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Alvelestat (MPH966)

For the potential treatment of severe Alpha-1 Antitrypsin Deficiency (“AATD”) Alvelestat (MPH966) is an oral drug that is being researched in people with alpha-1 antitrypsin deficiency (AATD) lung disease. Lung disease is the most common impact of AATD in adults. Alpha-1 antitrypsin deficiency is thought to be the cause of 1% of emphysema, but often the diagnosis is overlooked. Alvelestat acts to inhibit the neutrophil elastase enzyme and Mereo believes that it has the potential to protect AATD patients from further lung damage. Alvelestat is not expected to impact the liver disease, however, other companies are researching in this area.


The orphan drug designation for alvelestat represents an important regulatory milestone, recognizing the significant and urgent unmet need for new therapies to address AATD and specifically AATD-LD.”

Dr. Denise Scots-Knight, Chief Executive Officer of Mereo

What is alpha-1 antitrypsin deficiency (AATD)?

AATD is a rare, genetic disease that results in a deficiency of alpha-1 antitrypsin, a protein that protects the lungs against damaging enzymes that the body releases during inflammation. Without this protein, or with defective proteins, inflammation can lead to lung damage due to the irreversible destruction of the lungs’ supportive elastic tissues.

As a result, AATD can cause pulmonary emphysema, a progressive, life-threatening lung disease, which results in severe shortness of breath, wheezing, chronic cough and sputum production, as well as asthma, recurring chest infections and bronchiectasis – permanent enlargement of parts of the lungs airways.

How many people are affected?

AATD is a genetic condition, which runs in families and can be passed on from parents to their children. The most severe form of AATD is found in people who have the “PiZZ” or “NULL” genetic types, which mean that they produce either very low blood levels of either abnormal protein or even no protein at all. There are an estimated 50,000 people with severe deficiency (e.g., “PiZZ” or “NULL”) in North America and some 60,000 in Europe.

Clinical Status

Alvelestat is currently under investigation in a Phase 2 proof-of-concept trial ASTRAEUS (NCT03636347). ASTRAEUS has recently reported topline results. A companion investigator-initiated study ATALANTa (NCT036795908) in people with severe AATD is also ongoing in the US, led by Professor Mark Dransfield at the University of Alabama and funded by National Center for Advancing Translational Sciences (NCATS).

ASTRAEUS is a double-blind placebo-controlled study evaluated two different doses of alvelestat (high or low dose) or placebo, over a 12-week period (at weeks 4, 8 and 12) and the effect on three primary biomarker endpoints associated with AATD-related lung disease (AATD-LD), blood neutrophil elastase activity, Aα-val360 and the elastin breakdown product, desmosine.

A total of 99 patients were enrolled and 98 patients were dosed in the study. At the high dose, alvelestat demonstrated statistically significant changes versus placebo in all three primary biomarker endpoints.

We plan to analyze the additional data on the secondary and exploratory endpoints in the second half of 2022 and to then engage with the regulators in the US and Europe for an End of Phase 2 meeting to determine the design of a pivotal registrational trial for alvelestat for the treatment of AATD-LD. The investigator led ATALANTa trial studying alvelestat in a broader range of patient populations, including other genotypes and those on augmentation therapy, is expected to read out in the first half of 2023.

Press release: Mereo BioPharma announces Positive Top-Line Efficacy and Safety Data from “ASTRAEUS” Phase 2 Trial of Alvelestat in Alpha-1 Antitrypsin Deficiency- associated Emphysema – 09 May 2022 Further data analysis ongoing

Alvelestat in Bronchiolitis Obliterans Syndrome (BOS)

Bronchiolitis Obliterans Syndrome (BOS) is a rare condition where excessive inflammation causes thickening of the airways, severely limiting lung function. BOS occurs predominantly in people undergoing bone-marrow, stem-cell or lung transplant and is a progressive condition, with significant mortality.

Dr. Steve Pavletic at the National Institutes of Health (NIH) is leading a Phase 1b/2 trial of Alvelestat in patients with BOS following stem-cell transplantation in a study sponsored by the National Cancer Institute.

Patients received escalating doses of alvelestat over an 8-week period, from 60 mg twice daily to a maximum of 240 mg twice daily, which was tolerated in all patients.

Investigator-sponsored Trial Results

  • Phase 1b interim data - progressive reduction of plasma desmosine over 8 weeks in 6 of 7 treated patients, all of whom had improved or stable lung disease (FEV1 ) and reduction in stimulated neutrophil elastase activity.
  • Suppressive effect on biomarkers of elastase activity and collagen synthesis


These data, while early, are highly encouraging as this is the first evidence of elevated elastase activity in patients with BOS and GVHD that can be suppressed by a neutrophil elastase inhibitor.”

Dr. Jackie Parkin, Senior Vice President and Therapeutic Head at Mereo.

Alvelestat in COVID-19

Alongside the understanding of the role of uncontrolled neutrophil elastase in Alpha-1 antitrypsin deficiency (AATD), there is increasing knowledge about this enzyme in driving organ damage in a number of inflammatory conditions, either directly or through Neutrophil Extracellular Trap (NET) formation. Mereo is supporting investigator-initiated studies that will provide further understanding of the potential effect of Alvelestat in diseases where these pathways are active.

Critically, the recently emerged COVID-19 condition is characterised by severe inflammation and susceptibility to thromboses, with evidence suggesting that NET formation is a key underlying cause.

We initiated “COSTA”, a Phase 1b/2 Trial of Alvelestat in hospitalized patients with COVID-, in partnership with the University of Alabama, Birmingham.

The trial is a double-blind, randomized, placebo-controlled study in adult patients, evaluating the safety and tolerability of alvelestat on top of Standard of Care in patients hospitalised with proven COVID-19 lung disease.

Top-line results are positive and set the stage for future studies with relevant clinical end-points.

COSTA Interim Results

  • Alvelestat reported safe and well-tolerated in patients with COVID-19
  • Alvelestat, on top of standard of care resulted in a more rapid time to improvement in WHO Disease Severity score of >=2 in the first 5-7 days compared to placebo plus standard of care


There remains a significant unmet need to improve the outcomes of hospitalized patients with COVID-19. The early results with alvelestat suggest a potential for clinical benefit over and above standard of care including dexamethasone and remdesivir. This is exciting given the ease of administration of a well-tolerated oral therapy in this acutely ill population."

Principal Investigator Dr. Mike Wells, Associate Professor in Pulmonary, Allergy and Critical Care Medicine, UAB

Alvelestat News

Mereo BioPharma to Host Alvelestat R&D Update Call on October 31, 2022
24 October 2022

Mereo BioPharma today announced that it will host a R&D update call on Monday, October 31, 2022 at 8:00 am ET on the alvelestat (MPH966) program for alpha-1-antitrypsin deficiency (AATD). The update will include commentary from and Q&A with leading pulmonary experts, further to the receipt of Fast Track Designation for alvelestat from the FDA announced on October 17, 2022.

Mereo BioPharma Receives FDA Fast Track Designation for Alvelestat for Treatment of Alpha-1 Antitrypsin Deficiency (AATD)-associated Lung Disease
17 October 2022

Mereo BioPharma today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for its investigational oral neutrophil elastase inhibitor, alvelestat (MPH-966).

Mereo BioPharma announces Positive Top-Line Efficacy and Safety Data from “ASTRAEUS” Phase 2 Trial of Alvelestat in Alpha-1 Antitrypsin Deficiency- associated Emphysema
09 May 2022

Mereo BioPharma announces positive topline results from ASTRAEUS a Phase 2 trial of alvelestat in Alpha-1 Antitrypsin Deficiency- associated Emphysema. 

Mereo BioPharma to Host Conference Call Highlighting Top-line Clinical Data from “ASTRAEUS” Phase 2 Study of Alvelestat
06 May 2022

 Mereo BioPharma Group plc today announced it will host a conference call on Monday, May 9, 2022 at 10:30 a.m. ET to review top-line clinical data from its “ASTRAEUS” Phase 2 Study of Alvelestat in Alpha-1 Antitrypsin Deficiency-associated Emphysema.