Biomarkers and clinical outcomes after tezepelumab cessation: Extended follow-up from the 2-year DESTINATION study.

BACKGROUND: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. OBJECTIVE: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. METHODS: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. RESULTS: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. CONCLUSION: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03706079.

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.

Properties of Langmuir and solid supported lipid films with sphingomyelin.

Biological cell membranes play a crucial role in various biological processes and their functionality to some extent is determined by the hydrophilic/hydrophobic balance. A significant progress in understanding the membrane structure was the discovery of laterally segregated lipid domains, called the lipid rafts. These raft domains are of ordered lamellar liquid-crystalline phase, while rest of the membrane exists in a relatively disordered lamellar liquid-crystalline phase. Moreover, the chemical constitution of the lipid rafts consists of a higher content (up to 50%) of cholesterol (Chol) and sphingomyelin (SM). Sphingomyelin also plays a significant role in the red cells of blood and nerves, in some diseases, as a precursor to ceramides, and other sphingolipid metabolites. In this paper properties of Langmuir and solid supported mixed lipid films of DPPC/SM, DOPC/SM, and Chol/SM are described. Special attention has been paid to wetting properties (hydrophobic/hydrophilic balance) of these films transferred onto a hydrophilic glass surface. To our knowledge such results have not yet been published in the literature. The properties were determined via contact angle measurements and then calculation of the films' apparent surface free energy. The films' wettability and their apparent surface free energy strongly depend on their composition. The energy is affected by both the structure of hydrocarbon chains of glycerophospholipids (DPPC and DOPC) and their interactions with SM. Properties of mixed Chol/SM monolayer depend also on the film stoichiometry. At a low Chol content (XChol=0.25) the interactions between SM and Chol are strong and hence the formation of binary complex is possible. This is accompanied by a decrease in the film surface free energy in comparison to that of pure SM monolayer, contrary to a higher Chol content where the monolayer energy increases. This suggests that cholesterol is excluded from the membrane thus increasing the film hydrophilicity. These results are consistent with the literature data and somehow confirm the hypothesis of lipid raft formation. The roughness of the investigated monolayer surfaces was also determined using optical profilometry. The roughness parameters of the DPPC, SM, and mixed DPPC/SM generally correlate with the changes of their apparent surface free energy, i.e. with the decreasing roughness the apparent surface free energy also decreases. However, this is not the case for mixed DOPC/SM monolayers. Although the roughness increases with SM content the apparent surface free energy decreases. Therefore some other factors, like the presence of unsaturated bonds in the DOPC molecule, influence the film phase state and the energy too. More experiments are needed to explain this hypothesis.