Tezspire Drug Information

Clinical Studies in Patients with Asthma

The efficacy of TEZSPIRE for add-on maintenance treatment of severe asthma was evaluated in two randomized, double-blind, parallel group, placebo-controlled clinical trials (PATHWAY and NAVIGATOR ) of 52 weeks duration. The two trials enrolled a total of 1,609 patients 12 years of age and older with severe asthma. PATHWAY was a 52-week dose-ranging exacerbation trial that enrolled 550 adult patients with severe asthma who received treatment with tezepelumab-ekko 70 mg subcutaneously every 4 weeks, TEZSPIRE 210 mg subcutaneously every 4 weeks, tezepelumab-ekko 280 mg subcutaneously every 2 weeks, or placebo subcutaneously.

Patients were required to have a history of 2 or more asthma exacerbations requiring oral or injectable corticosteroid treatment or 1 asthma exacerbation resulting in hospitalization in the past 12 months. NAVIGATOR was a 52-week exacerbation trial that enrolled 1,061 patients (adult and pediatric patients 12 years of age and older) with severe asthma who received treatment with TEZSPIRE 210 mg subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or injectable corticosteroid treatment or resulting in hospitalization 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. 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. In both trials, patients were enrolled without requiring a minimum baseline level of blood eosinophils or FeNO. The demographics and baseline characteristics of PATHWAY and NAVIGATOR are provided in Table 3 below.

Table 3 Demographics and Baseline Characteristics of Patients in PATHWAY and NAVIGATOR PATHWAY N=550 NAVIGATOR N=1,059 Mean age (year) (SD) 52 50 Female (%) 66 64 White (%) 92 62 Black or African American (%) 3 6 Asian (%) 3 28 Hispanic or Latino (%) 1 15 Never smoked (%) 81 80 High-dose ICS use (%) 49 75 OCS use (%) 9 9 Mean number of exacerbations in previous year (SD) 2.4

Mean duration of asthma (years) (SD) 17 22 Mean baseline % predicted

FEV 1 (SD) 60 63 Mean post-bronchodilator FEV 1 reversibility (%) (SD) 23 15 Mean baseline blood EOS count (cells/µL) (SD) 371 340 Positive serum specific IgE to any perennial allergen (%) In the FEIA panel 46 64 Mean FeNO (ppb) (SD) 35 44 EOS, Eosinophils; FEIA, Fluorescent enzyme immunoassay; FeNO, Fractional exhaled nitric oxide; FEV 1, Forced expiratory volume in one second; ICS, Inhaled corticosteroid, IgE, Immunoglobulin E; OCS, Oral corticosteroid; ppb, Parts per billion; SD, Standard deviation The results summarized below are for the recommended TEZSPIRE 210 mg subcutaneously every 4 weeks dosing regimen. Exacerbations The primary endpoint for PATHWAY and NAVIGATOR 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 injectable corticosteroids for at least 3 days, or a single depo-injection of corticosteroids, and/or emergency department visits requiring use of oral or injectable corticosteroids and/or hospitalization.

In both PATHWAY and NAVIGATOR, patients receiving TEZSPIRE had significant reductions in the annualized rate of asthma exacerbations compared to placebo. There were also fewer exacerbations requiring emergency room visits and/or hospitalization in patients treated with TEZSPIRE compared with placebo (Table 4). Table 4 Rate of Clinically Significant Exacerbations Over 52 Weeks in PATHWAY and NAVIGATOR Trial Treatment Exacerbations per year Rate Rate Ratio (95% CI) Annualized Asthma Exacerbation Rate PATHWAY TEZSPIRE (N=137) 0.20 0.29 Placebo (N=138) 0.72 NAVIGATOR TEZSPIRE (N=528) 0.93 0.44 Placebo (N=531) 2.10 Exacerbations requiring emergency room visit/hospitalization PATHWAY TEZSPIRE (N=137) 0.03 0.15 Placebo (N=138) 0.18 NAVIGATOR TEZSPIRE (N=528) 0.06 0.21 Placebo (N=531) 0.28 Exacerbations requiring hospitalization PATHWAY TEZSPIRE (N=137) 0.02 0.14 Placebo (N=138) 0.14 NAVIGATOR TEZSPIRE (N=528) 0.03 0.15 Placebo (N=531) 0.19 In NAVIGATOR, patients receiving TEZSPIRE experienced fewer exacerbations than those receiving placebo regardless of baseline levels of blood eosinophils or FeNO (Figure 3). Similar results were seen in PATHWAY. Figure 3 Annualized Asthma Exacerbation Rate Ratio Over 52 Weeks Across Different Baseline Biomarkers in NAVIGATOR The time to first exacerbation was longer for the patients receiving TEZSPIRE compared with placebo in NAVIGATOR (Figure 4). Similar findings were seen in PATHWAY. Figure 4 Kaplan-Meier Cumulative Incidence Curves for Time to First Exacerbation in NAVIGATOR Lung Function Change from baseline in FEV 1 was assessed as a secondary endpoint in PATHWAY and NAVIGATOR. Compared with placebo, TEZSPIRE provided clinically meaningful improvements in the mean change from baseline in FEV 1 in both trials (Table 5). Table 5 Mean Change from Baseline in Pre-Bronchodilator FEV1 at End of Trial in PATHWAY and NAVIGATOR Week 52 in PATHWAY, Week 52 in NAVIGATOR Trial Treatment LS Mean Change from Baseline (L) Difference from Placebo (95% CI) PATHWAY TEZSPIRE (N=133) Number of patients contributing to the full analysis (FA) with at least 1 change from baseline value 0.08 0.13 Placebo (N=138) -0.06 NAVIGATOR TEZSPIRE (N=527) 0.23 0.13 Placebo (N=531) 0.10 In NAVIGATOR, improvement in FEV 1 was seen as early as 2 weeks after initiation of treatment and was sustained through week 52 (Figure 5). Figure 5 Mean Change (95% CI) from Baseline in Pre-Bronchodilator FEV1 (L) in NAVIGATOR Patient Reported Outcomes Changes from baseline in Asthma Control Questionnaire 6 (ACQ-6) and Standardized Asthma Quality of Life Questionnaire for ages 12 and older were also assessed as secondary endpoints in PATHWAY and NAVIGATOR. 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 both measures was defined as improvement in score of 0.5 or more at end of trial. In NAVIGATOR, the ACQ-6 responder rate for TEZSPIRE was 86% compared with 77% for placebo (OR=1.99; 95% CI 1.43, 2.76) and the AQLQ(S)+12 responder rate for TEZSPIRE was 78% compared with 72% for placebo (OR=1.36; 95% CI 1.02, 1.82). Similar findings were seen in PATHWAY. Additional Trial In a randomized, double-blind, parallel group, placebo-controlled clinical trial, the effect of TEZSPIRE (210 mg subcutaneously every 4 weeks) on reducing the use of maintenance OCS was evaluated.

The trial enrolled 150 adult patients with severe asthma who required treatment with daily OCS (7.5 mg to 30 mg per day) in addition to regular use of high-dose ICS and a long-acting beta-agonist with or without additional controller(s). The primary endpoint was categorized 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 any increase in OCS), while maintaining asthma control. TEZSPIRE did not demonstrate a statistically significant reduction in maintenance OCS dose compared with placebo (cumulative OR=1.28; 95% CI 0.69, 2.35). figure_2 figure_3 figure_4

Clinical Studies in Patients with Chronic Rhinosinusitis with Nasal Polyps

The efficacy of TEZSPIRE for add-on maintenance treatment of inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP) was evaluated in a randomized, double-blind, parallel group, multicenter, placebo-controlled trial (WAYPOINT ) of 52 weeks treatment duration conducted in 408 patients aged 18 years and older on standard of care treatment for CRSwNP. This study included patients with symptomatic CRSwNP despite treatment with nasal corticosteroids, and who had systemic corticosteroids within the past 12 months and/or any history of sino-nasal surgery, or with contraindications and/or intolerance to either. Patients received TEZSPIRE 210 mg or placebo subcutaneously every 4 weeks for 52 weeks in addition to nasal corticosteroid treatment for CRSwNP. The demographics and baseline characteristics of patients enrolled in WAYPOINT are provided in Table 6. Table 6 Demographics and Baseline Characteristics of Adult Patients in WAYPOINT WAYPOINT N=408 Number of patients (N) =407 for mean total NPS; N=406 for mean bi-weekly NCS and mean bi-weekly loss of smell; N=404 for mean LMK sinus CT total score and mean blood eosinophils; N=389 for mean total IgE. Mean age (years) (SD) 50 Male (%) 65 Mean CRSwNP duration (years) (SD) 13 Patients with ≥1 prior surgery (%) 71 Patients with systemic corticosteroid use for CRSwNP in the previous year (%) 58 Mean total NPS Higher scores indicate greater disease severity or symptom severity. (SD), range 0-8

Mean bi-weekly

NCS (SD), range 0-3

Mean

LMK sinus CT total score (SD), range 0-24 19 Mean bi-weekly loss of smell (SD), range 0-3

Mean blood eosinophils (cells/µL) (SD) 358 Mean total IgE IU/mL (SD) 176

Asthma Includes patients with asthma or AERD or NSAID-ERD. All but 3 patients with AERD or NSAID-ERD included in this subgroup also had a diagnosis of asthma reported. (%) 61 NSAID-ERD/AERD (%) 17 AERD, Aspirin exacerbated respiratory disease; CRSwNP, Chronic rhinosinusitis with nasal polyps; CT, Computed tomography; IgE, Immunoglobulin E; IU, International units; LMK, Lund-Mackay; NCS, Nasal congestion score; NPS, Nasal polyp score; NSAID‑ERD, Nonsteroidal anti-inflammatory drug exacerbated respiratory disease; SD, Standard deviation 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 change from baseline in bi-weekly mean nasal congestion score (NCS) evaluated at Week 52. For total NPS, polyps on each side of the nose were graded on a categorical scale (0=no polyps, 1=small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2=polyps reaching below the lower border of the middle turbinate, 3=polyps reaching the lower border of the inferior turbinate or a middle meatal polyp with a score of 2 with any additional polyp medial to the middle turbinate, 4=large polyps causing complete or near complete obstruction of the inferior nasal cavity ) for a total score of 0 to 8. Nasal congestion was rated daily by the patients on a 0 to 3 categorical severity scale (0=none, 1=mild, 2=moderate, 3=severe). Statistically significant efficacy was observed in WAYPOINT for the co-primary endpoints of improvement in total NPS and in bi-weekly mean NCS at Week 52 (Table 7). Table 7 Results of Change from Baseline in Total Nasal Polyp Score and Bi-weekly Mean Nasal Congestion Score at Week 52 in Adults with CRSwNP (WAYPOINT) TEZSPIRE 210 mg Q4W (N=203) Placebo (N=205) LS mean difference vs. placebo (95% CI) Scores Baseline mean LS mean change Baseline mean LS mean change NPS 6.1 -2.47 6.1 -0.47 -2.01 (-2.33, -1.68) NCS 2.59 -1.76 2.55 -0.81 -0.95 (-1.12, -0.78) LS mean change, Least squared mean change from baseline; reduction in score indicates improvement; NCS, Nasal congestion score; NPS, Nasal polyp score Figure 6 demonstrates the time course of improvement in the mean change from baseline in NPS. Figure 6 LS Mean Change from Baseline in Total Nasal Polyp Score up to Week 52 in Adults (WAYPOINT) Figure 7 demonstrates the time course of improvement in the bi-weekly mean change from baseline in NCS. Figure 7 LS Mean Change from Baseline in Bi-weekly Mean Nasal Congestion Score up to Week 52 in Adults (WAYPOINT) Key secondary endpoints at Week 52 included time to surgery decision and/or systemic corticosteroid use for nasal polyps, change from baseline in loss of smell, and change from baseline in Lund-Mackay (LMK) sinus CT scan score. TEZSPIRE significantly reduced the proportion of patients with need for sino-nasal surgery or systemic corticosteroids by 92% compared to placebo over 52 weeks (Hazard Ratio: 0.08; 95% CI: 0.03, 0.17) (Figure 8). Figure 8 Kaplan Meier Curve for Time to First Systemic Corticosteroid Use and/or Sino-Nasal Surgery Decision Over 52 Weeks in Adults (WAYPOINT) TEZSPIRE significantly reduced the proportion of patients requiring sino-nasal surgery by 98% compared to placebo over 52 weeks (Hazard Ratio: 0.02; 95% CI: 0.00, 0.09) and significantly reduced the proportion of patients requiring systemic corticosteroids for CRSwNP by 88% compared to placebo over 52 weeks (Hazard Ratio: 0.12; 95% CI: 0.04, 0.27). The loss of smell score was based on a subject’s daily rating of the severity of their worst difficulty with sense of smell over the past 24 hours on a 0 to 3 scale (0=none, 1=mild, 2=moderate, 3=severe). The loss of smell score was calculated every 2 weeks as the bi-weekly mean. TEZSPIRE significantly improved the loss of smell compared to placebo.

The LS mean difference for loss of smell at Week 52 in the TEZSPIRE group versus placebo was -1.01. The LMK sinus CT scan score evaluated the opacification of each sinus at baseline and Week 52 using a 0 to 2 scale (0=no abnormality; 1=partial opacification, 2=total opacification) deriving a maximum score of 12 per side and a total maximum score of 24 (higher scores indicate more opacification). A significant decrease in the LMK sinus CT scan score was observed. The LS mean difference for LMK sinus CT scan score at Week 52 in the TEZSPIRE group versus placebo was -5.76. Figure_6 Figure_7 Figure_8