECZTRA 1 and

ECZTRA 2 (FAS)

ECZTRA 1 ECZTRA 2

Week 16 Week 16

Placebo Tralokinumab Placebo Tralokinumab300 mg Q2W 300 mg Q2W

Number of patientsrandomised and dosed (FAS) 197 601 201 591

IGA 0 or 1, % respondersa,b) 7.1 15.8# 10.9 22.2§

EASI-50, % respondersa) 21.3 41.6§,e) 20.4 49.9§,e)

EASI-75, % respondersa) 12.7 25.0§ 11.4 33.2§

SCORAD, LS mean change -17.2 -24.9§ -13.8 -26.9§from baseline (± SE)c) (± 1.98) (± 1.23) (± 2.00) (± 1.06)

Pruritus NRS (≥ 4-point # §improvement, 10.3 20.0 9.5 25.0% responders)a,d) (20/194) (119/594) (19/200) (144/575)

DLQI, LS mean change from -5.7 -7.5# -5.2 -8.6§baseline (± SE)c) (± 0.63) (± 0.41) (± 0.68) (± 0.36)

LS=least squares; SE=standard error, FAS: Full Analysis Set - includes all patients randomised and dosed

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator.a) Patients who received rescue treatment or had missing data were considered non-responders.b) Responder was defined as a patient with IGA 0 or 1 (“clear“ or “almost clear” on a 0-4 IGA scale).c) Data after initiation of rescue medication or permanent discontinuation of treatment were consideredmissing. Placebo based multiple imputation of missing data.d) The percentage is calculated relative to the number of subjects with a baseline value ≥ 4.e) Not adjusted for multiplicity.

*p<0.05, #p<0.01, §p<0.001

In both monotherapy studies (ECZTRA 1 and ECZTRA 2), tralokinumab reduced itch, as measured bythe percent change from baseline in Worst Daily Pruritus NRS, already at Week 1 compared toplacebo. The reduction in itch was observed in parallel with improvements in objective signs andsymptoms of atopic dermatitis and quality of life.

In the two studies, fewer patients randomised to Adtralza 300 mg Q2W needed rescue treatment(topical corticosteroids, systemic corticosteroids, non-steroidal immunosuppressants) as compared topatients randomised to placebo (29.3% versus 45.3%, respectively, across both studies). Use of rescuetreatment was higher if patients had severe atopic dermatitis at baseline (39.3% if under tralokinumab300 mg Q2W treatment versus 56.7% in placebo group).

Monotherapy Studies (ECZTRA 1 and ECZTRA 2) - maintenance period (week 16-52)

To evaluate maintenance of response, 185 subjects from ECZTRA 1 and 227 subjects from

ECZTRA 2 treated with tralokinumab 300 mg Q2W for 16 weeks who achieved IGA 0 or 1 or

EASI-75 at week 16 were re-randomised to an additional 36-week treatment of 1) 300 mgtralokinumab every two weeks (Q2W) or 2) alternating tralokinumab 300 mg and placebo Q2W(tralokinumab Q4W) or 3) placebo Q2W, for a cumulative 52-week study treatment. Response rates(IGA 0/1 or EASI-75) at week 52 in the monotherapy pool were 56.2% and 50% for tralokinumab300 mg Q2W and tralokinumab 300 mg Q4W among subjects achieving clinical response at week 16,respectively.

Table 3: Efficacy results (IGA 0 or 1 or EASI-75) at week 52 of subjects responding totralokinumab 300 mg Q2W at week 16

ECZTRA 1 ECZTRA 2

Treatment regimen Week 16-52e) Treatment regimen Week 16-52e)

Assessment Tralokinumab Tralokinumab Placebo Tralokinumab Tralokinumab Placeboat Week 52 300 mg 300 mg 300 mg 300 mg

Q2W Q4W Q2W Q4W

IGA 0/1a) 51.3d) 38.9d) 47.4 59.3c) 44.9d) 25.0% responders f) (20/39) (14/36) (9/19) (32/54) (22/49) (7/28)

EASI-75a) 59.6d) 49.1d) 33.3 55.8b) 51.4c) 21.4% responders g) (28/47) (28/57) (10/30) (43/77) (38/74) (9/42)

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator.a) Subjects who received rescue treatment or had missing data were treated as non-responders. The percentageis calculated relative to the number of subjects with response at week 16.b) p<0.001 compared to placeboc) p<0.05 compared to placebod) p>0.05 compared to placeboe) All patients were initially treated with tralokinumab 300 mg Q2W week 0 to week 16.f) IGA 0/1 at week 52 was evaluated in those subjects that had IGA 0/1 at week 16.g) EASI-75 at week 52 was evaluated in those subjects that had EASI-75 at week 16.

Of the subjects randomised to tralokinumab, who did not achieve IGA 0 or 1 or EASI-75 at week 16and were transferred to open-label tralokinumab 300 mg Q2W + optional TCS, 20.8% in ECZTRA 1and 19.3% in ECZTRA 2 achieved IGA 0 or 1 at week 52, and 46.1% in ECZTRA 1 and 39.3% in

ECZTRA 2 achieved EASI-75 at week 52. The clinical response was mainly driven by continuedtralokinumab treatment rather than optional topical corticosteroids treatment.

32-Week concomitant TCS study (ECZTRA 3) - initial treatment period 0-16 weeks

In ECZTRA 3 from baseline to week 16, a significantly greater proportion of patients randomised totralokinumab 300 mg Q2W + TCS achieved IGA 0 or 1, EASI-75, and/or an improvement of≥ 4 points on the Worst Daily Pruritus NRS compared to placebo + TCS (see Table 4).

Table 4: Efficacy results of tralokinumab combination therapy with TCS at week 16 in

ECZTRA 3 (FAS)

ECZTRA 3

Week 16

Placebo + TCS Tralokinumab 300 mg

Q2W + TCS

Number of patientsrandomised and dosed (FAS) 126 252

IGA 0 or 1, % respondersa,b) 26.2 38.9*

EASI-50, % respondersa) 57.9 79.4§, e)

EASI-75, % respondersa) 35.7 56.0§

SCORAD, LS mean change -26.7 -37.5§from baseline (± SE)c) (± 1.83) (± 1.27)

Pruritus NRS (≥ 4-pointimprovement, 34.1 45.4*% responders)a,d) (43/126) (113/249)

DLQI, LS mean change from -8.8 -11.6§baseline (± SE)c) (± 0.57) (± 0.40)

LS=least squares; SE=standard error, FAS: Full Analysis Set - includes all patients randomised and dosed

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator. The supplied TCS did not constitute rescue medication.a) Subjects who received rescue treatment or had missing data were treated as non-responders.b) Responder was defined as a patient with IGA 0 or 1 (“clear“ or “almost clear” on a 0-4 IGA scale).c) Data after initiation of rescue medication or permanent discontinuation of treatment were considered missing.

Placebo based multiple imputation of missing data.d) The percentage is calculated relative to the number of subjects with a baseline value ≥ 4.e) Not adjusted for multiplicity.

*p<0.05, #p<0.01, §p<0.001.

In ECZTRA 3, subjects who received tralokinumab 300 mg Q2W from Week 0 to 16 used 50% less ofthe supplied topical corticosteroids at Week 16 as compared to subjects who received placebo.

In the concomitant TCS study (ECZTRA 3), tralokinumab + TCS reduced itch, as measured by thepercent change from baseline in Worst Daily Pruritus NRS, already at Week 2 compared toplacebo + TCS. The reduction in itch was observed in parallel with improvements in objective signsand symptoms of atopic dermatitis and quality of life.

32-Week concomitant TCS study (ECZTRA 3) - maintenance period 16-32 weeks

To evaluate maintenance of response, subjects treated with tralokinumab 300 mg + TCS for 16 weeksin the ECZTRA 3 study and who achieved IGA 0 or 1 or EASI-75 at week 16 were re-randomised toan additional 16-week treatment of 1) tralokinumab 300 mg every two weeks (Q2W) + TCS or2) alternating tralokinumab 300 mg + TCS and placebo every two weeks (tralokinumab Q4W) for acumulative 32-week study treatment. High maintenance of clinical efficacy at week 32 were seenacross tralokinumab 300 mg Q2W + TCS and tralokinumab 300 mg Q4W + TCS among subjectsachieving clinical response at week 16 (see Table 5).

Table 5: Efficacy results at week 32 of subjects achieving clinical response to tralokinumab300 mg + TCS Q2W at week 16

Tralokinumab 300 mg Tralokinumab 300 mg

Q2W + TCS Q4W + TCS

IGA 0/1 at week 32a) 89.6 77.6% respondersb) (43/48) (38/49)

EASI-75 at week 32a) 92.5 90.8% respondersc) (62/67) (59/65)

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator.a) Subjects who received rescue treatment or had missing data were treated as non-responders. The percentageis calculated relative to the number of subjects with response at week 16.b) IGA 0/1 at week 32 was evaluated in those subjects that had IGA 0/1 at week 16.c) EASI-75 at week 32 was evaluated in those subjects that had EASI-75 at week 16.

Among all the subjects who achieved either IGA 0 or 1 or EASI-75 at week 16, the mean percentageimprovement in EASI score from baseline was 93.5% at week 32 when maintained on tralokinumab300 mg Q2W + TCS and 91.5% at week 32 for subjects on tralokinumab 300 mg Q4W + TCS.

Of the subjects randomised to tralokinumab 300 mg Q2W + TCS who did not achieve IGA 0 or 1 or

EASI-75 at week 16, 30.5% achieved IGA 0/1 and 55.8% achieved EASI-75 at week 32 when treatedcontinuously with tralokinumab 300 mg Q2W + TCS for additional 16 weeks.

The continued improvement among the subjects who did not achieve IGA 0 or 1 or EASI-75 atweek 16 occurred in conjunction with the improvement of Worst Daily Pruritus NRS and objectivesigns of atopic dermatitis including SCORAD.

Table 6: Efficacy results of tralokinumab with concomitant TCS at weeks 16 and 32 in

ECZTRA 3 in patients initially treated with tralokinumab Q2W + TCS

Treatment regimen Week 16-32d)

Responders at Week 16e) Non-responders at

Week 16

Patients randomised Q2W + TCS Q4W + TCS Q2W + TCS

N=69 N=69 N=95

Week number W16 W32 W16 W32 W16 W32

EASI-50, % respondersa) 100.0 98.6 97.1 91.3 63.2 76.8

EASI-90, % respondersa) 58.0 72.5 60.9 63.8 1.1 34.7

EASI, LS % mean change from -90.5 -93.2 -89.3 -91.5 -46.9 -73.5baseline (SE)b) (2.7) (2.3) (2.7) (2.3) (2.4) (2.0)

Pruritus NRS (≥ 4-point 63.2 70.6 64.2 61.2 27.4 38.9improvement, % responders)a,c)

LS: Least squares, SE: Standard error

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator.a) Patients who received rescue treatment or had missing data were considered non-responders in the analyses.b) Data after initiation of rescue medication or permanent discontinuation of treatment was excluded from theanalyses.c) The percentage is calculated relative to the number of subjects with a baseline value ≥ 4.d) All patients were initially treated with tralokinumab 300 mg Q2W + TCS from week 0 to week 16. Theywere subsequently treated with tralokinumab 300 mg Q2W + TCS or Q4W + TCS.e) Responders at week 16 are identified as patients achieving either IGA 0/1 and/or EASI-75.

Patient-reported outcomes

In both monotherapy studies (ECZTRA 1 and ECZTRA 2) and in the concomitant TCS study(ECZTRA 3) tralokinumab improved patient-reported symptoms of atopic dermatitis, as measured by

POEM, and the impact of atopic dermatitis on sleep, as measured by Eczema-related sleep NRS, atweek 16 compared to placebo. A higher proportion of patients treated with tralokinumab had clinicallymeaningful reductions in POEM, (defined as at least 4 point improvement) from baseline to week 16compared to placebo.

Clinical efficacy and safety in adolescents

The efficacy and safety of tralokinumab monotherapy in adolescent patients was evaluated in amulticentre, randomised, double-blind, placebo-controlled study (ECZTRA 6) in 289 adolescentpatients 12 to 17 years of age with moderate-to-severe atopic dermatitis defined by IGA score ≥ 3 inthe overall assessment of atopic dermatitis lesions on a severity scale of 0 to 4, an EASI score ≥ 16 atbaseline, and a minimum BSA involvement of ≥ 10%. Eligible patients enrolled into this study hadprevious inadequate response to topical medication.

Patients received an initial dose of 600 mg tralokinumab or 300 mg on day 1 followed by300 mg Q2W or 150 mg Q2W, respectively, up to week 16. To evaluate the maintenance of responseup to week 52, patients responding (i.e. achieved IGA 0 or 1, or EASI-75) to the initial 16-weektreatment with tralokinumab 150 mg Q2W or 300 mg Q2W, without the use of rescue medication,were re-randomized to Q2W or Q4W (subjects initially treated with tralokinumab 300 mg werere-randomized 1:1 to tralokinumab 300 mg Q2W or tralokinumab 300 mg Q4W; subjects initiallytreated with tralokinumab 150 mg were re-randomized 1:1 to tralokinumab 150 mg Q2W ortralokinumab 150 mg Q4W). Patients not achieving IGA 0/1 or EASI-75 at week 16 and patients whodid not maintain the response during the maintenance treatment period and those that used rescuemedication during the initial period were transferred to open-label treatment with tralokinumab300 mg Q2W with optional use of topical corticosteroids. Patients randomised to placebo in the initialtreatment period who achieved a clinical response at week 16 continued to receive placebo Q2W in themaintenance treatment period.

In this study, the mean age was 14.6 years, the mean weight was 61.5 kg, 48.4% were female, 56.7%were White, 24.6% were Asian, and 11.1% were Black. At baseline 53.3% of patients had a baseline

IGA score of 3 (moderate atopic dermatitis), 46.7% of patients had a baseline IGA of 4 (severe atopicdermatitis), the mean BSA involvement was 51.1%, and 21.1% of patients had received prior systemicimmunosuppressants (cyclosporine, methotrexate, azathioprine and mycophenolate). Also, at baselinethe mean EASI score was 31.7, the baseline Adolescent Worst Pruritus NRS score was 7.6, thebaseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.4, and the baselinemean Children Dermatology Life Quality Index (CDLQI) was 13.2. Overall, 84.4% of patients had atleast one co-morbid allergic condition; 68.2% had allergic rhinitis, 50.9% had asthma, and 57.1% hadfood allergies. The primary endpoints were the proportion of patients with IGA 0 or 1 at week 16(“clear” or “almost clear”) and the proportion of patients with EASI-75 (improvement of at least 75%in EASI from baseline) at week 16. Secondary endpoints included the reduction in itch, as measuredby the proportion of subjects with ≥ 4 point improvement in Adolescent Worst Pruritus NRS frombaseline, the absolute change in SCORAD from baseline to week 16 and the absolute change in

CDLQI from baseline to week 16. Additional secondary endpoints included the proportion of subjectswith EASI-50 and EASI-90. Other endpoints included proportion of patients with ≥ 6 pointimprovement in CDLQI and POEM at week 16.

The efficacy results at week 16 in the adolescent patients are presented in Table 7.

Table 7: Efficacy results of tralokinumab monotherapy in the adolescent patients at week 16(FAS)

ECZTRA 6

Placebo Tralokinumab 150 mg Tralokinumab 300 mg

Q2W Q2W

Number of patientsrandomised and dosed (FAS) 94 98 97

IGA 0 or 1, % respondersa, b 4.3 21.4§ 17.5#

EASI-50, % respondersa 13.8 45.9 e 51.5e

EASI-75, % respondersa 6.4 28.6§ 27.8§

SCORAD, LS mean change -9.7 -23.5§ -26.0§from baseline (± SE)c (±3.3) (±2.7) (±2.5)

Pruritus NRS ≥4-point 3.3 23.2§ 25.0§improvement, % respondersa, d (3/90) (22/95) (24/96)

CDLQI, LS mean change from -3.8 -5.5 -6.2#baseline (± SE)c (±0.9) (±0.7) (±0.7)

LS=Least squares; SE=Standard error; FAS=Full Analysis Set - includes all patients randomised and dosed

If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescuetreatment at the discretion of the investigator.a) Patients who received rescue treatment from week 2 to week 16 or had missing data were considered non-respondersb) Responder was defined as a patient with IGA 0 or 1 (“clear“ or “almost clear” on a 0-4 IGA scale).c) Data after initiation of rescue medication or permanent discontinuation of treatment were considered missing.

Placebo based multiple imputation of missing data.d) The percentage is calculated relative to the number of subjects with a baseline value ≥ 4.e) Not adjusted for multiplicity.

*p<0.05, #p<0.01, §p<0.001

A greater proportion of patients achieved EASI-90 at week 16 in the tralokinumab 150 mg group(19.4%) and tralokinumab 300 mg group (17.5%) compared with the placebo group (4.3%).

Greater improvements in patient-reported symptoms and impacts on quality of life (e.g., sleep) wereobserved at week 16 in the tralokinumab 150 mg and tralokinumab 300 mg groups compared withplacebo, as measured by the proportion of patients with ≥ 6 point improvement in POEM and theproportion of patients with ≥ 6 point improvement in CDLQI.

In line with the monotherapy results in adults, adolescent efficacy data indicate that the clinical benefitachieved at Week 16 is sustained through Week 52.

Of the subjects randomised to tralokinumab who did not achieve IGA 0 or 1 or EASI-75 at week 16 orused rescue mediation during the initial period and were transferred to open label tralokinumab300 mg Q2W + optional TCS, 33.3% achieved IGA 0 or 1 at week 52, and 57.8% achieved EASI-75at week 52. The clinical response was mainly driven by continued tralokinumab treatment rather thanthe optional topical corticosteroids treatment.

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

After subcutaneous (SC) dose of tralokinumab median time to maximum concentration in serum (tmax)were 5-8 days. The absolute bioavailability of tralokinumab following SC dosing was estimated bypopulation PK analysis to be 76%. In a phase 1 trial (10 subjects per arm), bioavailability wasestimated to be 62% for the 150 mg dose and 60% for the 300 mg dose.

Steady-state concentrations were achieved by week 16 following a 600 mg starting dose and 300 mgevery other week. Across clinical studies (ECZTRA 1, ECZTRA 2 and ECZTRA 3), the mean ±SDsteady-state trough concentration ranged from 98.0±41.1 mcg/mL to 101.4±42.7 mcg/mL for 300 mgdose administered every other week.

A volume of distribution for tralokinumab of approximately 4.2 L was estimated by population PKanalysis.

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

Tralokinumab is eliminated through a non-saturable proteolytic pathway. Half-life is 22 days,consistent with the typical estimate for human IgG4 monoclonal antibodies targeting solublecytokines. In ECZTRA 1, ECZTRA 2, and ECZTRA 3, clearance was estimated by population PKanalysis to be 0.149 L/day. In phase 1 trials with IV dosing, clearance was estimated to be between0.179 and 0.211 L/day

Exposure of tralokinumab increases proportionally to the dose of tralokinumab between 150-600 mg.

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

Age was not found to be associated with clinically relevant impact of systemic exposure oftralokinumab determined by population PK analysis. 109 subjects above 65 years were included in theanalysis.

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

Tralokinumab, 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 thepharmacokinetics of tralokinumab. Mild hepatic impairment was not found to affect the PK oftralokinumab determined by population PK analysis. Very limited data are available in patients withmoderate or severe hepatic impairment.

Tralokinumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. Noclinical studies have been conducted to evaluate the effect of renal impairment on thepharmacokinetics of tralokinumab. Population PK analysis did not identify mild or moderate renalimpairment as having a clinically meaningful influence on the systemic exposure of tralokinumab.

Very limited data are available in patients with severe renal impairment.

High body weight

Tralokinumab exposure (AUC) was lower in subjects with higher body weight (see section 4.2).

Table 8: Area under the curve (AUC) by weight

Weight (kg) 75 100 120 140

AUC (mcg*day/mL) 1 532 1 192 1 017 889

Ratio AUC 75 kg 1 0.78 0.66 0.57

Calculated AUC at steady-state for the dosing interval for 300 mg Q2W for a subject of a certain weight basedon the relation between Clearance and weight. Clearance = 0.149 × (W/75)˄0.873. AUC = F × Dose Clearance,where F = 0.761.

The pharmacokinetics of tralokinumab in paediatric patients below 12 years has not yet been studied.

For adolescents 12 to 17 years of age with atopic dermatitis, the mean ±SD steady-state throughconcentration (at week 16) was 112.8±39.2 mcg/mL for 300 mg dose administered every other week.

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

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

Carcinogenicity studies have not been conducted with tralokinumab. An evaluation of the availableevidence related to IL-13 inhibition and animal toxicology data with tralokinumab does not suggest anincreased carcinogenic potential for tralokinumab.

Enhanced pre- and postnatal studies with tralokinumab in monkeys did not identify adverse effects inmaternal animals or their offspring up to 6 months post-partum.

No effects on fertility parameters such as reproductive organs, menstrual cycle and sperm analysiswere observed in sexually mature monkeys treated subcutaneously with tralokinumab up to350 mg/animal (females) or 600 mg/animal (males) (AUC exposure up to 15-fold higher than inhuman patients receiving tralokinumab 300 mg every 2 weeks).

Sodium acetate trihydrate (E262)

Acetic acid (E260)

Sodium chloride

Polysorbate 80 (E433)

Water for injections

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

Adtralza 150 mg solution for injection in pre-filled syringe5 years.

Adtralza 300 mg solution for injection in pre-filled pen3 years.

If necessary, pre-filled syringes or pre-filled pens may be kept at room temperature in the originalcarton up to 30 °C for a maximum of 14 days, within its shelf-life, without being refrigerated againduring this period. Do not store above 30 °C. If the carton needs to be removed permanently fromrefrigerator, the date of removal may be recorded on the carton. After removal from the refrigerator,

Adtralza must be used within 14 days or discarded.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

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

Adtralza 150 mg solution for injection in pre-filled syringe1 mL solution in a siliconised type-1 clear glass pre-filled syringe with 27 gauge ½ inch thin wallstainless steel staked needle, elastomer plunger stopper extended finger flange and needle guard.

- 2 pre-filled syringes

- Multipack containing 4 (2 packs of 2) pre-filled syringes

- Multipack containing 12 (6 packs of 2) pre-filled syringes.

Adtralza 300 mg solution for injection in pre-filled pen2 mL solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a 27 gauge ½ inch,thin wall stainless steel staked needle.

- 2 pre-filled pens

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

Not all pack sizes may be marketed.

The solution should be clear to opalescent, colourless to pale yellow. If the solution is cloudy,discoloured or contains visible particulate matter, the solution should not be used. Do not use if thepre-filled syringe or pre-filled pen is damaged or has been dropped on a hard surface.

After removing the pre-filled syringe or pre-filled pen from the refrigerator, it should be allowed toreach room temperature by waiting for:

- 30 minutes before injecting the pre-filled syringe

- 45 minutes before injecting the pre-filled pen.

Adtralza contains a sterile solution for injection. Discard any unused product remaining in thepre-filled syringe or in the pre-filled pen.

LEO Pharma A/S

Industriparken 55

DK-2750 Ballerup

Denmark

EU/1/21/1554/001

EU/1/21/1554/002

EU/1/21/1554/003

EU/1/21/1554/004

EU/1/21/1554/005

Date of first authorisation: 17 June 2021

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

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