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

Menzies‐Gow, Andrew; Wechsler, Michael E.; Brightling, Christopher; Bednarczyk, Artur; Ponnarambil, Sandhia; Caveney, Scott; Almqvist, Gun; Gołąbek, Monika; Simonsson, Linda; Lawson, Kaitlyn; Bowen, Karin; Colice, Gene; Hetzel, Jorge Lima; Fiterman, Jussara; Machado, Adelmir Souza; Antila, Martti; Lima, Marina Andrade; Tanni, Suzana Erico; Blanco, Daniela Cavalet; Bezerra, Patrícia Gomes de Matos; Houle, Pierre-Alain; Lemière, Catherine; Melenka, Lyle; Leigh, Richard; Mitchell, Patrick; Anees, Syed; Pek, Bonavuth; Chouinard, Guy; Cheema, Amarjit; Yang, William H.; Philteos, George; Chanez, Pascal; Bourdin, Arnaud; Devouassoux, Gilles; Taillé, Camille; Blay, F. De; Leroyer, Christophe; Beurnier, Antoine; Garcia, Gilles; Girodet, Pierre‐Olivier; Blanc, F.–X.; Magnan, A.; Wanin, Stéphanie; Just, Jocelyne; Linde, R.; Zielen, Stefan; Förster, Karin; Geßner, Christian; Jandl, Margret; Buhl, Roland; Korn, Stephanie; Kornmann, Marc Oliver; Linnhoff, Anneliese; Ludwig-Sengpiel, Andrea; Ehlers, Martin; Schmoller, Tibor; Steffen, Heiner; Hoffmann, Martin; Kirschner, J; Schmidt, Olaf; Welte, Tobias; Temme, Hilke; Wand, Ori; Bar-Shai, Amir; Izbicki, Gabriel; Berkman, Neville; Fink, Gershon; Shitrit, David; Adir, Yochai; Kuna, Piotr; Rewerska, Barbara; Pisarczyk-Bogacka, Ewa; Курбачева, О М; Mikhailov, Sergey L; Vasilev, M.P.; Emelyanov, Alexander; Wali, Siraj; Albanna, Amr S.; Zyl-Smit, Richard van; Abdullah, Ismail; Bernhardi, David; Hoosen, Farzana; Irusen, Elvis; Kalla, Ismail; Lakha, Deepak; Mitha, Essack; Naidoo, Visvakuren; Nell, Haylene; Padayachee, Trevenesan; Reddy, J. Vasudeva; Petrick, Friedrich; Walt, Eugene van der; Vawda, Zubar Fazal Ahmed; Park, Hae‐Sim; Lee, Sang Haak; Kim, Mi-Kyeong; Park, Jung Won; Cho, You Sook; Lee, Byung‐Jae; Chang, Yoon Seok; Park, Choon-Sik; Lee, Kwan Ho; Lee, Sook Young; Yoon, Hyoung‐Kyu; Sohn, Kyoung Hee; Park, Myung Jae; Min, Kyung Hoon; Cho, Young Joo; Park, Han Ki; Lee, YongChul; Lee, Jaechun; Sheu, Chau‐Chyun; Tu, Chih‐Yen; Lee, Kang‐Yun; Bavbek, Sevim; Gemicioğlu, Bilun; Ediger, Dane; Kalkan, İlkay Koca; Makieieva, Nataliia; Ostrovskyy, Мykola; Dytyatkovs'ka, Yevgeniya; Mostovoy, Yuriy Mykhaylovych; Lebed, Kyrylo; Yakovenko, Oleh; Adams, Atoya; Mooring, Timothy; Torres, Louis; Sexton, Marvin; Thompson, Evan; Bernstein, Jonathan A.; Lisi, Paul; Chappel, Christopher M; Cole, Jeremy; Greenwald, Gary I; Jones, Conigliaro; Klein, Ryan M.; Pham, David; Spangenthal, Selwyn; Weinstein, Steven F.; Windom, Hugh; Kao, Neil L.; Leong, Mila A.; Mehta, Vinay; Moore, Wendy C.; Bhat, Saligrama; Aish, Bassil; Meltzer, Steven M; Corren, Jonathan; Moss, Mark H.; Kerwin, Edward; Delgado, John Palsted; Lucksinger, Gregg Hudson; Thompson, Charles A.; Chupp, Geoffrey; Alpizar, Sady; Vadgama, Sanjay Virgi; Zafar, Zahid; Jacobs, Joshua; Lugogo, Njira L; Jain, Neal; Sher, Lawrence; Andrawis, Nabil S.; Fuentes, David; Boren, Eric Jason; Gonzalez, Erika G; Talreja, Neetu; Durrani, Sheharyar Sandy; Israel, Elliot; Sekhsaria, Sudhir; DeLeon, Samuel; Shukla, Mayank; Tarpay, Martha M Totszollosy; Fakih, Faisal; Hudes, Golda; Tillinghast, Jeffrey P; Korenblat, Phillip E.; Shenoy, Kartik; Que, Loretta G.; Kureishy, Shahrukh; Umeh, Fred Chukwuemeka; Nguyen, Vinh Nhu; Chu, Hanh Thi; Nguyen, Thuy Thi Dieu

doi:10.1016/s2213-2600(22)00492-1

Cited by 70 publications

(34 citation statements)

References 22 publications

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“…Serum concentrations of tezepelumab were quantifiable in all treated patients at week 12 and approached a PK steady state by week 12, consistent with observations in previous studies [ 14 ]. Tezepelumab was well tolerated by patients in this study, with no new or unexpected safety findings; this is also consistent with previous studies assessing the safety of tezepelumab [ 10 , 11 , 36 , 37 ].…”

Section: Discussionsupporting

confidence: 91%

Effect of Tezepelumab on the Humoral Immune Response to Seasonal Quadrivalent Influenza Vaccination in Patients with Moderate to Severe Asthma: The Phase 3b VECTOR Study

Cole,

Cąpała-Szczurko,

Roseti

et al. 2023

Pulm Ther

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Introduction Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma. Methods VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12–17 years) and young adults (aged 18–21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed. Results Seventy patients were randomized to tezepelumab ( n = 35) or placebo ( n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76–7.34 for tezepelumab and 1.46–4.75 for placebo. MN assay GMFRs were 4.00–14.56 for tezepelumab and 3.56–10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2–78.8% and 15.2–51.5% of tezepelumab and placebo recipients, respectively, and 97.0–100% of patients in both treatment groups achieved an antibody titer of at least 40 at week 16. No unexpected safety findings occurred. Conclusion There was no observed suppression of the humoral immune response after influenza vaccination in adolescents and young adults with moderate to severe asthma treated with tezepelumab. Therefore, the influenza vaccine can be administered to this patient population during tezepelumab treatment. ClinicalTrials.gov identifier NCT05062759 Supplementary Information The online version contains supplementary material available at 10.1007/s41030-023-00245-9.

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Section: Discussionsupporting

confidence: 91%

Effect of Tezepelumab on the Humoral Immune Response to Seasonal Quadrivalent Influenza Vaccination in Patients with Moderate to Severe Asthma: The Phase 3b VECTOR Study

Cole,

Cąpała-Szczurko,

Roseti

et al. 2023

Pulm Ther

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“…As with other biologics, it is crucial to assess safety in the long term, which was the aim of the Destination extension study. 66 In this RCT, after 104 weeks of treatment with TZP, the same results were reported as in the NAVIGATOR and SOURCE studies with regard to safety (low incidence of side effects) and efficacy (sustained reduction in the rate of exacerbations). These data were independent of the baseline eosinophil count, FeNO level, and atopy status, although patients with high levels of T2 biomarkers or chronic rhinosinusitis with nasal polyposis (CRSwNP) exhibited better results in terms of reduced exacerbations.…”

Section: Innovative Evidence From Clinical Trials Of Tzpsupporting

confidence: 63%

Tezepelumab: patient selection and place in therapy in severe asthma

Menzella,

Munari,

Corsi

et al. 2024

J Int Med Res

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Asthma is a disease characterised by heterogeneous and multifaceted airway inflammation. Despite the availability of effective treatments, a substantial percentage of patients with the type 2 (T2)-high, but mainly the T2-low, phenotype complain of persistent symptoms, airflow limitation, and poor response to treatments. Currently available biologicals target T2 cytokines, but no monoclonal antibodies or other specific therapeutic options are available for non-T2 asthma. However, targeted therapy against alarmins is radically changing this perspective. The development of alarmin-targeted therapies, of which tezepelumab (TZP) is the first example, may offer broad action on inflammatory pathways as well as an enhanced therapeutic effect on epithelial dysfunction. In this regard, TZP demonstrated positive results not only in patients with severe T2 asthma but also those with non-allergic, non-eosinophilic disease. Therefore, it is necessary to identify clinical features of patients who can benefit from an upstream targeted therapy such as anti-thymic stromal lymphopoietin. The aims of this narrative review are to understand the role of alarmins in asthma pathogenesis and epithelial dysfunction, examine the rationale underlying the indication of TZP treatment in severe asthma, summarise the results of clinical studies, and recognise the specific characteristics of patients potentially eligible for TZP treatment.

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“…Further studies to reassess tezepelumab efficacy on this outcome are currently ongoing. DESTINATION, the long-term safety and tolerability phase 3 study, with a unique placebo-controlled design, showed the positive benefit-risk profile of tezepelumab over 104 weeks with less adverse event in the treatment arm than in the placebo one ( 49 ).…”

Section: Anti-alarmins Biologicals Drugs Currently Available: Alarmin...mentioning

confidence: 99%

The last step to achieve barrier damage control

Baglivo,

Colantuono,

Lumaca

et al. 2024

Front. Immunol.

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Heterogeneity characterises inflammatory diseases and different phenotypes and endotypes have been identified. Both innate and adaptive immunity contribute to the immunopathological mechanism of these diseases and barrier damage plays a prominent role triggering type 2 inflammation through the alarmins system, such as anti-Thymic Stromal Lymphopoietin (TSLP). Treatment with anti-TSLP monoclonal antibodies showed efficacy in severe asthma and clinical trials for other eosinophilic diseases are ongoing. The aim of this perspective review is to analyse current advances and future applications of TSLP inhibition to control barrier damage.

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

Cited by 70 publications

References 22 publications

Effect of Tezepelumab on the Humoral Immune Response to Seasonal Quadrivalent Influenza Vaccination in Patients with Moderate to Severe Asthma: The Phase 3b VECTOR Study

Effect of Tezepelumab on the Humoral Immune Response to Seasonal Quadrivalent Influenza Vaccination in Patients with Moderate to Severe Asthma: The Phase 3b VECTOR Study

Tezepelumab: patient selection and place in therapy in severe asthma

The last step to achieve barrier damage control

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