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Pharmacodynamics: In a Phase 1 allergen inhalation challenge study of patients with mild allergic asthma, administration of tezepelumab 700 mg IV Q4W for a total of 3 doses (n=16) suppressed the inhaled allergen-induced increase in blood and sputum eosinophils and FeNO relative to placebo (n=15) and reduced both the late and early asthmatic response following allergen challenge.
In Trial 2 (NAVIGATOR), administration of tezepelumab 210 mg SC Q4W (n=528) reduced inflammatory biomarkers and cytokines from baseline compared with placebo (n=531) with an onset of effect by 2 weeks and sustained reduction to 52 weeks for blood eosinophil counts, FeNO, serum IL-5 concentration, and serum IL-13 concentration. Tezepelumab caused a progressive reduction in serum total IgE concentration, with levels continuing to decrease throughout 52 weeks of treatment. Similar effects were seen in Trial 1 (PATHWAY).
A 28-week Phase 2 randomised, double-blind, placebo-controlled, parallel-group mechanistic study evaluated the effect of tezepelumab 210 mg SC Q4W on airway inflammation in adults (n=116) with inadequately controlled moderate to severe asthma. Tezepelumab reduced submucosal eosinophil counts by 89% (end of treatment to baseline ratio 0.11 [90% CI 0.06, 0.21]) compared with a 25% reduction with placebo (0.75 [90% CI 0.41, 1.38]). Reduction was consistent regardless of baseline subgroup levels of blood eosinophils, FeNO, serum IL-5, serum IL-13 and allergic status (determined by a perennial aeroallergen specific IgE).
Immunogenicity: In Trial 2, 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 the 52-week study period. Of these 26 patients, 10 patients (1.9% of patients treated with tezepelumab) developed treatment-emergent antibodies 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.
Clinical efficacy in asthma: The efficacy of TEZSPIRE was evaluated in three randomised, double-blind, parallel group, placebo-controlled clinical trials (Trial 1 [PATHWAY], Trial 2 [NAVIGATOR] and Trial 3 [SOURCE]) of 48 to 52 weeks in duration in patients aged 12 years and older. In all three trials, patients were enrolled without requiring a minimum baseline level of blood eosinophils or other inflammatory biomarkers (e.g. FeNO or IgE).
Trial 1 was an exacerbation trial 52-weeks in duration that randomised a total of 550 patients (18 years of age and older) with severe, uncontrolled asthma to receive treatment with tezepelumab 70 mg SC Q4W, tezepelumab 210 mg SC Q4W, tezepelumab 280 mg SC Q2W or placebo. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment or 1 asthma exacerbation resulting in hospitalisation in the past 12 months.
Trial 2 was an exacerbation trial 52-weeks in duration that randomised a total of 1061 patients (adults and adolescents 12 years of age and older) with severe, uncontrolled asthma to receive treatment with tezepelumab 210 mg SC Q4W or placebo. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment or resulting in hospitalisation in the past 12 months.
In both Trial 1 and Trial 2, 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 inhaled corticosteroids (ICS) and at least one additional asthma controller with or without oral corticosteroids (OCS). Patients continued background asthma therapy throughout the duration of the trials.
Trial 3 was an OCS reduction trial 48-weeks in duration that randomised a total of 150 asthma patients (18 years of age and older) who required treatment with daily OCS (7.5 mg to 30 mg per day) in addition to regular use of high-dose ICS and long-acting beta-agonist (LABA) with or without additional controller(s). Patients were required to have a history of at least 1 exacerbation in the past 12 months. After an up to 8-week OCS optimisation phase, patients received either tezepelumab 210 mg SC Q4W or placebo for a total of 48 weeks. Patients continued to receive their baseline background asthma medications during the study; however, their OCS dose was reduced every 4 weeks during the OCS reduction phase (Week 4 to 40), as long as asthma control was maintained. This was followed by an 8-week maintenance phase during which patients were to remain on the OCS dose achieved by Week 40. Median OCS dose at the end of the optimisation phase (baseline) was 10 mg for the two treatment groups. (See Table 1.)
Click on icon to see table/diagram/imageThe results summarised as follows are for the recommended tezepelumab 210 mg SC Q4W dosing regimen.
Exacerbations: The primary endpoint for Trial 1 and Trial 2 was the rate of clinically significant asthma exacerbations measured over 52 weeks. Clinically significant asthma exacerbations were defined as worsening of asthma requiring the use of or increase in oral or systemic corticosteroids for at least 3 days or a single depo-injection of corticosteroids, and/or emergency department visits requiring use of oral or systemic corticosteroids and/or hospitalisation.
In both Trial 1 and Trial 2, patients receiving TEZSPIRE had significant reductions in the annualised rate of asthma exacerbations compared with placebo (Table 2). There were also fewer exacerbations requiring emergency room visits and/or hospitalisation in patients treated with TEZSPIRE compared with placebo. Additionally, a greater proportion of patients receiving TEZSPIRE did not experience an asthma exacerbation during the 52-week treatment compared with placebo. (See Table 2.)
Click on icon to see table/diagram/imageThe time to first exacerbation was longer for the patients receiving TEZSPIRE compared with placebo Trial 2 (Figure 1). Similar results were seen in Trial 1. (See Figure 1.)
Click on icon to see table/diagram/imageSubgroup Analysis: In Trial 2, TEZSPIRE demonstrated a reduction in the rate of asthma exacerbations regardless of the baseline levels of blood eosinophils, FeNO, as well as allergic status (determined by a perennial aeroallergen specific IgE) (Figure 2). Similar results were seen in Trial 1. (See Figure 2.)
Click on icon to see table/diagram/imageLung Function: Change from baseline in FEV1 was assessed as a secondary endpoint in Trial 1 and Trial 2. Compared with placebo, TEZSPIRE provided clinically meaningful improvements in the mean change from baseline in FEV1 in both Trial 1 and Trial 2 (see Table 3).
Click on icon to see table/diagram/imageIn Trial 2, improvement in FEV1 was seen as early as 2 weeks after initiation of treatment and was sustained through week 52 (see Figure 3).
Click on icon to see table/diagram/imagePatient Reported Outcomes: Changes from baseline in Asthma Control Questionnaire 6 (ACQ-6) and Standardised Asthma Quality of Life Questionnaire for ages 12 and older [AQLQ(S)+12] were assessed as secondary endpoints in Trial 1 and Trial 2. Results for Trial 2 are shown in Table 4. Improvements in ACQ-6 and AQLQ(S)+12 were seen as early as 2 weeks and 4 weeks after administration of TEZSPIRE, respectively, and sustained through Week 52 in both trials.
In both trials, more patients treated with TEZSPIRE compared to placebo had a clinically meaningful improvement in ACQ-6 and AQLQ(S)+12. Clinically meaningful improvement (responder rate) for ACQ-6 and AQLQ(S)+12 was defined as improvement in score of 0.5 at end of trial. In Trial 2, the ACQ-6 responder rate for TEZSPIRE was 86% compared with 77% for placebo (odds ratio=1.99; 95% CI 1.43, 2.76) and the AQLQ(S)+12 responder rate for TEZSPIRE was 78% compared with 72% for placebo (odds ratio=1.36; 95% CI 1.02, 1.82). Similar findings were seen in Trial 1.
Weekly mean Asthma Symptom Diary (ASD) scores were also assessed as a secondary endpoint in Trial 2. Severity of wheezing, shortness of breath, cough, and chest tightness were assessed twice daily (morning and evening). Night-time awakening and activity were assessed on a daily basis. The total ASD score was calculated as the mean of 10 items. More patients treated with TEZSPIRE compared to placebo had a clinically meaningful improvement in the ASD score. Clinically meaningful improvement (responder rate) was defined as improvement in score of 0.5 or more at end of trial. The ASD responder rate for TEZSPIRE was 58% compared with 51 % for placebo (odds ratio=1.68; 95% CI 1.12, 2.53). (See Table 4.)
Click on icon to see table/diagram/imageOral Corticosteroid Reduction: Trial 3 evaluated the effect of TEZSPIRE on reducing the use of maintenance OCS. The primary endpoint was categorised percent reduction from baseline of the final OCS dose at Week 48 (≥90% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and no change or no decrease in OCS), while maintaining asthma control. Compared with placebo, more patients receiving TEZSPIRE achieved a reduction from baseline in maintenance OCS dose without losing asthma control (cumulative odds ratio=1.28; 95% CI 0.69, 2.35), but the difference was not statistically significant. A total of 40 (54%) patients receiving tezepelumab compared with 35 (46%) patients receiving placebo achieved a ≥90% to 100% reduction in their OCS. Reductions of 50% or higher in the OCS dose were observed in 55 (74%) patients receiving TEZSPIRE compared to the 53 (70%) patients receiving placebo.
Paediatric Population: A total of 82 adolescents aged 12 to 17 with severe, uncontrolled asthma were enrolled in Trial 2 and received treatment with TEZSPIRE (n=41) or placebo (n=41). Compared with placebo, clinically meaningful improvements in annualised asthma exacerbation (rate ratio 0.70; 95% CI 0.34, 1.46) and FEV1 (LS mean change from placebo 0.17 L; 95% CI -0.01, 0.35) were observed in adolescents treated with TEZSPIRE. The safety profile and pharmacodynamic responses in adolescents were generally similar to the overall study population.
Pharmacokinetics: The pharmacokinetics of tezepelumab were dose-proportional following SC administration over a dose range of 2.1 mg to 420 mg.
Absorption: Following a single SC administration, the maximum serum concentration was reached in approximately 3 to 10 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 77%. There was no clinically relevant difference in bioavailability when administered to different injection sites (abdomen, thigh, or upper arm).
Distribution: Based on population pharmacokinetic analysis, central and peripheral volume of distribution of tezepelumab were 3.9 L and 2.2 L, respectively, for a 70 kg individual.
Metabolism: Tezepelumab is a human monoclonal antibody (IgG2λ) that is degraded by proteolytic enzymes widely distributed in the body and not metabolised by hepatic enzymes.
Elimination: As a human monoclonal antibody, tezepelumab is eliminated by intracellular catabolism and there is no evidence of target-mediated clearance. From population pharmacokinetic analysis, the estimated clearance for tezepelumab was 0.17 L/d for a 70 kg individual. The elimination half-life was approximately 26 days.
Special populations: Age, Gender, Race: Based on population pharmacokinetic analysis, age, gender, and race had no clinically meaningful effects on the pharmacokinetics of tezepelumab.
Body Weight: Based on population pharmacokinetic analysis, higher body weight was associated with lower exposure. However, the effect of body weight on exposure had no meaningful impact on efficacy or safety and does not require dose adjustment.
Paediatric patients: Based on the population pharmacokinetic analysis, there was no clinically meaningful age-related difference in the pharmacokinetics of tezepelumab between adults and adolescents aged 12 to 17 years. Tezepelumab has not been studied in children under 12 years of age (see Dosage & Administration).
Elderly patients (≥65 years old): Based on population pharmacokinetic analysis, there was no clinically meaningful difference in the pharmacokinetics of tezepelumab between patients 65 years of age or older and younger patients.
Of the 665 patients with asthma exposed to TEZSPIRE in the two placebo-controlled clinical studies of 52 weeks duration, a total of 119 patients were 65 years or older. Safety in this age group were similar to the overall study population.
Efficacy in this age group was similar to the overall study population in Trial 2. Trial 1 did not include sufficient numbers of patients aged 65 and over to determine efficacy in this age group.
Renal impairment: No formal clinical studies have been conducted to investigate the effect of renal impairment on tezepelumab. Based on population pharmacokinetic analysis, tezepelumab clearance was similar in patients with mild renal impairment (creatinine clearance 60 to < 90 mL/min), moderate renal impairment (creatinine clearance 30 to < 60 mL/min) and those with normal renal function (creatinine clearance ≥ 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.
Hepatic impairment: No formal clinical studies have been conducted to investigate the effect of hepatic impairment on tezepelumab. IgG monoclonal antibodies are not primarily cleared via hepatic pathway; change in hepatic function is not expected to influence tezepelumab clearance. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (ALT, AST, and bilirubin) had no effect on tezepelumab clearance.
Drug-Drug Interaction: No formal drug interaction studies have been conducted. A clinically relevant effect of tezepelumab on the pharmacokinetics of co-administered asthma medications is not expected. Based on the population pharmacokinetic analysis, commonly co-administered asthma medications (including leukotriene receptor antagonists, theophylline/aminophylline, and OCS) had no effect on tezepelumab clearance.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology and repeated dose toxicity studies in cynomolgus monkeys.
Mutagenicity and carcinogenicity: Tezepelumab is a monoclonal antibody, as such genotoxicity and carcinogenicity studies have not been conducted.
Reproductive toxicity: Developmental toxicity: In a prenatal and postnatal development study conducted in cynomolgus monkeys, following IV administration of tezepelumab up to 300 mg/kg/week from early gestation through delivery, no adverse effects on maternal health, pregnancy outcome, embryo-foetal development, or neonatal growth and development up to 6.5 months of age were observed. Tezepelumab concentrations in milk were <1% of the serum concentrations. Comparison of maternal and infant serum ratios suggested that the majority of tezepelumab transfer to the infant occurred in utero but transfer via milk cannot be excluded. No adverse effects on maternal health or neonatal health and development were observed.
Fertility: Effects on male and female fertility have not been directly evaluated in animal studies. Examination of surrogate fertility parameters (menstrual cycle, semen analysis, organ weights, and microscopic pathology) was performed in sexually mature male and female cynomolgus monkeys as part of a 6-month repeated dose toxicology study. There were no tezepelumab-related effects on these parameters at doses up to 300 mg/kg/week by SC administration.
