velsecorat (AZD7594) / AstraZeneca - LARVOL DELTA

Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator Velsecorat (AZD7594) Following Inhalation in Healthy Volunteers. (PubMed, Drug Des Devel Ther) - "The early clinical evaluation of inhaled velsecorat suggests that this novel SGRM is well tolerated in the dose range investigated. It shows dose proportional plasma exposure, low accumulation, and has dose-dependent effects on markers of glucocorticoid activity."

Journal • PK/PD data • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Characterization of clinical ADME and pharmacokinetics of velsecorat using an intravenous microtracer combined with an inhaled dose in healthy subjects. (PubMed, Drug Metab Dispos) - "This study provides a comprehensive assessment of the disposition of velsecorat in humans. It also highlights a number of complexities associated with determining human absorption, distribution, metabolism and excretion for velsecorat, related to the inhaled route, the high metabolic clearance, sequential metabolite formation and the low intravenous dose."

Clinical • Journal • PK/PD data

GRANIT Study Compares Velsecorat Versus Placebo in Asthma (DocWire) - P2, N=805; GRANIT (NCT03622112); Sponsor: AstraZeneca; "The multicenter, placebo-controlled, double-blind trial enrolled 805 adults with asthma that was inadequately controlled following run-in on low-dose budesonide. A total of 661 patients had completed the study protocol, which included a high percentage of early discontinuations in the placebo group....Over the entire treatment period, velsecorat demonstrated a dose-dependent improvement in trough FEV1 from baseline, compared with placebo. However, the change was not significant at week 12....The researchers added that velsecorat appeared to be safe and well-tolerated."

P2 data • Asthma

[VIRTUAL] Results and Learnings from AMBER, a Decentralized Phase I Study Assessing the Pharmacokinetic and Pharmacodynamic Profile of Inhaled Velsecorat, a Non-Steroidal, Selective Glucocorticoid Receptor Modulator, in Adolescents with Asthma (ATS 2021) - P1 | "AMBER offered a convenient and patient-centric study experience for adolescents and their families during the pandemic. Decentralized studies has the potential to become a new standard by offering a flexible convenient, safe and patient-friendly study format for an adolescent population, as shown by the high recruitment and retention rate during the peak of the COVID-19 pandemic."

P1 data • PK/PD data • Asthma • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Results of a Phase 2b Dose Finding Study of Velsecorat, an Inhaled Non-Steroidal, Selective Glucocorticoid Receptor Modulator in Asthma (GRANIT) (ATS 2021) - P2b | "This multi-center, parallel-arm, PBO-controlled, double-blind study enrolled adult patients with asthma inadequately controlled following run-in on low-dose budesonide (GINA step 3) to receive velsecorat (50, 90, 180, 360, 720µg), PBO or open-label 100µg fluticasone furoate (FF), once-daily for 12 weeks. Conclusions Velsecorat improved lung function and reduced time to first event and annual rate of CompEx events vs PBO. Primary endpoint results were likely influenced by the large proportion of early discontinuations on the PBO arm."

P2b data • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Velsecorat (AZD7594), a Selective Glucocorticoid Receptor Modulator (SGRM) Demonstrates Favorable Pre-Clinical Efficacy vs Safety Profile Compared to Current Clinical Inhaled Steroid, Fluticasone Furoate (ATS 2021) - "These exciting data suggest that velsecorat, when dosed appropriately, possesses the beneficial effects of ICS with fewer of the side-effects that plague this class of compound. velsecorat, currently in phase 2 clinical trials, represents a new therapeutic opportunity for patients with asthma."

Preclinical • Asthma • Eosinophilia • Immunology • Infectious Disease • Inflammation • Osteoporosis • Pulmonary Disease • Respiratory Diseases • Rheumatology

AstraZeneca drops breast, prostate cancer programs in Q4 pipeline cull (FierceBiotech) - "The fourth-quarter pipeline update also saw AstraZeneca drop velsecorat, a selective glucocorticoid receptor modulator that it was developing as a treatment for asthma and chronic obstructive pulmonary disease (COPD). AstraZeneca said it dropped the program for strategic reasons. Another asthma and COPD candidate, abediterol, landed on the scrapheap for the same reasons."

Discontinued • Asthma • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review. (PubMed, J Exp Pharmacol) - "Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine."

Journal • Review • Asthma • Immune Modulation • Inflammation • Respiratory Diseases

A Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of 2-Week Treatment With Inhaled AZD7594 in Adolescents (12 to 17 Years) With Asthma (clinicaltrials.gov) - P1; N=34; Completed; Sponsor: AstraZeneca; Recruiting ➔ Completed; N=24 ➔ 34; Trial completion date: Nov 2020 ➔ Jul 2020; Trial primary completion date: Nov 2020 ➔ Jul 2020

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Asthma • Respiratory Diseases

[VIRTUAL] Design of a Phase 1 Virtual Hybrid Study of AZD7594, an Inhaled Non-Steroidal, Selective Glucocorticoid Receptor Modulator, in Adolescents with Asthma (ATS-I 2020) - P2b | "Conclusion The results of this study will characterize the PK, PD and safety of AZD7594 in adolescents with GINA 2 asthma. The hybrid virtual study concept will provide detailed insight into the feasibility of similar designs in this age group."

P1 data • Asthma • Immunology • Respiratory Diseases

Stereoretentive Etherification of an α-aryl-β-amino-alcohol using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594. (PubMed, J Org Chem) - "Process analytical techniques were used to establish reaction understanding and mixing on large scale was modelled in silico. The process provided a selective and efficient method of preparing the non-steroidal, inhaled selective glucocorticoid receptor modulator, AZD7594."

Journal

A study to investigate how the drug AZD7594 is absorbed in the blood stream, how safe and tolerable it is when administered by DPI once daily via inhalation over two weeks of treatment in adolescent patients with asthma. (clinicaltrialsregister.eu) - P1; N=24; Sponsor: AstraZeneca AB

Clinical • New P1 trial • Asthma • Respiratory Diseases

Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers. (PubMed, Drug Des Devel Ther) - "In conclusion, the early clinical evaluation of inhaled AZD7594 suggests that this novel SGRM is well tolerated in the dose range investigated and also in a Japanese population. It shows dose-proportional plasma exposure, moderate accumulation and has limited impact on systemic markers of glucocorticoid activity."

Clinical • Journal • PK/PD data • Asthma • Chronic Obstructive Pulmonary Disease • Respiratory Diseases

A Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of 2-Week Treatment With Inhaled AZD7594 in Adolescents (12 to 17 Years) With Asthma (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: AstraZeneca; Active, not recruiting ➔ Recruiting; Trial completion date: Jun 2020 ➔ Nov 2020; Trial primary completion date: Jun 2020 ➔ Nov 2020

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

A Study to Assess the Bioavailability and to Compare the Pharmacokinetics of AZD7594 Inhaled Via Monodose Inhaler and Multiple-dose Dry Powder Inhalers (DPI) or Pressurized Metered-dose Inhaler (pMDI) in Healthy Male Subjects (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Enrollment closed • Asthma • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

A Study to Assess the Effect of Particle Size of AZD7594 on Pharmacokinetics (PK) After a Single Inhaled Dose When Administered Using the Dry Powder Inhaler in Healthy Volunteers. (clinicaltrials.gov) - P1; N=18; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Enrollment open • Asthma • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

Design of a Phase 1 Virtual Hybrid Study of AZD7594, an Inhaled Non-Steroidal, Selective Glucocorticoid Receptor Modulator, in Adolescents with Asthma (ATS 2020) - P2b | "For the first time, we will run a virtual hybrid clinical trial concept, adapting the trial around the patient by (Figure);● Home nursing visits to perform PK-sampling, spirometry and plasma cortisol as pharmacodynamic (PD) assessments and safety evaluation through physical examination, electrocardiogram vital signs, adverse events and laboratory measurements.● Telemedicine visits through a digital platform for real time video consultations with the physician at study site, as well as capturing daily diary data regarding SABA use and ACQ-5, reading and signing informed consent form, visit scheduling and caregiver/patient end of study evaluation.● Remote PK and PD through a finger-prick micro-sampling device will be explored, with the aim of reducing lengthy and burdensome blood sampling in future trials.Conclusion The results of this study will characterize the PK, PD and safety of AZD7594 in adolescents with GINA 2 asthma. The hybrid virtual study concept will provide..."

P1 data

A Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of 2-Week Treatment With Inhaled AZD7594 in Adolescents (12 to 17 Years) With Asthma (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study to Evaluate the Amount of Drug That Becomes Available to the Blood Circulation When Inhaled by a Nebulizer and Dry Powder Inhaler in Healthy Subjects. (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Clinical • Trial completion • CRP

A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects (clinicaltrials.gov) - P2b; N=808; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Trial completion

A Study to Evaluate the Amount of Drug That Becomes Available to the Blood Circulation When Inhaled by a Nebulizer and Dry Powder Inhaler in Healthy Subjects. (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • CRP

A Study to Assess the Pharmacokinetics (PK), Pharmacodynamics (PD) and Safety of 2-Week Treatment With Inhaled AZD7594 in Adolescents (12 to 17 Years) With Asthma (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: AstraZeneca; Trial completion date: Mar 2020 ➔ Jun 2020; Trial primary completion date: Mar 2020 ➔ Jun 2020

Clinical • Trial completion date • Trial primary completion date

A Study to Evaluate the Amount of Drug That Becomes Available to the Blood Circulation When Inhaled by a Nebulizer and Dry Powder Inhaler in Healthy Subjects. (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects (clinicaltrials.gov) - P2b; N=808; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study to Evaluate the Amount of Drug That Becomes Available to the Blood Circulation When Inhaled by a Nebulizer and Dry Powder Inhaler in Healthy Subjects. (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P1 trial