O-STA

Dosežen je bil primarni cilj klinične raziskave NAVIGATOR faze III s tezepelumabom - statistično značilno in klinično pomembno zmanjšanje pogostnosti poslabšanj v široki populaciji bolnikov s težko astmo

Primarni cilj klinične raziskave je bil dosežen tudi pri bolnikih z nizkim številom eozinofilcev.

Družbi AstraZeneca in Amgen sta danes objavili pozitivne rezultate klinične raziskave NAVIGATOR faze III s potencialnim novim zdravilom tezepelumabom pri bolnikih s težko, neurejeno astmo.

Dosežen je bil primarni cilj klinične raziskave NAVIGATOR, saj je zdravljenje s tezepelumabom, dodano k standardnemu zdravljenju, v primerjavi s placebom ob standardnem zdravljenju statistično značilno in klinično pomembno1 zmanjšalo letno pogostnost poslabšanj astme v 52 tednih v celotni populaciji bolnikov. Standardno zdravljenje so predstavljali srednji ali veliki odmerki inhalacijskih kortikosteroidov in vsaj eno dodatno zdravilo za preprečevanje poslabšanj s peroralnimi glukokortikosteroidi ali brez njih.

Primarni cilj raziskave, statistično značilno in klinično pomembno zmanjšanje letne pogostnosti poslabšanj astme, je bil dosežen tudi v podskupini bolnikov z izhodiščnim številom eozinofilcev manj kot 300 celic na mikroliter. Primerljivo zmanjšanje letne pogostnosti poslabšanj astme so opazili tudi v podskupini bolnikov z izhodiščnim številom eozinofilcev manj kot 150 celic na mikroliter.

Tezepelumab so bolniki s težko astmo zelo dobro prenašali. Preliminarne analize ne kažejo klinično pomembnih razlik v rezultatih o varnosti med skupino s tezepelumabom in skupino s placebom. Rezultati klinične raziskave NAVIGATOR bodo predstavljeni na prihajajočem strokovnem kongresu.

Težka astma je izčrpavajoča bolezen, zaradi katere je po svetu prizadetih približno 34 milijonov ljudi.2.3 Mnogi bolniki s težko astmo še naprej doživljajo simptome in pogosta poslabšanja kljub uporabi velikih odmerkov zdravil za preprečevanje poslabšanj, trenutno razpoložljivih bioloških zdravil in peroralnih glukokortikosteroidov.3-5

Profesor Andrew Menzies-Gow, direktor Oddelka za pljučne bolezni bolnišnice Royal Brompton Hospital, London, Združeno kraljestvo, in glavni raziskovalec klinične raziskave NAVIGATOR faze III, je dejal: "Zaradi zapletene narave težke astme se številni bolniki še naprej soočajo z izčrpavajočimi simptomi kljub temu, da prejemajo standardna inhalacijska zdravila in trenutno odobrena biološka zdravila. Današnji revolucionarni rezultati kažejo, da lahko tezepelumab spremeni zdravljenje za široko populacijo bolnikov s težko astmo, ki danes niso zadostno zdravljeni, vključno s tistimi, ki nimajo eozinofilnega fenotipa."

Mene Pangalos, izvršni podpredsednik oddelka raziskav in razvoja bioloških zdravil, je dejal: "Tezepelumab deluje drugače kot katerokoli drugo biološko zdravilo za astmo in cilja na več vnetnih poti, ki prispevajo k simptomom in poslabšanju astme. Na podlagi široke učinkovitosti tezepelumaba, ki smo jo videli že prej, so to vznemirljivi podatki, ki nas vodijo še korak bližje k temu, da bi zdravilo lahko ponudili bolnikom s težko astmo, tudi tistim z majhnim številom eozinofilcev."

Tezepelumab je potencialno prvo zdravilo v razredu, ki blokira delovanje timusnega stromalnega limfopoetina (TSLP), epitelijskega citokina, ki ima ključno vlogo za razvoj vnetja pri astmi.6,7 NAVIGATOR je prva klinična raziskava faze III, ki je pokazala korist ciljanja TSLP pri težki astmi.

Statistično značilno in klinično pomembno zmanjšanje pogostnosti poslabšanj, doseženo s tezepelumabom pri bolnikih z izhodiščnim številom eozinofilcev manj kot 300 celic na mikroliter, podpira oznako prebojnega zdravljenja Ameriške agencije za hrano in zdravila, ki je bila tezepelumabu dodeljena septembra 2018 za zdravljenje bolnikov s težko astmo brez eozinofilnega fenotipa. Zdravilo tezepelumab razvija družba AstraZeneca v sodelovanju s družbo Amgen (glejte spodaj "Sodelovanje med družbama AstraZeneca in Amgen").

OPOMBE ZA UREDNIKE

Severe asthma

Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.2,3 Approximately 10% of asthma patients have severe asthma.3,4 Despite the use of inhaled asthma controller medicine, currently available biologic therapies and OCS, many severe asthma patients remain uncontrolled.3-5 Due to the complexity of severe asthma, many patients have unclear or multiple drivers of inflammation and may not qualify for or respond well to a current biologic medicine.4,8,9

Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.3,5,10 Patients with severe asthma are at an increased risk of mortality and account for twice as many asthma-related hospitalisations.11-13 There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.14

NAVIGATOR and the PATHFINDER clinical trial programme

Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR and SOURCE.15,16 The programme includes additional planned mechanistic and long-term safety trials.

NAVIGATOR is a Phase III, randomised, double-blinded, placebo-controlled trial in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose ICS plus at least one additional controller medication with or without OCS. The trial population included approximately equal proportions of patients with high (≥ 300 cells/µL) and low (< 300 cells/µL) blood eosinophil counts. The trial comprised a five to six week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients received their prescribed controller medications without change throughout the trial.15,17

The primary efficacy endpoint was the annualised asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints included the effect of tezepelumab on lung function, asthma control and health-related quality of life.15,17

SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebo-controlled trial for 48 weeks in adult patients with severe asthma who require continuous treatment with ICS plus long-acting beta2-agonists (LABA), and chronic treatment with maintenance OCS therapy. The primary endpoint is the categorised percentage reduction from baseline in the daily OCS dose, while not losing asthma control.16,18

Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in DESTINATION, a Phase III extension trial assessing long term safety and efficacy.19

Tezepelumab

Tezepelumab is a potential first-in-class human monoclonal antibody that inhibits the action of TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is critical in the initiation and persistence of allergic, eosinophilic and other types of airway inflammation associated with severe asthma.6,7 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.6,7 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.7,20 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.7,20 Tezepelumab acts at the top of the inflammation cascade and has the potential to treat a broad population of severe asthma patients regardless of their type of inflammation.7,20

AstraZeneca and Amgen collaboration

Earlier in 2020, Amgen and AstraZeneca updated the 2012 collaboration agreement for tezepelumab. Both companies will continue to share costs and profits equally after payment by AstraZeneca of a mid single-digit royalty to Amgen. AstraZeneca continues to lead development and Amgen continues to lead manufacturing. All aspects of the collaboration are under the oversight of joint governing bodies. Under the amended agreement in North America, Amgen and AstraZeneca will jointly commercialise tezepelumab; Amgen will record sales in the US and AstraZeneca will record sales in Canada. AstraZeneca's share of gross profits from tezepelumab in the US will be recognised as collaboration revenue. In all countries outside the US and Canada, AstraZeneca will solely commercialise tezepelumab. AstraZeneca will record all sales outside of the US as product sales and recognise Amgen's share of gross profit as cost of sales.

AstraZeneca in Respiratory & Immunology

Respiratory & Immunology is one of AstraZeneca's three therapy areas and is a key growth driver for the Company.

AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 53 million patients in 2019. Building on a 50-year heritage, the Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Company's early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.

With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company's growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including Systemic Lupus Erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca's ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

  1. Bonini M, Di Paolo M, Bagnasco D, et al. Minimal clinically important difference for asthma endpoints: an expert consensus report. Eur Respir Rev. 2020; 29: 190137.

  2. The Global Asthma Network. The Global Asthma Report 2018. [Online]. Available at: http://www.globalasthmareport.org/Global%20Asthma%20Report%202018.pdf. [Last accessed: November 2020].

  3. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43: 343-73.

  4. Wenzel S. Severe Asthma in Adults. Am J Respir Crit Care Med. 2005; 172; 149-60.

  5. Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006; 100 (7): 1139-51.

  6. Varricchi G, Pecoraro A, Marone G, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018; 9: 1595.

  7. Corren J, Parnes JR, Wang L, et al. Tezepelumab in Adults with Uncontrolled Asthma [published correction appears in N Engl J Med. 2019 May 23;380(21):2082]. N Engl J Med. 2017; 377 (10): 936-946.

  8. Hyland ME, Masoli M, Lanario JW, et al. A Possible Explanation for Non-responders, Responders and Super-responders to Biologics in Severe Asthma. Explor Res Hypothesis Med. 2019; 4:35-38.

  9. Tran TN, Zeiger RS, Peters SP, et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann Allergy Asthma Immunol. 2016; 116:37-42.

  10. Fernandes AG, Souza-Machado C, Coelho RC, et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014; 40 (4): 364-372.

  11. Chastek B, et al. Economic Burden of Illness Among Patients with Severe Asthma in a Managed Care Setting. J Manag Care Spec Pharm. 2016; 22: 848-861.

  12. Hartert TV, Speroff T, Togias A, et al. Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma. Ann Allergy Asthma Immunol. 2002; 89: 467-73.

  13. Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014; 12; 24: 14009.

  14. World Allergy Organization (WAO). The management of severe asthma: economic analysis of the cost of treatments for severe asthma. Available from: https://www.worldallergy.org/educational_programs/world_allergy_forum/anaheim2005/blaiss.php [Last accessed: November 2020].

  15. Clinicaltrials.gov. Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma (NAVIGATOR) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03347279. [Last accessed: November 2020].

  16. Clinicaltrials.gov. Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma (SOURCE) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03406078. [Last accessed: November 2020].

  17. Menzies-Gow A, Colice G, Griffiths JM et al. NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020; 21(1): 266.

  18. Weschler ME, Colice G, Griffiths JM et al. SOURCE: A Phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of Tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respir Res. 2020; 21(1), 264.

  19. Clinicaltrials.gov. Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma (DESTINATION) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03706079. [Last accessed: November 2020].

  20. Li Y, Wang W, LV Z et al. Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease. The Journal of Immunology. 2018; 200: 2253-2262.

Adrian Kemp

Company Secretary

AstraZeneca PLC