Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study.

Background: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin. The drug has been tested previously in the phase 3 NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) studies, and was subsequently approved as a treatment for severe asthma. This extension study recruited from NAVIGATOR and SOURCE and aimed to evaluate the long-term safety and efficacy of tezepelumab in individuals with severe, uncontrolled asthma.
Methods: DESTINATION was a phase 3, multicentre, randomised, double-blind, placebo-controlled, long-term extension study. The study was done across 182 sites (including hospitals, clinics, medical centres, clinical trial centres, and private practices) in 18 countries. Participants (aged 12-80 years) were required to have good treatment compliance in the parent study. Randomisation was stratified by the parent study and all participants were re-randomised. Those who were previously randomised to receive tezepelumab in either parent study continued treatment of subcutaneous tezepelumab (210 mg every 4 weeks); those who were previously randomised to receive placebo in either parent study were re-randomised 1:1 to receive either subcutaneous tezepelumab (210 mg every 4 weeks) or placebo (every 4 weeks) using a randomisation list prepared by a computerised system. Total treatment duration (including the parent studies) was 104 weeks for all groups. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoints were exposure-adjusted incidence of adverse events and serious adverse events and the secondary endpoint was the annualised asthma exacerbation rate; these were assessed from week 0 of the parent studies to week 104 of DESTINATION in all participants who were randomised and who received at least one dose of tezepelumab or placebo in either of the parent studies. The trial is registered with ClinicalTrials.gov, NCT03706079, and is closed to new participants.
Findings: Participants were recruited between Jan 7, 2019, and Oct 15, 2020. For individuals who initially received tezepelumab (n=528) in NAVIGATOR, incidence of adverse events over 104 weeks was 49·62 (95% CI 45·16 to 54·39) per 100 patient-years, compared with 62·66 (56·93 to 68·81) for those receiving placebo (n=531; difference -13·04, 95% CI -17·83 to -8·18). For serious adverse events, incidence was 7·85 (6·14 to 9·89) per 100 patient-years for individuals who initially received tezepelumab and 12·45 (9·97 to 15·35) for those who received placebo (difference -4·59, -7·69 to -1·65). In SOURCE, incidence of adverse events was 47·15 (36·06 to 60·56) per 100 patient-years for those who initially received tezepelumab (n=74) and 69·97 (54·54 to 88·40) for those who received placebo (n=76; difference -22·82, -34·77 to -10·01). For serious adverse events, incidence was 13·14 (7·65 to 21·04) per 100 patient-years for those who initially received tezepelumab and 17·99 (10·66 to 28·44) for those who received placebo (difference -4·85, -14·88 to 4·53). Tezepelumab reduced the annualised asthma exacerbation rate over 104 weeks compared with placebo. In participants initially from NAVIGATOR, the annualised asthma exacerbation rate ratio over 104 weeks was 0·42 (95% CI 0·35 to 0·51); in those initially from SOURCE, the ratio over 104 weeks was 0·61 (0·38 to 0·96).
Interpretation: Tezepelumab treatment was well tolerated for up to 2 years and resulted in sustained, clinically meaningful reductions in asthma exacerbations in individuals with severe, uncontrolled asthma. These findings are consistent with previous randomised, placebo-controlled studies and show the long-term safety and sustained efficacy of tezepelumab in individuals with severe, uncontrolled asthma.
Funding: AstraZeneca and Amgen.
Competing Interests: Declaration of interests AM-G has attended advisory board meetings for AstraZeneca, GlaxoSmithKline, Novartis, Regeneron, Sanofi, and Teva Pharmaceuticals; has received speaker fees from AstraZeneca, Novartis, Sanofi, and Teva Pharmaceuticals; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva Pharmaceuticals; and has consultancy agreements with AstraZeneca and Sanofi. MEW is an employee of National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, resTORbio, Sanofi, and Teva Pharmaceuticals. CEB has received consultancy fees and grants from 4D Pharma, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Mologic, Novartis, Regeneron, Roche, and Sanofi. SK has received fees for lectures or advisory board meetings from AstraZeneca, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis, and Teva Pharmaceuticals. JC has received grants and personal fees from AstraZeneca, Genentech, and Vectura and has received grants from Optinose, Sanofi, and Teva Pharmaceuticals. EI has served as a consultant to and received personal fees from 4D Pharma, AB Science, Amgen, AstraZeneca, Avillion, Biometry, Cowen, Equillium, Genentech, GlaxoSmithKline, Merck, Novartis, Pneuma Respiratory, PPS Healthcare, Regeneron Pharmaceuticals, Sanofi, Sienna Biopharmaceuticals, and Teva Pharmaceuticals; has received non-financial support from Circassia, Teva Pharmaceuticals, and Vorso Corp; and has received clinical research grants from AstraZeneca, Avillion, Genentech, Gossamer Bio, Novartis, and Sanofi. GCh has received speaker and consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals. AB, SP, GA, MG, KB, and GCo are employees of AstraZeneca and might own stock or stock options in AstraZeneca. SC is an employee of Amgen and owns stock in Amgen. LS is a consultant to AstraZeneca. KL is an employee of Cytel.
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