New Tezspire data at ERS International Congress 2022 continue to strengthen profile for a broad population of severe asthma patients

DESTINATION Phase III extension trial demonstrates sustained long-term safety and efficacy of Tezspire compared to placebo

CASCADE Phase II trial shows Tezspire as first biologic to reduce mucus plugging compared to placebo

NAVIGATOR analysis demonstrates more patients achieved clinical remission with Tezspire compared to placebo

Results from the DESTINATION Phase III extension trial showed Tezspire (tezepelumab) demonstrated an overall long-term safety and efficacy profile consistent with the previous PATHWAY Phase II and NAVIGATOR Phase III trials, sustained over 104 weeks in a broad population of patients with severe asthma.¹ AstraZeneca’s and Amgen’s Tezspire is the first and only biologic for severe asthma with two-year placebo-controlled safety and efficacy data.

In the safety analysis, which included patients from the NAVIGATOR and SOURCE trials, the incidence rates (per 100 patient years) for adverse events (AEs) in patients who initially received Tezspire or placebo in NAVIGATOR, were 49.62 and 62.66 and for serious AEs (SAEs) were 7.85 and 12.45, respectively. In those who initially received Tezspire or placebo in SOURCE, incidence rates for AEs were 47.15 and 69.97 and for SAEs were 13.14 and 17.99, respectively.¹

In the efficacy analysis in NAVIGATOR patients, Tezspire demonstrated sustained reductions in the annualised asthma exacerbation rate (AAER) over 104 weeks of 58% in the overall population and irrespective of baseline levels of inflammatory biomarkers, compared to placebo.¹

Results from the CASCADE Phase II mechanistic trial showed that Tezspire reduced mucus plugging, compared to placebo, in a broad population of moderate to severe asthma patients. The reduction seen in mucus scores with Tezspire correlated with improvements in lung function.² Mucus plugging as a clinical feature may predict the risk of future exacerbations and lung function decline in severe asthma.³

Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, and principal investigator of the NAVIGATOR Phase III trial, said: “Managing severe asthma is challenging, with multiple inflammatory pathways often contributing to the complexity of a patient's disease. These results from the DESTINATION and CASCADE trials provide unprecedented data that should support physicians’ and patients’ confidence in Tezspire’s ability to improve outcomes for a broad population of patients with severe asthma.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The results from DESTINATION confirm that the overall long-term efficacy and safety profile for Tezspire is consistent with the previously reported PATHWAY and NAVIGATOR trials and sustained over two years. The CASCADE data further differentiate and strengthen the clinical profile of Tezspire and its potential to transform treatment for a broad population of severe asthma patients.”

Further results from the Tezspire PATHFINDER clinical trial programme being presented at ERS include results from an exploratory analysis of the pivotal NAVIGATOR Phase III trial. The analysis showed that the odds of a severe asthma patient achieving clinical remission were more than threefold higher with Tezspire at week 52, compared to placebo treatment.⁴ On-treatment clinical remission was predefined using composite component measures that included no exacerbations, no maintenance oral corticosteroid use, asthma symptom control, healthcare professional assessment of change, and patient assessment of severity.⁵

There were no clinically meaningful differences in safety results between the Tezspire and placebo groups in the NAVIGATOR and CASCADE trials. The most frequently reported adverse events for Tezspire in the NAVIGATOR trial were nasopharyngitis, upper respiratory tract infection, headache and asthma,⁶ and in the CASCADE trial were nasopharyngitis, post-procedural (bronchoscopy) complications and headache.⁷

Results from the DESTINATION, CASCADE and NAVIGATOR trials were presented at the European Respiratory Society (ERS) International Congress 2022 (#OA9002. Monday 5 September, 09:45-11:00 CEST, session 257), (#RCT4445. Tuesday 6 September, 16:00-17:00 CEST, session 499), (#OA3676. Tuesday 6 September, 09:45-11:00 CEST, session 414).

Tezspire is approved in the US and other countries for the treatment of severe asthma⁸ and is under regulatory review in Japan and many other countries around the world. In July 2022, Tezspire was recommended for approval in the EU by The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency.⁹ If approved, Tezspire would be the first and only biologic in the EU for patients with severe asthma with no phenotype or biomarker limitations.

Notes

Severe asthma
Asthma is a heterogeneous disease affecting approximately 14 million people living with the disease in the European Union and an estimated 339 million people worldwide.^10,11 Up to 10% of asthma patients have severe asthma.^12,13 Despite the use of inhaled asthma controller medicine, currently available biologic therapies and oral corticosteroids (OCS), many severe asthma patients remain uncontrolled.^12-14 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.^13-16

Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.^12,13,17 Patients with severe asthma are at an increased risk of mortality and compared to patients with persistent asthma have twice the risk of asthma-related hospitalisations.^18-20 There is also a significant socio-economic burden, with these patients accounting for approximately 50% of asthma-related costs.²¹

Clinical trials
In addition to the Phase IIb PATHWAY trial, the PATHFINDER programme included two Phase III trials, NAVIGATOR^6,22 and SOURCE.^23,24 The programme also includes additional mechanistic and long-term safety trials.^7,25

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 standard of care (SoC). SoC was treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without daily OCS treatment. The trial population included approximately equal proportions of patients with high (≥300 cells per microlitre) and low (<300 cells per microlitre) 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.⁶

The primary efficacy endpoint was the annualised asthma exacerbation rate (AAER) during the 52-week treatment period. Key secondary endpoints included the effect of Tezspire on lung function, asthma control and health-related quality of life.⁶

As part of prespecified analyses, the AAER over 52 weeks was also assessed in patients grouped by baseline blood eosinophil count, FeNO level and serum specific immunoglobin E (IgE) status (perennial aeroallergen sensitivity positive or negative).⁶ These are inflammatory biomarkers used by clinicians to inform treatment options and involve tests analysing a patient’s blood (eosinophils/IgE) and exhaled air (FeNO).

Results from NAVIGATOR exploratory analysis: Proportion of patients who achieved on-treatment clinical remission at week 52⁴

CI: confidence interval; OR: odds ratio; Q4W: every 4 weeks

There were no clinically meaningful differences in safety results between the Tezspire and placebo groups in the NAVIGATOR trial.⁶ The most frequently reported adverse events for Tezspire were nasopharyngitis, upper respiratory tract infection and headache.⁶

DESTINATION is a randomised, double-blind, placebo-controlled, long-term extension trial in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids.²⁵ The study population comprise patients who completed the 52- and 48-week NAVIGATOR and SOURCE studies, respectively.²⁵ The primary objective is to evaluate the long-term safety and tolerability of Tezspire over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of Tezspire on asthma exacerbations.²⁵

AE: Adverse Event; Randomised Placebo: All Patients Randomized to Placebo in Predecessor Study, Excluding Patients Re-randomized to Tezspire During LTE; Randomised Tezspire: All Patients Randomized to Tezspire in Predecessor Study SAE: Serious Adverse Event

CASCADE was a Phase II, exploratory, mechanistic, double-blind, randomised, placebo-controlled, parallel-group, multicentre trial. Adults aged 18–75 years with uncontrolled, moderate-to-severe asthma were randomly assigned (1:1) to receive tezepelumab 210 mg or placebo administered subcutaneously every 4 weeks for a planned 28 weeks, extended to up to 52 weeks if COVID-19-related disruption delayed participants’ end-of-treatment assessments.⁷

The primary endpoint was the change from baseline to the end of treatment in the number of airway submucosal inflammatory cells in bronchoscopic biopsy samples. Eosinophils, neutrophils, CD3+ T cells, CD4+ T cells, tryptase+ mast cells, and chymase+ mast cells were evaluated separately.⁷ In a separate analysis, mucus plugging was scored at baseline and end of treatment (at least 28 weeks) in 18 lung segments using standardized computed tomography imaging. Correlation of mucus score against inflammatory markers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5 and IL-13) and lung function (FEV1 and FEF 25-75%) was also assessed.²

Tezspire
Tezspire (Tezspire) is being developed by AstraZeneca in collaboration with Amgen as a 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, including airway hyperresponsiveness.^26,27 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.^26,27 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.^26,28 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.^6,26,28 Tezspire acts at the top of the inflammation cascade and has the potential to help address a broad population of severe asthma patients irrespective of biomarker levels.^6,26

Tezspire is approved in the US for the add-on maintenance treatment of adult and paediatric patients aged 12 years and older with severe asthma.⁸ Tezspire is also in development for other potential indications including chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria and eosinophilic esophagitis (EoE). In October 2021, Tezspire was granted Orphan Drug Designation by the FDA for the treatment of EoE.

Amgen collaboration
In 2020, Amgen and AstraZeneca updated a 2012 collaboration agreement for Tezspire. Both companies will continue to share costs and profits equally after payment by AstraZeneca of a mid single-digit inventor 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, Amgen and AstraZeneca will jointly commercialise Tezspire in North America. Amgen will record product sales in the US, with AZ recording its share of US profits as Collaboration Revenue. Outside of the US, AstraZeneca will record product sales, with Amgen recording profit share as Other/Collaboration revenue.

AstraZeneca in Respiratory & Immunology
Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca’s main disease areas and a key growth driver for the Company.

AstraZeneca is an established leader in respiratory care with a 50-year heritage and a growing portfolio of medicines in immune-mediated diseases. We are committed to addressing the vast unmet needs of these chronic, often debilitating, diseases with a portfolio of inhaled and biologic medicines. Our pipeline for the future aims to address the vast unmet medical needs of patients by targeting the underlying biology of disease, advancing new drug modalities and combinations, driving earlier diagnosis and applying a precision medicine approach to our early research.

Our ambition is to transform care in respiratory & immune-mediated diseases by moving beyond symptom control to achieve disease modification, remission and, one day, cures for the 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 in Oncology, Rare Diseases, and BioPharmaceuticals, including 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

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2. Brightling C, et al. Tezepelumab reduces mucus plugging in patients with uncontrolled, moderate-to-severe asthma: the phase 2 CASCADE study. ERS Oral presentation: RCT4445. Presentation at the European Respiratory Society (ERS) International Congress 2022, 6 September 2022; 16:00-17:30 CEST.

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23. Wechsler ME, et al. Evaluation of the oral corticosteroid-sparing effect of Tezspire in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. Lancet Respir Med. 2022;S2213–S2600(21):00537-3.

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^{Veeva ID: Z4-46697
Date of preparation: August 2022}