Mereo BioPharma Group plc announced that data from the Phase 2 “ASTRAEUS” trial of alvelestat for the treatment of Alpha-1 Antitrypsin Deficiency-associated Lung Disease (AATD-LD), as well as post-hoc analyses demonstrating the association between biomarker reductions with alvelestat and improvements in SGRQ, a key Patient-Reported Outcome (PRO) measure, were presented for the first time to the scientific community at the 2023 American Thoracic Society International Conference. The ASTRAEUS data were presented during an oral abstract session on novel treatments and targets by Prof. Robert Stockley, Lung Investigation Unit, University of Birmingham (United Kingdom) and Chief Investigator of the ASTRAEUS trial, while the post-hoc analyses were presented in a poster session by Dr. Jackie Parkin, Senior Vice President and Therapeutic Head at Mereo. Consistent with previously reported biomarker analyses, alvelestat demonstrated significant and consistent reductions in all three biomarkers related to AATD-LD disease activity: blood neutrophil elastase (NE), Aa-val360 and the elastin breakdown product, desmosine.

Low - and high-dose alvelestat significantly suppressed NE activity compared to baseline (-83.5% and -93.3%, p=0.023 and p<0.001 respectively) and versus placebo (p=0.001 and p<0.001). In the high dose arm, Aa-val360 and desmosine progressively decreased from baseline, -22.7% (p=0.004) and -13.2% (p=0.045) respectively, with significant reductions compared to placebo as well (p=0.001 and p=0.041). The low dose did not generate consistent changes in Aa-val360 or desmosine.

Based on these data, Mereo is completing preparatory work for a single pivotal Phase 3 study evaluating the high dose of alvelestat (240mg), which, if successful, is expected to support submissions for full regulatory approvals in both the U.S. and EU. The planned study will have two independent primary endpoints, based on the recommendations of the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA): i) a Patient-Reported Outcome (PRO) expected to be change from baseline in the SGRQ-Activity Domain score, as guided by the FDA, and ii) lung density measured by CT scan, as guided by the EMA. In line with previous guidance, Mereo is continuing to explore potential partnerships to fund the Phase 3 development of alvelestat.

Findings from the biomarker-SGRQ post-hoc analysis showed an association between the extent of reduction in biomarkers and degree of improvement in the SGRQ-Activity domain in alvelestat-treated subjects. By week 12, there was an observed difference in improvement in SGRQ-Activity in biomarker responders compared to non-responders, with a mean improvement of 4.4 in those showing a >0% biomarker decrease and 6.1 in those with >5% biomarker decrease (P=0.05 and p=0.02 respectively), compared to those on alvelestat without biomarker decrease. This association was not observed in the patients who received placebo.

These data support a potential association between the effect of alvelestat on the NE pathway and improvement in how a patient feels and functions based on SGRQ score. Data from ASTRAEUS and other research support the hypothesis that longer term treatment is expected to lead to a deepening of the biomarker and associated clinical response. Alvelestat has been generally safe, with no safety signals of concern observed to date.

Adverse events leading to study drug discontinuation (one liver function and one prolonged QTc) resolved on study drug cessation. Three treatment-related SAEs of headache were reported in the alvelestat arms. Headache is a known adverse event associated with alvelestat and is being addressed through dose-escalation during initiation of alvelestat treatment.