RARE Daily

Mereo Reports Positive Data from Phase 2 Study of Alvelestat in AATD-related Emphysema

May 9, 2022

Rare Daily Staff

Mereo BioPharma reported positive top-line efficacy and safety results from the ASTRAEUS Phase 2 study of its investigational oral neutrophil elastase inhibitor, alvelestat, in patients with severe alpha-1 antitrypsin deficiency-associated emphysema.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition that results in progressive alveolar destruction leading to emphysema. People with alpha-1 antitrypsin deficiency have significantly reduced levels of AAT, a protective protein that inhibits the protease neutrophil elastase (NE). Unopposed neutrophil elastase is believed to the key enzyme in the causal pathologic pathway of AATD-LD. AATD-LD presents at age 20 to 50 with symptoms including, shortness of breath, cough, and reduced exercise tolerance. People with AATD may progress to chronic oxygen therapy, lung surgery, transplant, and death.

The double-blind placebo-controlled study evaluated two different doses of alvelestat (high or low dose) or placebo, over a 12-week period (at weeks four, eight 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.

“These positive top-line results demonstrate the clear impact of alvelestat on key known biomarkers along the pathogenic pathway of AATD-LD,” said Denise Scots-Knight, CEO of Mereo. “Alvelestat has the potential to be the first-in-class oral neutrophil elastase inhibitor for the treatment of AATD-LD. We look forward to analyzing the additional data on the secondary and exploratory endpoints and to engaging with the regulators on the design of a pivotal study.”

The Alpha-1 Foundation provided funding in support of the study.

ASTRAEUS was a randomized double-blind placebo-controlled study in patients naïve to augmentation or following a 6-month wash-out period. The study enrolled 99 adults with severe AATD related emphysema across 26 sites in North America, EU, and U.K. of which 98 were dosed. To support the use of a biomarker development strategy interrogating the pathogenic pathway, an amendment elevated two secondary biomarkers (NE activity and Aα-val360) to primary endpoints in addition to desmosine, resulting in three biomarker primary endpoints. Patients were randomized to one of three different arms, high dose, low dose, or placebo, following Independent Safety Data Monitoring Committee (IDMC) review of the safety from the initial cohorts. The protocol allowed prioritization of enrollment to the high dose arm in the case of recruitment challenges and this change was implemented during the COVID-19 pandemic. As previously announced, the company took the decision to close the study when it was determined an adequate number of patients had been recruited to the high dose arm to assess the primary endpoints.

Patients underwent a twelve-week dosing period followed by a four-week follow-up. The primary endpoints included within individual % change from baseline up to end of treatment within a treatment arm and in comparison to placebo at weeks, four, eight and 12 in blood neutrophil elastase activity, Aα-Val360 levels and desmosine levels. The secondary endpoints were the proportion of patients with NE below the limit of quantitation and PK, safety, and tolerability. Exploratory endpoints included rate of acute exacerbations of COPD, pulmonary function tests, St George’s Respiratory Questionnaire, inflammatory and lung damage biomarkers.

At the close of the study the number of patients enrolled and completed in the arms were, 41 in the high dose arm, 22 in the low dose arm and 36 in the placebo arm. All patients were of the PiZZ genotype representing the more severe patient population which occurs in Z allele homozygotes and is associated with early-onset emphysema. All patients had low AAT levels and only 11% of the patients had received prior augmentation therapy. The wash-out period was greater than two years for those patients who had received prior augmentation therapy.

Statistically significant inhibition of NE was observed from first assessment at week four, and this was maintained over the course of the study. The effect was greater in the high dose compared to the low dose. No significant changes from baseline were observed in the placebo arm.

At the high dose of alvelestat, Aα-val360 decreased below baseline at week four with progressive decreases resulting in statistical significance versus placebo at weeks 8 and 12. The placebo showed an increase at all time points. Smaller effects were observed in the low dose arm, and these generally did not reach statistical significance.

At the high dose of alvelestat, desmosine levels decreased with time whereas placebo increased over time. No changes in the level of desmosine in the low dose could be detected at any time point. However, the number of patients in the low dose arm were small due to the preferential enrollment to the high dose group, reducing the power to detect effects in this arm. The percentage changes in desmosine and Aα-val360 at the high dose were comparable to those reported with placebo-controlled augmentation studies following 3 and 6 months of treatment. Desmosine and Aα-val360 have been demonstrated to correlate with lung function and lung density in patients with AATD and respond to AAT replacement during weekly intravenous augmentation therapy.

Consistent with the known safety profile of alvelestat, no safety signals were observed in adverse event (AE) monitoring. Most AEs were mild to moderate, including within Adverse Events of Special Interest (AESI) which were observed in 23 subjects.

Treatment emergent adverse events, including SAEs, were more frequent in the alvelestat groups predominantly due to headache. Dose-escalation for the high dose arm was instigated to manage the headaches.

Mereo plans 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 United States 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.

Photo: Denise Scots-Knight, CEO of Mereo BioPharma

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