Summary Basis of Decision for Tezspire

Clinical Pharmacology

Tezepelumab, the medicinal ingredient in Tezspire, is a human monoclonal antibody directed against human thymic stromal lymphopoietin (TSLP).

Pharmacodynamic data of tezepelumab in asthma patients were obtained from a Phase II study, CASCADE, a Phase IIb dose-ranging study, PATHWAY, and the pivotal Phase III study, NAVIGATOR (the pivotal study is described in the Clinical Efficacy section). These data showed that the administration of tezepelumab reduced inflammatory mediators such as blood eosinophils, immunoglobulin E (IgE), fractional exhaled nitric oxide (FeNO), interleukin-5 (IL-5), and interleukin-13 (IL-13). However, the primary pharmacodynamic effect of tezepelumab in asthma remains to be definitively established.

Pharmacokinetic data of tezepelumab were derived from six Phase I studies, the PATHWAY study, the NAVIGATOR study, and the Phase III study PATH-HOME.

In single-ascending-dose and multiple-ascending-dose studies, healthy adult subjects received up to 420 mg of tezepelumab administered subcutaneously and up to three doses of 700 mg administered intravenously every four weeks. Exposure to tezepelumab was found to be dose proportional following subcutaneous administration over a dose range of 2.1 mg to 420 mg. After repeated subcutaneous administration every four weeks, serum tezepelumab concentrations approached steady state by 12 weeks, with an estimated mean accumulation ratio of 1.86. The estimated absolute bioavailability was 77%.

A Phase I comparative bioavailability study (PATH-BRIDGE) demonstrated that tezepelumab exposures following single-dose subcutaneous administration via the to-be-marketed prefilled syringe and autoinjector presentations or via the vial presentation used in the NAVIGATOR study were within the bioequivalence margins specified in the relevant Health Canada’s guidance document. Consistent exposures were also observed between at-home or in-clinic administration of tezepelumab via either the prefilled syringe or autoinjector in the PATH-HOME study.

The population pharmacokinetic model submitted by the sponsor was a two-compartment model with first-order absorption and elimination. The model was appropriately parameterized and provided accurate fits to the observed data. For the recommended dosing regimen of 210 mg tezepelumab administered subcutaneously every four weeks to an individual with a body weight of 70 kg, the model-predicted mean (standard deviation) exposure values at steady state were 40.9 (14) µg/mL for the maximum serum concentration (C_max) and 901 (328) µg*day/mL for the area under the concentration-time curve (AUC). The estimated half-life of tezepelumab was approximately 26 days, which was consistent with observed data.

The recommended dosing regimen of 210 mg tezepelumab administered subcutaneously every four weeks was also supported by two exposure-response models derived from pharmacokinetic data collected in PATHWAY and NAVIGATOR, respectively. The models show that the predicted tezepelumab exposures for this dosing regimen lie on the plateau phase of the exposure-response curve.

In the population pharmacokinetic analysis, body weight was the most influential covariate for tezepelumab exposure, as higher body weight was shown to be associated with lower exposure. An increase in exposure was also observed in adolescent patients compared with adults; body weight was the main driver of this difference. However, the model-predicted exposures of tezepelumab in an adolescent weighing 30 kg were consistent with the exposures observed in patients treated with the dosing regimen of 280 mg of tezepelumab administered subcutaneously every two weeks in the PATHWAY study. This dosing regimen was well tolerated and no dose-dependent safety signals were observed. Accordingly, no dose adjustment of tezepelumab is required in terms of body weight.

Tezepelumab exhibited low immunogenicity across the clinical studies. In the pivotal study (NAVIGATOR), 26 out of 527 subjects (4.9%) tested positive for anti-drug antibodies (ADAs), with treatment-emergent ADAs occurring in 10 out of 522 subjects (1.9%). Only one subject had neutralizing ADAs. There was no apparent effect of ADAs on the pharmacokinetics or the safety profile of tezepelumab.

The clinical pharmacology data support the use of Tezspire for the recommended indication.

For further details, please refer to the Tezspire Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Tezspire as an add-on maintenance treatment in adults and adolescents aged 12 years and older with severe asthma is primarily supported by data derived from three core studies: two asthma exacerbation studies (the pivotal study, NAVIGATOR, and the dose-ranging study, PATHWAY) and one oral corticosteroid-reduction study, SOURCE.

The pivotal study was a Phase III, randomized, double-blind, placebo-controlled study, with a 52-week treatment period. It included 1,059 patients (82 adolescents and 977 adults) with inadequately controlled severe asthma. Patients had to have experienced two or more asthma exacerbations requiring oral or systemic corticosteroid treatment, or resulting in hospitalization in the 12 months prior to enrollment, despite receiving regular treatment with medium- or high-dose inhaled corticosteroids and at least one additional asthma control therapy with or without oral corticosteroids. Background asthma therapy was continued throughout the duration of the study. Notably, NAVIGATOR enrolled patients with a broad range of baseline blood eosinophil counts, total serum IgE levels, FeNO levels, and patients with allergic or non-allergic status, as determined by a positive serum IgE result specific to any perennial aeroallergen. Patients were randomized to receive Tezspire 210 mg (528 patients) or placebo (531 patients) administered subcutaneously every four weeks. The dosing regimen of Tezspire was chosen based on results obtained in the Phase IIb, dose-ranging study (PATHWAY), which evaluated three different dose levels of Tezspire.

The primary efficacy endpoint of the pivotal study was the annualized asthma exacerbation rate (AAER) over 52 weeks. An asthma exacerbation was defined as a worsening of asthma that led to any of the following: a temporary bolus/burst of systemic corticosteroids (or a temporary increase in a stable background dose of oral corticosteroids for at least 3 consecutive days); an emergency room or urgent care visit (that lasts less than 24 hours) due to asthma that required systemic corticosteroids; or an in-patient hospitalization (for at least 24 hours) due to asthma.

Treatment with Tezspire resulted in a clinically meaningful and statistically significant reduction of 56% in the AAER over 52 weeks compared with placebo (AAER rate ratio of 0.44; 95% confidence interval [CI]: 0.37, 0.53; p < 0.001). The reduction in AAER over 52 weeks was observed in Tezspire-treated patients across clinically relevant subgroups, including patients with low blood eosinophil counts. In Tezspire-treated patients who had blood eosinophil counts lower than 150 eosinophils/µL at baseline, the AAER over 52 weeks was reduced by 39% relative to placebo.

Compared to placebo, treatment with Tezspire resulted in benefits across multiple endpoints related to exacerbations, including a reduction of 79% in the rate of asthma exacerbations requiring hospitalizations and emergency room visits over 52 weeks, and a reduction of 85% in the rate of asthma exacerbations requiring hospitalization over 52 weeks.

Additionally, treatment with Tezspire led to clinically meaningful and statistically significant improvements in key secondary endpoints, including lung function (as measured by forced expiratory volume in the first second [FEV₁]; the difference from placebo in the mean change from baseline in FEV₁ was 0.13 L [95% CI: 0.08, 0.18]). Clinically meaningful improvements from baseline that were statistically significant versus placebo were also found in two clinically relevant patient-reported outcomes: asthma-related quality of life, as assessed by the Asthma Quality of Life Questionnaire (Standardized) for 12 years and older, AQLQ(S)+12; and asthma control, as assessed by the Asthma Control Questionnaire, ACQ‑6.

While the small subgroup of 82 adolescents (41 of whom received Tezspire) was not powered to demonstrate statistical significance for the primary endpoint, it showed a decrease of 30% in the AAER over 52 weeks compared to placebo (AAER rate ratio of 0.70 [95% CI: 0.34, 1.46]). Lung function results in this subgroup also favoured Tezspire.

The oral corticosteroid-reduction study, SOURCE, aimed to evaluate the effect of Tezspire 210 mg administered subcutaneously every four weeks versus placebo on reducing the maintenance oral corticosteroid dose in adult patients with severe, oral corticosteroid-dependent asthma. This was a Phase III, randomized, double-blind, placebo-controlled study with a 48-week treatment period. The study enrolled 150 asthma patients (18 years of age and older) who required treatment with daily oral corticosteroids (7.5 mg to 30 mg per day) in addition to regular use of high-dose inhaled corticosteroids and a long-acting beta-agonist with or without additional asthma controller(s). Of the 150 patients, 74 received Tezspire.

The primary endpoint was the categorized percent reduction from baseline in daily oral corticosteroid dose at Week 48 while maintaining asthma control. The categories of percent change from baseline in daily oral corticosteroid dose were ≥90% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and no change or no reduction in the daily oral corticosteroid dose. Treatment with Tezspire did not demonstrate a statistically significant reduction in maintenance oral corticosteroid dose compared with placebo (cumulative odds ratio [OR] = 1.28; 95% CI: 0.69, 2.35). While the primary endpoint was not met, secondary endpoints, including the AAER, showed improvements with Tezspire relative to placebo despite patients reducing their maintenance oral corticosteroid dose. Subgroup analyses for patients on maintenance oral corticosteroids in NAVIGATOR further support the efficacy trends noted in SOURCE. Based on these results, a limitation of use of Tezspire in patients on maintenance oral corticosteroids was not included in the Tezspire Product Monograph.

Indication

The New Drug Submission for Tezspire was filed by the sponsor with the following indication, which was subsequently approved by Health Canada:

• Tezspire (tezepelumab injection) is indicated as an add-on maintenance treatment in adults and adolescents aged 12 years and older with severe asthma.
• Tezspire is not indicated for relief of acute bronchospasm or status asthmaticus.

For more information, refer to the Tezspire Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Tezspire was based on data derived from the pooled safety population (primary safety pool) from the pivotal study NAVIGATOR (described in the Clinical Efficacy section) and the supportive dose-ranging study PATHWAY. The primary safety pool included 665 asthma patients who received Tezspire 210 mg via subcutaneous administration every four weeks for up to one year, representing approximately 640 patient-years of exposure.

The overall incidence of subjects with adverse events in the on-treatment period was similar between the Tezspire and placebo groups (74.6% and 76.5% of subjects, respectively). These adverse events were mostly non-serious in nature and of mild or moderate intensity.

The incidence of adverse events considered causally related to the investigational product by the investigator was 9.0% in the Tezspire group and 8.1% in the placebo group. Permanent discontinuation due to adverse events (including serious adverse events) occurred in 2.0% of patients in the Tezspire group and 3.0% of patients in the placebo group. The four most commonly reported adverse events in the Tezspire group were nasopharyngitis (19.5%), upper respiratory tract infection (9.3%), headache (7.8%), and asthma (7.4%); in comparison, incidences of patients with these adverse events in the placebo group were 19.1%, 13.3%, 7.5%, and 15.7%, respectively.

The incidence of serious adverse events in the on-treatment period was 8.6% in the Tezspire-treated patients and 13.0% in the placebo-treated patients. Asthma was the most commonly reported serious adverse event in both treatment groups, with an incidence of 2.3% in the Tezspire group versus 6.9% in the placebo group. Apart from asthma, no serious adverse events by a preferred term (as per the Medical Dictionary for Regulatory Activities [MedDRA]) were reported in more than two patients in the Tezspire group. The incidence of serious adverse events considered causally related to the investigational product was 0.9% in the Tezspire group and 0.7% in the placebo group.

Additionally, the adverse event profile of Tezspire appeared similar across predefined subgroups, including subgroups defined by baseline blood eosinophil count, allergic status (determined by a perennial aeroallergen-specific IgE), baseline inhaled corticosteroid dose, baseline oral corticosteroid dose, age, gender, body mass index, race, country, and region. Based on data derived from a small subgroup of adolescents (only 41 patients aged 12 to 17 years received Tezspire in NAVIGATOR), the safety profile of Tezspire was similar to that observed in Tezspire-treated adults.

In patients with oral corticosteroid-dependent asthma in the SOURCE study (described in the Clinical Efficacy section), Tezspire was well tolerated and demonstrated an adverse event profile similar to that seen in the primary safety pool.

In a long-term extension study, DESTINATION, the safety profile of Tezspire was generally similar to that observed in the primary safety pool. However, there was a notable increased incidence of serious adverse events in the MedDRA System Organ Class (SOC) Cardiac disorders among Tezspire-treated patients relative to placebo (exposure-adjusted incidence rates [95% CI]: 1.30 [0.77, 2.06] versus 0.23 [0.03, 0.83], respectively). Notably, all patients had risk factors for cardiac disease and some patients also had a confounding medical history. There was no pattern in specific MedDRA preferred terms (i.e., adverse events were spread across the MedDRA SOC Cardiac disorders). Similarly, the data did not reveal any pattern in time to onset for the serious cardiac events, there were no imbalances in the overall (serious and non-serious) cardiac events between treatment arms, no causal relationship to Tezspire treatment as deemed by both investigators and a blinded adjudication committee, and no identified pathophysiologic link based upon literature, non-clinical data, and data from other clinical studies. A small increase was also noted in fatalities reported in this study for Tezspire-treated patients relative to placebo; there was no causal association for this finding, nor was it observed in other clinical studies.

Based on the clinical data available at this time, the safety profile of Tezspire was considered acceptable. Appropriate warnings and precautions are in place in the approved Tezspire Product Monograph to address the identified safety concerns.

For more information, refer to the Tezspire Product Monograph, approved by Health Canada and available through the Drug Product Database.