For the potential treatment of severe Alpha-1 Antitrypsin Deficiency-associated Lung Disease
Alvelestat (MPH966) is an oral drug that is being investigated for the treatment of Alpha-1 Antitrypsin Deficiency-associated Lung Disease (AATD-LD). Alvelestat acts to inhibit the neutrophil elastase enzyme and Mereo believes that it has the potential to help protect people with AATD by slowing progressive lung damage. While AATD may affect both the lungs and the liver, alvelestat’s mechanism of action only addresses lung disease, which is the most common effect of AATD in adults. Other companies are researching the effects of AATD on the liver.
"We are excited by the potential of alvelestat to become the first oral neutrophil elastase inhibitor for the treatment of AATD-LD and look forward to continued collaboration with the regulatory authorities, scientific and patient communities as we further refine our development plans for the Phase 3 pivotal study.”
Dr. Denise Scots-Knight, Chief Executive Officer of Mereo
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.
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 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. At the end of Q2 2024, Mereo submitted the initial validation work for SGRQ in AATD and the detailed Phase 3 package including the study protocol to the FDA.
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).
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.
Mereo is making data available through publications and posters at medical meetings. Here you can access links to available data:
European Respiratory Congress, 2024:
Efficacy of Alvelestat on SGRQ in Patients with AATD and Mild Airflow Limitation: A Pooled Analysis from two Phase 2 Studies
An analysis of 39 patients with GOLD 1 airflow limitation at baseline in the ASTRAEUS and ATALANTa studies to determine the effect of alvelestat on SGRQ Total and SGRQ Activity domain scores.
No Infection Risk with Alvelestat in Patients with AATD in Two Phase 2 Trials
Presentation of combined safety data from patients in the ASTRAEUS and ATALANTa studies.
American Thoracic Society, 2024:
Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (ATALANTa): A Phase 2, multicenter, double-blind, randomized, placebocontrolled study to evaluate efficacy, safety, and tolerability of alvelestat in alpha-1 antitrypsin deficiency
An investigator-led Phase 2 study investigating the mechanistic effect and safety of alvelestat in AATD (ATALANTa).
Association of Biomarker Suppression with SGRQ and CAT in Patients with AATD Treated with Alvelestat: Results from the Treatment of Alpha-1-ANTitrypsin Deficiency (ATALANTa) Study
A planned post-hoc analysis examining the association of SGRQ Total score and CAT score with biomarker response in the ATALANTa study.
American Thoracic Society, 2023:
Analysis from Phase II clinical trial, Alvelestat, NE (neutrophil elastase) inhibitor in AATD-LD: Correlation between biomarker response (Desmosine and Aa-Val 360 ) and Clinical Outcome (SGRQ)
Analysis of data from ASTRAEUS to investigate the association between a reduction in disease activity biomarker responses and the SGRQ Activity domain to support clinical trial design.
Alvelestat: An Oral Neutrophil Elastase (NE) Inhibitor In Alpha-1 Antitrypsin Deficiency (AATD): Results Of A Phase II Trial (ASTRAEUS)
A Phase 2 study investigating the mechanistic effect and safety of alvelestat in AATD (ASTRAEUS).
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.
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.
LONDON, January 08, 2024 – Mereo BioPharma Group plc (NASDAQ: MREO) (“Mereo” or the “Company”), a clinical-stage biopharmaceutical company focused on rare diseases, today provided an update on its pipeline programs as well as an update on recent corporate developments.
London, May 23, 2023 - Mereo BioPharma Group plc (NASDAQ: MREO), (“Mereo” or “the Company”), a clinical-stage biopharmaceutical company focused on rare diseases today 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.
London, March 21, 2023 – Mereo BioPharma Group plc (NASDAQ: MREO) (Mereo or the Company), a clinical-stage biopharmaceutical company focused on rare diseases, today announced regulatory feedback following recent end-of-Phase 2 meetings with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) related to its alvelestat program for the treatment of alpha-1-antitrypsin deficiency-associated lung disease (AATD-LD).
Company to host conference call today at 8:30am ET. Join the conference call
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.
