Caterina Paparsenos1, Jose-Maria Cendros1, Carlos Traynor1, Jacqueline Ernest1, Diansong Zhou2, Anna Lundahl3, Yanyan Zhang4, Ludna Abuqayyas5, Yun Chon5
1AstraZeneca, 2AstraZeneca, 3AstraZeneca, 4AstraZeneca, 5Amgen Inc, 6AstraZeneca
Introduction: Tezepelumab is a human anti-thymic stromal lymphopoietin, immunoglobulin G2? human monoclonal antibody. Tezepelumab is approved in US, EU and Japan and other countries for the treatment of severe asthma in adults and adolescents. Tezepelumab also demonstrated clinically meaningful efficacy and acceptable safety in a previous pivotal asthma phase 3 study (NAVIGATOR) conducted in non-Chinese patients with severe asthma. Objectives: To characterize the population pharmacokinetics (popPK) and exposure-response (ER) relationships of tezepelumab in Chinese population to support the recommended fixed dose regimen of 210 mg every 4 weeks (Q4W) administered subcutaneously (SC) in adult and adolescent Chinese patients with severe asthma. Methods: The popPK of tezepelumab was characterized using pooled PK data from eight clinical studies involving both Chinese and non-Chinese asthma patients, as well as healthy subjects. The ER analysis was conducted using exclusively data from the Phase 3 Chinese study (DIRECTION). The annualized asthma exacerbation rate (AAER) (primary endpoint) and the change from baseline in pre-bronchodilator (BD) forced expiratory volume in one second (FEV1) (secondary endpoint) were analyzed in relation to tezepelumab exposure. Efficacy endpoints were evaluated by dividing the results into exposure quartiles according to the through concentration in steady state (Cthrought). A negative binomial regression model assessed the treatment effect of tezepelumab on AAER during the 52-week planned treatment period. For pre-BD FEV1, a mixed model with repeated measures (MMRM) was utilized. Tezepelumab drug exposure was simulated for a virtual Chinese adolescent population. Results: The popPK model effectively described the pharmacokinetic (PK) results in the DIRECTION study, revealing no PK differences between non-Chinese and Chinese populations. This indicates that tezepelumab exposure is unlikely to be affected by Chinese ethnicity. While the analysis identified body weight as a major covariate influencing tezepelumab clearance (CL), its effect was not clinically significant due to the overall variability in exposure. Although slightly higher tezepelumab exposure was predicted for Chinese adolescents compared to Chinese adults, these minor exposure variations were not considered clinically meaningful. Therefore, no dose adjustment of tezepelumab is anticipated for Chinese adolescents aged 12 to 17 years. In the exposure-response evaluation, the tezepelumab-to-placebo rate ratios (95% CI) of AAER over 52 weeks were 0.49 (0.25, 0.96), 0.19 (0.09, 0.42), 0.20 (0.10, 0.43), and 0.24 (0.12, 0.50) for the four Cthrough-based quartiles, respectively. The differences in least-squares (LS) means (95% CI) of pre-BD FEV1 between the tezepelumab group and the placebo group at Week 52 were 0.092 L (-0.038 L, 0.222 L), 0.336 L (0.208 L, 0.465 L), 0.215 L (0.087 L, 0.342 L), and 0.292 L (0.165 L, 0.420 L) for the four Cthrough-based quartiles, respectively. The reductions in AAER and LS means change in pre-BD FEV1 from baseline was larger in the tezepelumab groups than in the placebo group and consistent across the exposure quartiles for the subjects treated with tezepelumab 210 mg SC Q4W. Conclusions: No statistically significant PK differences were found between non-Chinese and Chinese populations, supporting that tezepelumab exposure is unlikely to be impacted by Chinese ethnicity. The slightly higher drug exposure found in Chinese adolescents was not clinically significant, so no dose adjustments are anticipated for Chinese asthma patients aged 12 to 17. The efficacy results showed consistent effect on reduction in AAER and pre-BD FEV1 across the exposure range at the dose of 210 mg SC Q4W. These PK and efficacy results support the established fixed dosing regimen for Chinese adults and adolescents with severe asthma.
Reference: PAGE 33 (2025) Abstr 11613 [www.page-meeting.org/?abstract=11613]
Poster: Drug/Disease Modelling - Other Topics