Pulmicort Turbuhaler (budesonide dry-powder inhaler) / AstraZeneca, Cheplapharm - LARVOL DELTA

START CARE: STep-wise Anti-inflammatory Reliever Therapy Children’s Asthma REsearchn: A Randomised Controlled Trial of the efficacy and safety of an Inhaled Corticosteroid and Long Acting Beta Agonist maintenance and/or reliever therapy versus standard maintenance with separate reliever therapy in children with mild, moderate and severe asthma. (ANZCTR) - P3 | N=400 | Active, not recruiting | Sponsor: Medical Research Institute of New Zealand | Recruiting ➔ Active, not recruiting

Enrollment closed • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Inhaled Budesonide for REcurrence Prevention and Adjuvant THerapy in Checkpoint Inhibitor Pneumonitis (clinicaltrials.gov) - P2 | N=94 | Not yet recruiting | Sponsor: AHS Cancer Control Alberta | Trial completion date: Sep 2030 ➔ Dec 2030 | Initiation date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2029 ➔ Dec 2029

Checkpoint inhibition • Trial completion date • Trial initiation date • Trial primary completion date • Inflammation • Oncology • Pneumonia • Respiratory Diseases

Inhaled Budesonide for REcurrence Prevention and Adjuvant THerapy in Checkpoint Inhibitor Pneumonitis (clinicaltrials.gov) - P2 | N=94 | Not yet recruiting | Sponsor: AHS Cancer Control Alberta

Checkpoint inhibition • New P2 trial • Inflammation • Oncology • Pneumonia • Respiratory Diseases

A Randomised Controlled Trial of the efficacy and safety of an Inhaled Corticosteroid and Long Acting Beta Agonist maintenance and/or reliever therapy versus standard maintenance with separate reliever therapy in children with mild, moderate and severe asthma. (ANZCTR) - P3 | N=400 | Recruiting | Sponsor: Medical Research Institute of New Zealand | Initiation date: Dec 2000 ➔ Dec 2022

Trial initiation date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

As-needed Budesonide/Formoterol Turbuhaler in Stepping Down Period (clinicaltrials.gov) - P3 | N=31 | Completed | Sponsor: Hat Yai Medical Education Center | Recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ May 2022

Trial completion • Trial completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

"Hmm. Vox mentions the major 2 components of the outpatient regimen I generally prescribe. Luvox + Pulmicort flexhaler. https://t.co/DnVOx4UqYS" (@EdoajoEric)

Clinical

"STOIC trial used @AstraZeneca #budesonide dry powder inhaler (brand: Pulmicort Turbuhaler) at dose 400 µg per actuation (two puffs to be taken twice per day; total dose 1600 µg). https://t.co/TDMSEwYQln" (@ChrisGStreet)

"C and D. Pulmicort Flexhaler 180mcg/actuation, 2 puffs q6h until feeling improved, plus fluvoxamine 50mg start 1 po bid and uptitrate to 2 po bid. Fluvox often requires prior auth and is therefore delayed." (@EdoajoEric)

As-needed Budesonide/Formoterol Turbuhaler in Stepping Down Period (clinicaltrials.gov) - P3; N=40; Recruiting; Sponsor: Hat Yai Medical Education Center; N=100 ➔ 40

Clinical • Enrollment change • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Inhaled Corticosteroid Treatment of COVID19 Patients With Pneumonia (clinicaltrials.gov) - P4; N=120; Completed; Sponsor: Sara Varea; Recruiting ➔ Completed; N=300 ➔ 120

Enrollment change • Trial completion • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers. (PubMed, Pharm Res) - "Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods."

Journal

H1 2021 results : Accelerating top-line growth with continued pipeline progress underpins the transition to long-term sustainable growth (AstraZeneca Press Release) - "Symbicort - mild asthma: application for registration has been voluntarily withdrawn (EU)....H2 2021: PT027 - asthma: overall results....Symbicort: Total Revenue, entirely comprising Product Sales, amounted to $1,371m in the half and represented a decrease of 5% (9% at CER)....Pulmicort: Total Revenue, entirely comprising Product Sales, amounted to $497m in the half and represented an increase of 4% (decline of 2% at CER)....Fasenra: Total Revenue, entirely comprising Product Sales, increased by 36% (32% at CER) in the half to $580m....Breztri: Total Revenue, entirely comprising Product Sales, amounted to $82m in the half (H1 2020: $11m)."

European regulatory • Sales • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases

AstraZeneca's Pulmicort, Bayer's Xarelto among big losers in China's largest round of price cuts on generics (Fierce Pharma) - "AstraZeneca can kiss its Pulmicort blockbuster sales rebound goodbye. The aging asthma inhaler was among originator drugs that lost valuable government contracts to cheap generics during China’s latest price-cutting scheme for off-patent drugs, known as the volume-based procurement (VBP) program. All told, drugmakers slashed prices by an average 56%—across 61 molecular entities—to get products into the program in the latest round....The majority of winners (Chinese, PDF) were local manufacturers, with Sanofi, GlaxoSmithKline, GE Healthcare and Mitsubishi Tanabe among the few foreign drugmakers to show up in final roster."

Commercial • Asthma • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

AstraZeneca PLC’s earnings report for the first quarter of 2021 (Cisionwire) - "Respiratory and Immunology (R&I) decreased by 1% (4% at constant exchange rates) to MUSD 1,546, which mainly reflects the impact on inventory from an approved generic version of Symbicort in the US during Q1 2020 and the phasing of impact from COVID-19....Q1 2021 total revenue for selected drugs in the respiratory tract and immunology: Symbicort - 691 MUSD; Pulmicort - 330 MUSD; Fasenra - 260 MUSD; Breztri - 27 MUSD...Respiratory and Immunology (R&I) decreased by 1% (4% at constant exchange rates) to MUSD 1,546, which mainly reflects the impact on inventory from an approved generic version of Symbicort in the US during Q1 2020 and the phasing of impact from COVID-19."

Commercial • Regulatory • Sales • Asthma • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

As-needed Budesonide/Formoterol Turbuhaler in Stepping Down Period (clinicaltrials.gov) - P3; N=100; Recruiting; Sponsor: Hat Yai Medical Education Center; Trial primary completion date: Sep 2020 ➔ Dec 2021; Trial completion date: Aug 2021 ➔ Dec 2022

Clinical • Trial completion date • Trial primary completion date • Asthma • Immunology • Respiratory Diseases

Common asthma drug cuts COVID-19 hospitalization risk, recovery time - Oxford study (Reuters) - P2, N=146; STOIC (NCT04416399); "The 28-day study of 146 patients suggested that inhaled budesonide reduced the risk of urgent care or hospitalization by 90% when compared with usual care...Initial data from the study also found volunteers treated with budesonide had a quicker resolution of fever and fewer persistent symptoms."

P2 data • Infectious Disease • Novel Coronavirus Disease

AZN: full-year 2020 results (Cisionwire) - "Other key trials in COVID-19: Farxiga: DARE-19 Phase III - First data anticipated H1 2021; TACTIC-E Phase II - First data anticipated H1 2021 - Recruitment ongoing; Symbicort: INHASCO Phase IIIa - First data anticipated H1 2021 - Recruitment ongoing; Pulmicort: TACTIC-COVID Phase IIIa - First data anticipated H1 2021 - Recruitment ongoing; MEDI3506 (IL33 monoclonal antibody) ACCORD Phase II - First data anticipated H1 2021 - Recruitment ongoing."

P2 data • P3 data • Infectious Disease • Novel Coronavirus Disease

Inhaled Corticosteroid Treatment of COVID19 Patients With Pneumonia (clinicaltrials.gov) - P4; N=300; Recruiting; Sponsor: Sara Varea; Trial completion date: Oct 2020 ➔ Aug 2021; Trial primary completion date: Aug 2020 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Year-to-date and Q3 2020 results: On track to meet full-year guidance; executing the strategy of sustainable growth through innovation (AstraZeneca Press Release) - "AZD1222 (SARS-CoV-2 vaccine): Results from late-stage trials are anticipated later this year, depending on the rate of infection within the communities where the clinical trials are being conducted. Data readouts will be submitted to regulators.... AZD7442 (long-acting antibody combination for the prevention and treatment of COVID-19....AstraZeneca is continuing to evaluate the use of Calquence (acalabrutinib)....The Company is also looking at the prospect of protecting organs in the DARE-19 Phase III trial, assessing whether Farxiga can potentially reduce organ failure....The Company has joined the UK Government’s ACCORD proof-of-concept clinical-trial platform..."

P2 data • P2/3 data • P3 data: top line • Infectious Disease • Novel Coronavirus Disease

[VIRTUAL] Predicting Pharmacokinetics from Three Marketed Dry Powder Inhalers (ATS-I 2020) - "In the present work, we link real-world emulative in vitro measurements of inhaler performance with numerical models of lung deposition and pharmacokinetics for budesonide (BUD) delivered from three marketed dry powder inhalers (DPIs) to illustrate how such a process can inform device/formulation design...Conclusions Coupling emulative in vitro experimentation with the modeling of regional lung deposition, ASL, and drug disposition allows for predictions of systemic drug exposure. The present method may prove useful in drug development."

PK/PD data

An Exploration of Factors Affecting In Vitro Deposition of Pharmaceutical Aerosols in the Alberta Idealized Throat. (PubMed, J Aerosol Med Pulm Drug Deliv) - "Three dry-powder inhalers (DPIs; Pulmicort Turbuhaler, Budelin Novolizer, and Easyhaler Budesonide) were examined at two insertion angles, one with the inhaler directed toward the back of the oral cavity, the other with the inhaler directed toward the tongue. Three pressurized metered-dose inhalers (pMDIs; QVAR, Ventolin Evohaler, and Flovent HFA) were examined considering the joint effects of insertion angle (as above) and relative humidity at low (15%-25%) and high (>95%) conditions...When oriented toward the back of the oral cavity, the filter dose decreased from 46.5% to 36.9% for Ventolin Evohaler (p = 0.005) and from 56.7% to 44.2% for Flovent HFA (p < 0.001) at high humidity relative to low. High humidity may cause a reduction in total in vitro lung doses for some pMDI aerosols."

Journal • Preclinical

A Comparative Study Evaluating Patients' Satisfaction With Different Dry Powder Inhalers (CHEST 2017) - "At visit 1, participants were switched from their usual preventer MDI to a Budesonide DPI: Giona Easyhaler®, Frenolyn Miat-haler® or Pulmicort Turbuhaler®. Most patients preferred using the Easyhaler compared to using the Miat-haler and the Turbuhaler. Patients were significantly more willing to continue using the Easyhaler compared to the Miat-haler and Turbuhaler.nCLINICAL IMPLICATIONS: Adherence to preventer inhalers may be improved by taking into consideration patients’ inhaler preferences."

Clinical • Asthma • Biosimilar • Immunology

AstraZeneca PLC - Third quarter and nine months results 2011 (AstraZeneca) - Symbicort sales in the US were $201 million in the third quarter a 15% increase over last year and US sales for past nine months were $604M an increase of 14%; Symbicort sales in other markets in the third quarter were $554M in Japan,Canada, Australia and emerging Europe 7% ahead of the third quarter last year; Pulmicort in the third quarter were down 15% to $52M and nine months sales were down by 8%; Due to the lack of efficacy in a P2b trial, the decision was made to discontinue the development programme for MEDI-528

Quarterly results • Sales update • Asthma

Effect of budesonide on fibroblast-mediated collagen gel contraction and degradation (ERS 2011) - Inflammatory cytokines significantly inhibited collagen gel contraction mediated by lung fibroblasts; Budesonide counteracted the effect of cytokines in a concentration-dependent manner (to 50%, p<0.01)

Preclinical-other • Asthma

Activated protein phosphatase PP2A by formoterol enhances nuclear translocation of glucocorticoid receptor induced by budesonide (ERS 2011) - Formeterol directly activates PP2A in a β2-adrenoceptor-independent manner. PP2A associated with GR enhances GR nuclear translocation by BUD; This mechanism may contribute to the clinical benefits of BUD+FM combination therapy

Mechanism of action • Asthma