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.
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.