AATD is a rare, genetic condition that results in a deficiency of alpha-1 antitrypsin, a protein that protects the lungs against environmental damage as well as against attack by neutrophil elastase, a key enzyme that the body releases during inflammation. Without this protein, or with defective proteins, inflammation has both acute and long-term effects. Over time it can lead to lung damage due to the irreversible destruction of the lungs’ supportive elastic tissues.

In the most severely affected, AATD results in progressive lung disease and deterioration, often starting in early adulthood. People living with AATD experience gradual, irreversible loss of lung function, resulting in early onset emphysema or chronic obstructive pulmonary disease (COPD), even in the absence of smoking. Treatment approaches include avoidance of cigarette smoke, use of inhalers to help control symptoms, and in some cases intravenous infusion of alpha-1 antitrypsin protein. These do not halt disease, and AATD can be life-threatening and lead to the need for a lung transplant. However, a lung transplant does not remove the underlying cause of the disease, and the replacement lungs continue to experience progressive damage and consequent loss of function.

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 has received U.S. Orphan Drug Designation for the treatment of AATD-LD and Fast Track Designation from the FDA. Two Phase 2 trials of alvelestat in severe AATD-LD have been completed, ASTRAEUS (NCT03636347) and ATALANTa (NCT03679598). Based on these data, Mereo is completing preparatory work for a pivotal Phase 3 study evaluating alvelestat (240 mg) compared to placebo. 

In the US, following interactions with the FDA; the Division of Clinical Outcomes Assessment (DCOA), and the Division of Pulmonology, Allergy and Critical Care (DPACC), the Company has aligned on a Phase 3 study design using SGRQ Total Score as the primary endpoint with a functional assessment as a key secondary endpoint. If successful, this is expected to support submissions for full regulatory approval in the US. 

In Europe, Mereo has received guidance from the European Medicines Agency (EMA) that a Phase 3 primary endpoint of lung density by computed tomography (CT) scan with a relaxed p value (p<0.1) may, if the study is successful, be sufficient for full approval. 

Press release: Mereo BioPharma Provides Update on Pipeline Progress and Corporate Developments

ASTRAEUS was a randomized double-blind placebo-controlled study in patients naïve to augmentation or following a 6-month wash-out period. ASTRAEUS evaluated two different doses of alvelestat (120 mg and 240 mg) or placebo, over a 12-week period (at weeks 4, 8 and 12) and the effect on three primary biomarker endpoints associated with AATD-LD: blood neutrophil elastase activity, Aα-val³⁶⁰ and the elastin breakdown product, desmosine.

A total of 99 patients were enrolled across 26 sites in North America, EU and U.K. and 98 patients were dosed in the study. At the high dose (240 mg), alvelestat demonstrated significant and consistent reductions versus placebo in all three primary biomarkers related to AATD-LD activity.

Additionally, post-hoc analyses demonstrated the association between extent of biomarker reductions with alvelestat and improvements in a Patient Reported Outcome of St George's Respiratory Questionnaire-Activity (SGRQ) domain.

No safety signals were associated with alvelestat. Headache was the most frequent adverse event, generally mild or moderate and resolving on continued dosing. Three cases were reported as serious adverse events (SAEs).

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 

The companion Phase 2 investigator-led ATALANTa study, led by Professor Mark Dransfield, Director of the Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham (UAB), evaluated the safety and efficacy of alvelestat 120 mg or matched placebo, twice daily, for 12 weeks, in a broader range of individuals with AATD-LD, including subjects with less severe phenotypes (Pi*SZ), and those receiving augmentation therapy. The study randomized 63 patients, 32 in the 120 mg alvelestat arm (44% on augmentation therapy) and 31 in the placebo arm (48% on augmentation therapy). 

The results demonstrated with the 120 mg dose of alvelestat (the low dose used in the Phase 2 ASTRAEUS study) are consistent with those observed in ASTRAEUS on blood neutrophil elastase activity and changes in the biomarkers desmosine and Aα-val³⁶⁰. The data from ATALANTa also show an effect of alvelestat on the SGRQ Total (p=0.10 versus placebo) and reaching significance for SGRQ Activity domain (p=0.01 versus placebo) in patients not on augmentation.

Overall alvelestat was well-tolerated. The most common adverse events were headache/migraines in the alvelestat group and worsening of COPD symptoms in the placebo group.

The data demonstrate that the 120 mg dose of alvelestat is safe on top of augmentation and support Mereo’s selection of the 240 mg dose to be studied in the planned Phase 3 pivotal trial.

The ATALANTa study was funded by the National Center for Advancing Translational Sciences (NCATS) through the National Institutes of Health (NIH)-Industry program for discovering new therapeutic uses for existing molecules.

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 an investigator-sponsored 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. Alvelestat was tolerated in all patients.

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

References

• Im A. et al. 2021. Effects of Alvelestat, an Oral Neutrophil Elastase Inhibitor, on Elevated Elastase and Collagen Turnover Biomarkers in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Blood: 138 (Sup 1): 1815
• Blanco I. et al. 2017. Alpha-1 Antitrypsin Pi*Z Gene Frequency And Pi*ZZ Genotype Numbers Worldwide: An Update, Int J COPD:12:561–569
• Blanco I. et al., 2017. Alpha-1 Antitrypsin Pi*SZ Genotype: Estimated Prevalence And Number Of SZ Subjects Worldwide, Int J COPD:12:1683–1694
• Stockley R. et al. 2013, Phase II Study Of A Neutrophil Elastase Inhibitor (AZD9668) In Patients With Bronchiectasis, Respir Med:107(4):524-533
• Rodriguez-Frias et al. 2012. Rare Alpha-1-antitrypsin Variants: Are They Really So Rare? Ther Adv Respir Dis: 6:79-84
• Vogelmeier C. et al. 2012. A Randomised, Placebo-controlled, Dose-finding Study Of AZD9668, An Oral Inhibitor Of Neutrophil Elastase, In Patients With Chronic Obstructive Pulmonary Disease Treated With Tiotropium. COPD:9 (2):111-120 
• Elborn JS et al. 2012. Efficacy, Safety And Effect On Biomarkers Of AZD9668 In Cystic Fibrosis. Eur Respir J:40(4):969-976 
• Silverman E. & Sandhaus R. 2009. Alpha1-Antitrypsin Deficiency. NEJM 360: 2749-2757
• Health-related Quality of Life in Alpha-1 Antitrypsin Deficiency-associated COPD." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.