Leaflet TEZSPIRE 210mg 110mg / ml solution for injection in pre-filled syringe

Tezspire 210 mg solution for injection in pre-filled syringe

Tezspire 210 mg solution for injection in pre-filled pen

Each pre-filled syringe contains 210 mg tezepelumab in 1.91 mL solution (110 mg/mL).

Pre-filled pen

Each pre-filled pen contains 210 mg tezepelumab in 1.91 mL (110 mg/mL).

Tezepelumab is a human monoclonal antibody produced in Chinese hamster ovary (CHO) cells byrecombinant DNA technology.

This medicine contains 48 mg of L-proline and 0.19 mg of polysorbate 80 in each 210 mg dose(1.91 mL).

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colourless to light yellow solution.

Asthma

Tezspire is indicated as an add-on maintenance treatment in adults and adolescents 12 years and olderwith severe asthma who are inadequately controlled despite high dose inhaled corticosteroids plusanother medicinal product for maintenance treatment.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

Tezspire is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adultpatients with severe CRSwNP for whom therapy with systemic corticosteroids, and/or surgery do notprovide adequate disease control.

Treatment should be initiated by physicians experienced in the diagnosis and treatment of conditionsfor which Tezspire is indicated (see section 4.1).

Tezspire is intended for long-term treatment. A decision to continue the therapy should be made atleast annually based on the patient's level of disease control.

Asthma

The recommended dose is 210 mg of tezepelumab by subcutaneous injection every 4 weeks.

CRSwNP

The recommended dose for adult patients is 210 mg of tezepelumab by subcutaneous injection every4 weeks.

If a dose is missed, the dose should be administered as soon as possible. Thereafter, the patient canresume dosing on the scheduled day of administration. If the next dose is already due, then administeras planned. A double dose must not be administered.

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

No dose adjustment is required for patients with renal or hepatic impairment (see section 5.2).

The safety and efficacy of Tezspire in children under 12 years of age for the treatment of asthma havenot been established. No data are available.

The safety and efficacy of Tezspire in children under 18 years of age for the treatment of CRSwNPhave not been established. No data are available.

Tezspire is administered as a subcutaneous injection.

A patient may self-inject or the patient’s caregiver may administer this medicinal product after trainingin subcutaneous injection technique. Proper training should be provided to patients and/or caregiverson the preparation and administration of Tezspire prior to use according to the “Instructions for Use”.

Tezspire should be injected into the thigh or abdomen, except for the 5 cm around the navel. If ahealthcare professional or caregiver administers the injection, the upper arm can also be used. Apatient should not self-inject in the arm. It should not be injected into areas where the skin is tender,bruised, erythematous, or hardened. It is recommended to rotate the injection site with each injection.

Comprehensive instructions for administration using the pre-filled syringe or pre-filled pen is providedin the “Instructions for Use”.

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.

Tezspire should not be used to treat acute asthma exacerbations.

Asthma-related symptoms or exacerbations may occur during treatment. Patients should be instructedto seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment.

Abrupt discontinuation of corticosteroids after initiation of therapy is not recommended. Reduction incorticosteroid doses, if appropriate, should be gradual and performed under the supervision of aphysician.

Hypersensitivity reactions (e.g. anaphylaxis, rash) may occur following administration of tezepelumab(see section 4.8). These reactions may occur within hours of administration, but in some instanceshave a delayed onset (i.e. days).

A history of anaphylaxis unrelated to tezepelumab may be a risk factor for anaphylaxis following

Tezspire administration. In line with clinical practice, patients should be monitored for an appropriatetime after administration of Tezspire.

In the event of a serious hypersensitivity reaction (e.g. anaphylaxis), administration of tezepelumabshould be discontinued immediately and appropriate treatment as clinically indicated should beinitiated.

Blocking thymic stromal lymphopoietin (TSLP) may theoretically increase the risk of seriousinfections. In placebo-controlled studies, no increase in serious infections was observed withtezepelumab.

Patients with pre-existing serious infections should be treated before initiating therapy withtezepelumab. If patients develop a serious infection while receiving tezepelumab treatment, therapywith tezepelumab should be discontinued until the serious infection resolves.

In a long-term clinical study, a numerical imbalance in serious cardiac adverse events was observed inpatients treated with tezepelumab compared to placebo. No causal relationship between tezepelumaband these events has been established, nor has a patient population at risk of these events beenidentified.

Patients should be advised of signs or symptoms suggestive of a cardiac event (for example, chestpain, dyspnoea, malaise, feeling lightheaded or faint) and to seek immediate medical attention if suchsymptoms occur. If patients develop a serious cardiac event while receiving tezepelumab treatment,therapy with tezepelumab should be discontinued until the acute event stabilises.

There is currently no data on re-treatment of patients who develop a serious cardiac event or seriousinfection.

TSLP may be involved in the immunological response to some helminth infections. Patients withknown helminth infections were excluded from participation in clinical trials. It is unknown iftezepelumab may influence a patient’s response against helminth infections.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per 210 mg dose, that is to sayessentially ‘sodium-free’.

This medicinal product contains 48 mg of L-proline in each 210 mg dose (1.91 mL). L-proline may beharmful for patients with hyperprolinaemia.

This medicinal product contains 0.19 mg of polysorbate 80 in each 210 mg dose (1.91 mL).

Polysorbates may cause allergic reactions.

No interaction studies have been performed.

The use of live attenuated vaccines should be avoided in patients receiving tezepelumab.

In a randomised, double blind, parallel group study of 70 patients aged between 12 and 21 years withmoderate to severe asthma, tezepelumab treatment did not appear to affect the humoral antibodyresponses induced by seasonal quadrivalent influenza vaccination.

A clinically relevant effect of tezepelumab on the pharmacokinetics of co-administered asthmamedicinal products is not expected. Based on the population pharmacokinetic analysis, commonlyco-administered asthma medicinal products (including leukotriene receptor antagonists,theophylline/aminophylline and oral corticosteroids) had no effect on tezepelumab clearance.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use oftezepelumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects withrespect to reproductive toxicity (see section 5.3).

Human IgG antibodies, such as tezepelumab, are transported across the placenta barrier; therefore,

Tezspire may be transmitted from the mother to the developing foetus.

As a precautionary measure, it is preferable to avoid the use of Tezspire during pregnancy unless theexpected benefit to the pregnant mother is greater than any possible risk to the foetus.

It is unknown whether tezepelumab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which decreases to low concentrations soonafterwards; consequently, a risk to the breast-fed child cannot be excluded during this short period.

For this specific period, a decision should be made whether to discontinue/abstain from tezepelumabtherapy, taking into account the benefit of breast-feeding to the child and the benefit of therapy to thewoman.

Afterwards, tezepelumab could be used during breast-feeding if clinically needed.

See section 5.3 for information on the excretion of tezepelumab in animal (cynomolgus monkey) milk.

There are no fertility data in humans. Animal studies showed no adverse effects of tezepelumabtreatment on fertility (see section 5.3).

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

The most commonly reported adverse reactions during treatment for asthma are arthralgia (3.8%) andpharyngitis (4.1%) and during treatment for CRSwNP is pharyngitis (5.4%).

Table 1 presents the adverse reactions from clinical studies in patients with severe asthma and

CRSwNP who received at least one dose of Tezspire in trials of 52 weeks duration, and frompost-marketing experience.

The frequency of adverse reactions is defined using the following convention: very common (≥ 1/10);common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); veryrare (< 1/10,000); and not known (cannot be estimated from available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 List of adverse reactions

System organ class Adverse reactions Frequency

Infections and infestations Pharyngitisa Common

Immune system disorders Hypersensitivity Not known(includinganaphylactic reaction)

Skin and subcutaneous tissue disorders Rashb Common

Musculoskeletal and connective tissue disorders Arthralgia Common

General disorders and administration site Injection site reactionc Commonconditionsa Pharyngitis was defined by the following grouped preferred terms: pharyngitis, pharyngitis bacterial,pharyngitis streptococcal and viral pharyngitis.

b Rash was defined by the following grouped preferred terms: rash, rash pruritic, rash erythematous, rashmaculo-papular, rash macular.c See ‘Description of selected adverse reactions’.

In the pooled safety data from PATHWAY and NAVIGATOR, injection site reactions (e.g. injectionsite erythema, injection site swelling, injection site pain) occurred at a rate of 3.8% in patients treatedwith tezepelumab 210 mg subcutaneous every 4 weeks (Q4W).

A total of 82 adolescents aged 12 to 17 with severe, uncontrolled asthma were enrolled in the 52-week

Phase 3 NAVIGATOR study (see section 5.1). The safety profile in adolescents was generally similarto the overall study population.

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.

In clinical trials, doses of up to 280 mg were administered subcutaneously every 2 weeks (Q2W) anddoses of up to 700 mg were administered intravenously every 4 weeks (Q4W) to patients with asthmawithout evidence of dose-related toxicities.

There is no specific treatment for an overdose with tezepelumab. If overdose occurs, the patient shouldbe treated supportively with appropriate monitoring as necessary.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs forobstructive airway diseases, ATC code: R03DX11

Tezepelumab is a monoclonal antibody (IgG2λ) directed against thymic stromal lymphopoietin(TSLP), preventing its interaction with the heterodimeric TSLP receptor. In asthma and CRSwNP,both allergic and non-allergic triggers induce TSLP production. Blocking TSLP with tezepelumabreduces a broad spectrum of biomarkers and cytokines associated with airway and mucosalinflammation in asthma and CRSwNP (e.g. blood eosinophils, airway submucosal eosinophils, IgE,

FeNO, IL-5, and IL-13); however, the mechanism of action of tezepelumab in asthma and CRSwNPhas not been definitively established.

In asthma clinical trials, administration of tezepelumab 210 mg subcutaneously every 4 weeks reducedblood eosinophils counts, FeNO, IL-5 concentration, IL-13 concentration and serum IgE concentrationfrom baseline compared with placebo. These markers were near maximal suppression after 2 weeks oftreatment, except for IgE which declined more slowly. These effects were sustained throughouttreatment.

In a CRSwNP clinical trial, administration of tezepelumab 210 mg subcutaneously every 4 weeksresulted in reductions of inflammatory biomarkers (blood eosinophils, FeNO [in participants withco-morbid asthma] and serum IgE).

In a clinical trial, administration of tezepelumab 210 mg subcutaneously every 4 weeks reducedsubmucosal eosinophil counts by 89% compared with a 25% reduction with placebo. Reduction wasconsistent regardless of baseline inflammatory biomarkers.

In patients with asthma (NAVIGATOR), anti-drug antibodies (ADA) were detected at any time in 26(4.9%) out of 527 patients who received tezepelumab at the recommended dosing regimen during the52-week study period. Of these 26 patients, 10 patients (1.9% of patients treated with tezepelumab)developed treatment-emergent ADA and 1 patient (0.2% of patients treated with tezepelumab)developed neutralising antibodies. ADA titres were generally low and often transient. No evidence of

ADA impact on pharmacokinetics, pharmacodynamics, efficacy, or safety was observed.

In patients with CRSwNP (WAYPOINT), a treatment-emergent ADA response developed in 6 (4%)out of 164 patients treated with tezepelumab 210 mg subcutaneously every 4 weeks during the52-week treatment period. Neutralising antibody activity was detected in 1 of the ADA positivepatients. While there was no apparent impact of ADA on pharmacokinetics, pharmacodynamics,efficacy, or safety, there were insufficient numbers of patients with treatment-emergent ADA to makea formal assessment in CRSwNP.

Asthma

The efficacy of tezepelumab was evaluated in two randomised, double-blind, parallel group,placebo-controlled clinical trials (PATHWAY and NAVIGATOR) of 52 weeks in duration involving atotal of 1609 patients aged 12 years and older with severe asthma. In both trials, patients were enrolledwithout requiring a minimum baseline level of blood eosinophils or other inflammatory biomarkers(e.g. FeNO or IgE).

PATHWAY was a 52-week exacerbation trial which enrolled 550 patients (18 years of age and older)with severe, uncontrolled asthma to receive treatment with tezepelumab 70 mg subcutaneous Q4W,tezepelumab 210 mg subcutaneous Q4W, tezepelumab 280 mg subcutaneous Q2W or placebo.

Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemiccorticosteroid treatment or 1 asthma exacerbation resulting in hospitalisation in the past 12 months.

NAVIGATOR was a 52-week exacerbation trial which enrolled a total of 1061 patients (adults andadolescents 12 years of age and older) with severe, uncontrolled asthma to receive treatment withtezepelumab 210 mg subcutaneous Q4W or placebo. Patients were required to have a history of 2 ormore asthma exacerbations requiring oral or systemic corticosteroid treatment or resulting inhospitalisation in the past 12 months.

In both PATHWAY and NAVIGATOR, patients were required to have an Asthma Control

Questionnaire 6 (ACQ-6) score of 1.5 or more at screening, and reduced lung function at baseline(pre-bronchodilator FEV1 below 80% predicted in adults, and below 90% predicted in adolescents).

Patients were required to have been on regular treatment with medium- or high-dose inhaledcorticosteroids (ICS) and at least one additional asthma control therapy with or without oralcorticosteroids (OCS). High ICS dose was defined as > 500 mcg fluticasone propionate or equivalentper day. Medium ICS dose was defined as > 250 to 500 mcg fluticasone propionate or equivalent perday in PATHWAY and as 500 mcg fluticasone propionate or equivalent per day in NAVIGATOR.

Patients continued background asthma therapy throughout the duration of the trials.

The demographics and baseline characteristics of these two trials are provided in Table 2 below.

Table 2 Demographics and baseline characteristics of asthma trials

PATHWAY NAVIGATOR

N=550 N=1059

Mean age (year) (SD) 52 (12) 50 (16)

Female (%) 66 64

White (%) 92 62

Black or African American (%) 3 6

Asian (%) 3 28

Hispanic or Latino (%) 1 15

Mean duration of asthma, (years) (SD) 17 (12) 22 (16)

Never smoked (%) 81 80

High-dose ICS use (%) 49 75

OCS use (%) 9 9

Mean number of exacerbations in previous 2.4 (1.2) 2.8 (1.4)year (SD)

Mean baseline % predicted FEV1 (SD) 60 (13) 63 (18)

Mean pre-bronchodilator FEV1 (L) (SD) 1.9 (0.6) 1.8 (0.7)

Mean post-bronchodilator FEV1 reversibility 23 (20) 15 (15)(%) (SD)

Mean baseline blood EOS count (cells/µL) 371 (353) 340 (403)(SD)

Blood EOS count ≥ 150 cells/µL (%) 76 74

Positive allergic status (%)a 46 64

Mean FeNO (ppb) (SD) 35 (39) 44 (41)

FeNO ≥ 25 ppb (%) 44 59

Mean ACQ-6 (SD) 2.7 (0.8) 2.8 (0.8)

Blood EOS count ≥ 150 cells/µL and FeNO 38 47≥ 25 ppb (%)a Positive allergic status as defined by a positive serum IgE result specific to any perennial aeroallergen in the

FEIA panel.

ACQ-6, Asthma Control Questionnaire 6; EOS, Eosinophils; FEIA, Fluorescent enzyme immunoassay; FeNO,

Fractional exhaled nitric oxide; FEV1, Forced expiratory volume in one second; ICS, Inhaled corticosteroid; IgE,

Immunoglobulin E; OCS, Oral corticosteroid; ppb, Parts per billion; SD, Standard deviation

The results summarised below are for the recommended tezepelumab 210 mg subcutaneous Q4Wdosing regimen.

The primary endpoint for PATHWAY and NAVIGATOR was the rate of severe asthma exacerbationsmeasured over 52 weeks. Severe asthma exacerbations were defined as worsening of asthma requiringthe use of or increase in oral or systemic corticosteroids for at least 3 days or a single depo-injection ofcorticosteroids, and/or emergency department visits requiring use of oral or systemic corticosteroidsand/or hospitalisation.

In both PATHWAY and NAVIGATOR, patients receiving tezepelumab had significant reductions inthe annualised rate of severe asthma exacerbations compared with placebo (Table 3 and Table 4).

There were also fewer exacerbations requiring emergency room visits and/or hospitalisation in patientstreated with tezepelumab compared with placebo. In PATHWAY and NAVIGATOR, severe asthmaexacerbations requiring emergency room visits and/or hospitalisation were reduced by 85% and 79%with tezepelumab 210 mg subcutaneous Q4W, respectively.

Table 3 Rate of severe exacerbations at week 52 in NAVIGATORa

Tezepelumab (N=528) Placebo (N=531)

Annualised severe asthma exacerbation rate

Rate 0.93 2.10

Rate ratio (95% CI) 0.44 (0.37, 0.53)p-value <0.001a Time at risk is defined as the total duration of time in which a new exacerbation can occur (i.e. total follow-uptime minus time during exacerbation and 7 days after).

CI, Confidence interval

Table 4 Rate of severe exacerbations at week 52 in PATHWAYa

Tezepelumab (N=137) Placebo (N=138)

Annualised severe asthma exacerbation rate

Rate 0.20 0.72

Rate ratio (95% CI) 0.29 (0.16, 0.51)p-value <0.001a Time at risk is defined as the total follow-up time.

CI, Confidence interval

In NAVIGATOR, tezepelumab demonstrated a reduction in the rate of severe asthma exacerbationsregardless of the baseline levels of blood eosinophils, FeNO, as well as allergic status (determined bya perennial aeroallergen specific IgE). Similar results were seen in PATHWAY. See Figure 1.

In NAVIGATOR, reductions in the rate of severe asthma exacerbations were greater with increasingbaseline blood eosinophil counts and FeNO values (rate ratio = 0.79 [95% CI: 0.48, 1.28] for patientswith both baseline blood eosinophil count < 150 cells/µL and baseline FeNO < 25 ppb; rateratio = 0.30 [95% CI: 0.23, 0.40] for patients with both baseline blood eosinophil count ≥ 150 cells/µLand baseline FeNO ≥ 25 ppb).

Figure 1 Annualised severe asthma exacerbation rate ratio over 52 weeks acrossdifferent baseline biomarkers for the Full Analysis Set (pooled NAVIGATORand PATHWAY)a

Tezepelumab210 mg Q4W Placebo

Rate Ration/Estimate n/Estimate (95% CI)

Overall

Eosinophils at baseline (cells/µL)

Eosinophils at baseline (cells/µL)

FeNO at baseline (ppb)

Allergic statusb

Positive allergic status

N egative allergic status

Eosinophils (cells/µL) and FeNO (ppb)at baseline

Eosinophils <150 and FeNO <25

Eosinophils >=150 and FeNO <25

E osinophils <150 and FeNO >=25

Eosinophils >=150 and FeNO >=25

Favours Tezepelumab Favours Placebo

Rate Ratio (95% CI)a Time at risk is defined as the total duration of time in which a new ex acerbation can occur (i.e. total follow-uptime minus time during exacerbation and 7 days after).

b Allergic status as defined by a serum IgE result specific to any perennial aeroallergen in the FEIA panel.

Change from baseline in FEV1 was assessed as a secondary endpoint in NAVIGATOR. Comparedwith placebo, tezepelumab provided clinically meaningful improvements in the mean change frombaseline in FEV1 (Table 5).

Changes from baseline in ACQ-6, Standardised Asthma Quality of Life Questionnaire for ages 12 andolder [AQLQ(S)+12] and weekly mean Asthma Symptom Diary (ASD) scores were assessed assecondary endpoints in NAVIGATOR. Severity of wheezing, shortness of breath, cough, and chesttightness were assessed twice daily (morning and evening). Night-time awakening and activity wereassessed on a daily basis. The total ASD score was calculated as the mean of 10 items (Table 5).

Improvements in ACQ-6 and AQLQ(S)+12 were seen as early as 2 weeks and 4 weeks afteradministration of tezepelumab, respectively, and sustained through week 52 in both trials.

Table 5 Results of key secondary endpoints at week 52 in NAVIGATORa

Tezepelumab Placebo

Pre-bronchodilator FEV1

N 527 531

LS Mean Change from Baseline (L) 0.23 0.10

LS Mean Difference from Placebo (L) 0.13 (0.08, 0.18)(95% CI)p-value <0.001

AQLQ(S)+12 total score

N 525 526

LS Mean Change from Baseline 1.48 1.14

Difference from Placebo (95% CI) 0.33 (0.20, 0.47)p-value <0.001

ACQ-6 score

N 527 531

LS Mean Change from Baseline -1.53 -1.20

Difference from Placebo (95% CI) -0.33 (-0.46, -0.20)p-value <0.001

ASD

N 525 531

LS Mean Change from Baseline -0.70 -0.59

Difference from Placebo (95% CI) -0.11 (-0.19, -0.04)p-value 0.004a Estimates are derived from a Mixed Model for Repeated Measures (MMRM) using all available data frompatients with at least 1 change from baseline value, including data post-discontinuation.

ACQ-6, Asthma Control Questionnaire 6; AQLQ(S)+12, Standardised Asthma Quality of Life Questionnaire for12 years and older; ASD Asthma Symptom Diary; CI, Confidence interval; FEV1, Forced expiratory volume inone second; LS, Least square; N, Number of patients contributing to the analysis (FA) with at least 1 changefrom baseline value

Of the 665 patients with asthma exposed to tezepelumab 210 mg subcutaneous Q4W in PATHWAYand NAVIGATOR, a total of 119 patients were 65 years of age or older, of which 32 patients were75 years of age or older. Safety in these age groups were similar to the overall study population.

Efficacy in these age groups were similar to the overall study population in NAVIGATOR.

PATHWAY did not include sufficient numbers of patients aged 65 and over to determine efficacy inthis age group.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

The efficacy of tezepelumab was evaluated in a randomised, double-blind, parallel group, multicentre,placebo-controlled trial (WAYPOINT) of 52 weeks treatment duration conducted in 408 patients aged18 years and older on standard of care treatment for CRSwNP. This study included patients withsymptomatic CRSwNP despite treatment with systemic corticosteroids within the past 12 monthsand/or any history of sino-nasal surgery, or contraindications/intolerance to either.

Patients received tezepelumab 210 mg or placebo subcutaneously Q4W for 52 weeks in addition tointranasal corticosteroid treatment (e.g. mometasone furoate nasal spray) for CRSwNP.

The demographics and baseline characteristics of WAYPOINT are provided in Table 6 below.

Table 6 Demographics and baseline characteristics of WAYPOINT

WAYPOINT

N=408a

Mean age (years) (SD) 50 (14)

Male (%) 65

Mean CRSwNP duration (years) (SD) 13 (10)

Patients with ≥1 prior surgery (%) 71

Patients with systemic corticosteriod use for CRSwNP 58in the previous year (%)

Mean total NPSb (SD), range 0-8 6.1 (1.2)

Mean bi-weekly NCSb, c (SD), range 0-3 2.6 (0.5)

Mean LMK sinus CT total scoreb (SD), range 0-24 19 (4)

Mean bi-weekly loss of smellb, d (SD), range 0-3 2.9 (0.4)

Mean SNOT-22 total scoreb (SD), range 0-110 69 (18)

Mean blood eosinophils (cells/µL) (SD) 360 (235)

Mean total IgE IU/mL (SD) 176 (285)

Asthma/NSAID-ERD/AERDe (%) 61

NSAID-ERD/AERD (%) 17

Allergic rhinitis (%) 14a Number of patients (N) =407 for mean total NPS; N=406 for mean bi-weekly NCS and mean bi-weekly loss ofsmell; N=404 for mean LMK sinus CT total score and mean blood eosinophils; N=389 for mean total IgE.b Higher scores indicate greater disease severity or symptom severity.c Evaluated as part of the Nasal Polyposis Symptom Diary (NPSD).d Evaluated via difficulty with sense of smell score in the NPSD.e All but 3 patients with AERD or NSAID-ERD included in this subgroup also had a diagnosis of asthmareported.

AERD, Aspirin exacerbated respiratory disease; CRSwNP, Chronic rhinosinusitis with nasal polyps; CT,

Computed tomography; IgE, Immunoglobulin E; IU, International units; LMK, Lund-Mackay; NCS, Nasalcongestion score; NPS, Nasal polyp score; NSAID-ERD, Nonsteroidal anti-inflammatory drug exacerbatedrespiratory disease; SD, Standard deviation; SNOT-22, 22-item Sino-Nasal Outcome Test

The co-primary efficacy endpoints were change from baseline in total nasal polyp score (NPS)evaluated by nasal endoscopy at week 52 as graded by independent blinded assessors, and changefrom baseline in bi-weekly mean nasal congestion score (NCS) evaluated as part of the Nasal

Polyposis Symptom Diary (NPSD) at week 52. Total NPS was graded on a categorical scale (0-8).

Nasal congestion was rated daily by the patients on a 0 to 3 categorical severity scale. Unadjustedp-values are presented for WAYPOINT.

Patients who received tezepelumab had statistically significant improvements in total NPS andbi-weekly mean NCS at week 52 compared with placebo (see Table 7).

The results for the co-primary and key secondary endpoints in WAYPOINT are presented in Table 7.

Table 7 Results of co-primary and key secondary endpoints in WAYPOINT

Tezepelumab Placebo p-valuea(N=203) (N=205)

Co-primary endpoints

NPS at week 52

Baseline Mean 6.1 6.1

LS Mean Change -2.46 -0.38

LS Mean Difference vs. Placebo (95% CI) -2.08 (-2.40, -1.76) <0.0001

NCS at week 52

Baseline Mean 2.59 2.55

LS Mean Change -1.74 -0.70

LS Mean Difference vs. Placebo (95% CI) -1.04 (-1.21, -0.87) <0.0001

Key secondary endpoints

Loss of smellb at week 52

Baseline Mean 2.9 2.8

LS Mean Change -1.26 -0.26

LS Mean Difference vs. Placebo (95% CI) -1.01 (-1.18, -0.83) <0.0001

SNOT-22 at week 52

Baseline Mean 68.2 69.2

LS Mean Change -45.02 -17.58

LS Mean Difference vs. Placebo (95% CI) -27.44 (-32.51, -22.37) <0.0001

Lund Mackay score (LMK) at week 52

Baseline Mean 18.9 18.5

LS Mean Change -6.27 -0.57

LS Mean Difference vs. Placebo (95% CI) -5.70 (-6.37, -5.03) <0.0001

Time to first sino-nasal surgery decision and/or SCS for CRSwNP up to week 52

Proportion of Patients (%)c 5.7 31.4% Reduction vs. Placebo [Hazard ratio (95% CI)] 92% [0.08 (0.03, 0.16)] <0.0001

Time to first sino-nasal surgery decision up to week 52

Proportion of Patients (%)c 0.5 22.0% Reduction vs. Placebo [Hazard ratio (95% CI)] 98% [0.02 (0.00, 0.09)] <0.0001

Time to first SCS use for CRSwNP up to week 52

Proportion of Patients (%)c 5.2 19.3% Reduction vs. Placebo [Hazard ratio (95% CI)] 89% [0.11 (0.04, 0.25)] <0.0001

Total Symptom Score (TSS) at week 52

Baseline Mean 16.3 16.4

LS Mean Change -10.39 -3.43

LS Mean Difference vs. Placebo (95% CI) -6.96 (-8.09, -5.83) <0.0001a Unadjusted p-values are presented. Statistically significant after multiplicity adjustment.b Change from baseline in loss of smell evaluated as bi-weekly mean difficulty with sense of smell item score inthe NPSD.c Kaplan-Meier estimates for the proportion of patients with events.

CRSwNP, Chronic rhinosinusitis with nasal polyps; CI, Confidence interval; LS mean change, Least squaredmean change from baseline; reduction in score indicates improvement; NCS, Nasal congestion score; NPS,

Nasal polyp score; SCS, Systemic corticosteroids; SD, Standard deviation; SNOT-22, 22-item Sino-Nasal

Outcome Test.

Figure 2 LS mean change from baseline in total nasal polyp score (NPS) and bi-weeklymean nasal congestion score (NCS) up to week 52

Figure 2a. Total NPS Figure 2b. Bi-weekly mean NCS

Tezepelumab 210 mg Q4W (N=203) Tezepelumab 210 mg Q4W (N=203)

Placebo (N=205) Placebo (N=205)

Time (Weeks) Time (Weeks)

Improvement in loss of smell in patients treated with tezepelumab compared with those treated withplacebo was seen as early as the first assessment at 2 weeks.

Asthma

A total of 82 adolescents aged 12 to 17 with severe, uncontrolled asthma were enrolled in

NAVIGATOR and received treatment with tezepelumab (n=41) or placebo (n=41). Of the41 adolescents receiving treatment with tezepelumab, 15 were taking high-dose ICS at baseline. Theannualised asthma exacerbation rate observed in adolescents treated with tezepelumab was 0.68 versus0.97 for placebo (rate ratio 0.70; 95% CI 0.34, 1.46). The LS mean change from baseline for FEV1observed in adolescents treated with tezepelumab was 0.44 L versus 0.27 L for placebo (LS meandifference 0.17 L; 95% CI -0.01, 0.35). The pharmacodynamic responses in adolescents weregenerally similar to the overall study population.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Tezspire in one or more subsets of the paediatric population in asthma (see section 4.2 for informationon paediatric use).

CRSwNP

The European Medicines Agency has waived the obligation to submit the results of studies with

Tezspire in all subsets of the paediatric population in CRSwNP (see section 4.2 for information onpaediatric use).

The pharmacokinetics of tezepelumab is similar in patients with asthma and CRSwNP.

The pharmacokinetics of tezepelumab were dose-proportional following subcutaneous administrationover a dose range of 2.1 mg to 420 mg.

LS Mean Change (95% CI)

LS Mean Change (95% CI)

Following a single subcutaneous administration, the maximum serum concentration was reached inapproximately 3 to 10 days. Based on population pharmacokinetic analysis, the estimated absolutebioavailability was approximately 77%. There was no clinically relevant difference in bioavailabilitywhen administered to different injection sites (abdomen, thigh, or upper arm).

Based on population pharmacokinetic analysis, central and peripheral volume of distribution oftezepelumab were 3.9 L and 2.2 L, respectively, for a 70 kg individual.

Tezepelumab is a human monoclonal antibody (IgG2λ) that is degraded by proteolytic enzymeswidely distributed in the body and not metabolised by hepatic enzymes.

As a human monoclonal antibody, tezepelumab is eliminated by intracellular catabolism and there isno evidence of target-mediated clearance. From population pharmacokinetic analysis, the estimatedclearance for tezepelumab was 0.17 L/d for a 70 kg individual. The elimination half-life wasapproximately 26 days.

Based on population pharmacokinetic analysis, age, gender and race had no clinically meaningfuleffects on the pharmacokinetics of tezepelumab.

Based on population pharmacokinetic analysis, higher body weight was associated with lowerexposure. However, the effect of body weight on exposure had no meaningful impact on efficacy orsafety and does not require dose adjustment.

Based on the population pharmacokinetic analysis, there was no clinically meaningful age-relateddifference in the pharmacokinetics of tezepelumab between adults and adolescents aged 12 to 17 yearswith asthma. Tezepelumab has not been studied in children under 12 years of age for the treatment ofasthma or in children under 18 years of age for the treatment of CRSwNP (see section 4.2).

Based on population pharmacokinetic analysis, there was no clinically meaningful difference in thepharmacokinetics of tezepelumab between patients 65 years of age or older and younger patients.

No formal clinical studies have been conducted to investigate the effect of renal impairment ontezepelumab. Based on population pharmacokinetic analysis, tezepelumab clearance was similar inpatients with mild renal impairment (creatinine clearance 60 to < 90 mL/min), moderate renalimpairment (creatinine clearance 30 to < 60 mL/min) and those with normal renal function (creatinineclearance ≥ 90 mL/min). Tezepelumab has not been studied in patients with severe renal impairment(creatinine clearance < 30 mL/min); however, tezepelumab is not cleared renally.

No formal clinical studies have been conducted to investigate the effect of hepatic impairment ontezepelumab. IgG monoclonal antibodies are not primarily cleared via hepatic pathway; change inhepatic function is not expected to influence tezepelumab clearance. Based on populationpharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had noeffect on tezepelumab clearance.

Non-clinical data revealed no special hazard for humans based on repeated dose toxicity studiesincluding safety pharmacology and fertility evaluations, and an ePPND (enhanced Pre- and Post-Natal

Development) reproductive toxicity study in cynomolgus monkeys at doses of up to 300 mg/kg/week(producing exposures of greater than 100-times the clinical exposure at maximum recommendedhuman dose [MRHD]).

Tezepelumab is excreted in milk in monkeys, although at low concentrations (< 1%).

Tezepelumab is a monoclonal antibody, as such genotoxicity and carcinogenicity studies have notbeen conducted.

Acetic acid (E 260)

L-proline

Polysorbate 80 (E 433)

Sodium hydroxide (for pH adjustment)

Water for injections

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

3 years.

Tezspire may be kept at room temperature (20°C - 25°C) for a maximum of 30 days. After removalfrom the refrigerator, Tezspire must be used within 30 days or discarded.

Store in a refrigerator (2°C - 8°C). For storage after removal from refrigeration, see section 6.3.

Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.

Do not freeze. Do not shake. Do not expose to heat.

Pre-filled syringe1.91 mL solution in a siliconised Type I glass pre-filled syringe subassembly consisting of a 27-gauge½-inch (12.7 mm) stainless steel special thin wall needle covered with a rigid needle cover andbromobutyl plunger-stopper. The pre-filled syringe subassembly is assembled with a needle guard andan extended finger flange.

Pack containing 1 pre-filled syringe.

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

Pre-filled pen1.91 mL solution in a siliconised Type I glass pre-filled syringe subassembly consisting of a 27-gauge½-inch (12.7 mm) stainless steel special thin wall needle covered with a needle cover andplunger-stopper. The pre-filled pen consists of the pre-filled syringe subassembly and handheld,mechanical (spring-based) injection device.

Pack containing 1 pre-filled pen.

Multipack containing 3 (3 packs of 1) pre-filled pens.

Not all pack sizes may be marketed.

This medicinal product is for single-use only.

Prior to administration, remove carton from refrigerator and allow Tezspire to reach roomtemperature. This generally takes 60 minutes.

Visually inspect Tezspire for particulate matter and discolouration prior to administration. Tezspireis clear to opalescent, colourless to light yellow. Do not use this medicinal product if liquid iscloudy, discoloured, or if it contains large particles or foreign particulate matter.

Additional information and instructions for the preparation and administration of Tezspire using thepre-filled syringe or pre-filled pen are given in the package leaflet and ‘Instructions for Use’.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/22/1677/001 1 pre-filled syringe

EU/1/22/1677/002 Multipack: 3 (3 packs of 1) pre-filled syringes

EU/1/22/1677/003 1 pre-filled pen

EU/1/22/1677/004 Multipack 3 (3 packs of 1) pre-filled pens

Date of first authorisation: 19 September 2022

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

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