Alvelestat (MPH-966) is an oral neutrophil elastase inhibitor being explored for the potential treatment of alpha-1 antitrypsin deficiency (AATD)-related lung disease. AATD is a rare, genetic disease that results in a deficiency of alpha-1 antitrypsin, a protein that, under normal circumstances, protects the lungs against damaging enzymes that the body releases during inflammation. When people do not have enough alpha-1 antitrypsin protein or defective alpha-1 antitrypsin protein, whenever the body experiences inflammation, these damaging enzymes, specifically neutrophil elastase, lead to lung damage because of 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. Lung symptoms start in early adult life and, over time, people with Alpha-1 lung disease may progress to needing oxygen to perform even normal daily tasks, which significantly impacts quality of life. People with severe lung disease that has progressed often require lung surgery or lung transplant and many may die from the condition. People, in particular children,  with some forms of Alpha-1 antitrypsin deficiency develop severe liver disease and experience jaundice and swelling of the abdomen as the liver damage progresses as a result of the build-up of abnormal alpha-1 antitrypsin protein in the liver.

Alpha-1 Antitrypsin Deficiency is a genetic condition, which runs in families and can be passed on from parents to their children.  The most severe form of Alpha-1 Antitrypsin Deficiency 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, which can  be determined via genetic and laboratory testing for the protein . 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 ( MPH-966) is an oral drug that is being researched in people with AATD lung disease. Lung disease is the most common impact of Alpha-1 Antitrypsin Deficiency in adults. Alpha-1 Antitrypsin deficiency is thought to be the cause of 1% of emphysema, but often the diagnosis is overlooked.

Alvelestat acts to inhibit the neutrophil elastase enzyme and Mereo believes that ithas the potential to protect AATD patients from further lung damage. Alvelestat is not expected to impact the liver disease, however, other companies are researching in this area.

Clinical Status

We are currently running a Phase 2, 12-week randomized, placebo-controlled trial evaluating two doses of alvelestat compared to placebo, which is expected to enrol approximately 165 patients with the PiZZ, NULL or other severe AATD deficiencies. The primary endpoint of the study is the change from baseline of desmosine,  which is a biomarker of neutrophil elastase activity. Desmosine has been shown to correlate with deterioration of lung tissue as determined by imaging scans in previous studies in people with AATD lung disease. Mereo expects to report topline data in 2H 2021 and, if the results are positive, we will seek regulatory advice on the design of a pivotal trial that could go on to see a potential future therapy in AATD lung disease.

A companion investigator-initiated study 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).

Click here for the alvelestat (MPH-966) clinical trial website.

A total of 12 clinical studies have been completed to date with alvelestat in more than 1,100 people, including in a range of lung diseases, and where alvelestat demonstrated safety and good tolerability.  As such, alvelestat could have a role to play beyond our primary research area of AATD.

Alvelestat in COVID-19 and Bronchiolitis Obliterans Syndrome (BOS)

Alongside the understanding of the role of uncontrolled neutrophil elastase in Alpha-1 antitrypsin deficiency (AATD), there is increasing knowledge about this enzymein driving organ damage in a number of inflammatory conditions, either directly or through Neutrophil Extracellular Trap (NET) formation. Mereo is supporting investigator-initiated studies that will provide further understanding of the potential effect of alvelestat in diseases where these pathways are active.

Critically, the recently emerged COVID-19 condition is characterised by severe inflammation and susceptibility to thromboses, with evidence suggesting that NET formation is a key underlying cause. Dr Mike Wells at the University of Alabama, Birmingham, is exploring the  safety and tolerability of alvelestat and its potential impact on regulation of NETosis in a Phase 1b/2 study in patients with SARS-Cov2 respiratory disease.

ClinicalTrials.gov Identifier  NCT04539795

Additionally, 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 a Phase 1b/2 trial of alvelestat in patients with BOS following stem-cell transplantation in a study sponsored by the National Cancer Institute.

ClinicalTrials.gov Identifier NCT02669251

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Bringing the patient perspective into our work

Nothing about us without us

Alastair Kent OBE, Ambassador, Genetic Interest Group, UK

Mereo is committed to developing and making available therapies in collaboration with all stakeholders, most importantly, the people who we are seeking to serve.  This means that we are committed to ensuring that the patient voice is included in every step of the way;  and we actively seek opportunities for having leadership from the Alpha-1 community as part of our development programme for alvelestat.

Rare diseases, individually, each affect small numbers of people.  This means that patients are rare but it also means that expertise and experience is rare, too.  A primary care physician might never see one case of a given rare disease.  Patients and their families, on the other hand, are often extremely well-informed – more often than not becoming experts in their condition.  This means that their point of view and their experience is crucially important in all decision-making, because they have the lived experience and are able to point to what will make a real and meaningful difference in their lives.

In the case of our development programme for alvelestat, the collaboration between Mereo and Alpha community has taken a step further, with the Alpha-1 Foundation making an investment in the clinical development programme: 
http://www.thealpha-1project.com/AboutUs/News/tabid/84/ID/17/First-patient-dosed-in-Phase-2-Alpha-1-Antitrypsin-Deficiency-Study.aspx

The respect for and inclusion of the rare disease patients’ point of view is also recognised by Regulatory, Health Technology Assessment and Pricing & Reimbursement authorities, who are increasingly including patient representation in their evaluation and decision-making processes, both in the USA and in Europe.  Mereo is committed to maximising those opportunities to include the patient voice, while respecting the independence of patient representatives and community leaders.  Conflict of interest policies and procedures are in place to respect the different roles and responsibilities of all actors in such processes and Mereo adheres to these.  We also make available all financial support that we provide to patient organisations via our transparency reporting

Multi-stakeholder collaboration is a fundamental condition to achieving patient access to rare disease medicines 

EURORDIS Multi-Stakeholder Forum, February 2019

In addition to the formal external engagements, we also believe that it is important for all of our team members at Mereo to be able to feel and understand the potential benefits that our shared work is providing for patients. We are proud that organisations from the Alpha-1 community spend time with our broad company team in order to secure that we are always keeping the patient perspective in our minds.

 

ALPHA-1 COMMUNITY REPRESENTATION ORGANISATIONS 

  • Alpha-1 Global - European and international support & advocacy groups:  “Alpha-1 around the globe”

  

ALPHA-1 COMMUNITY REPRESENTATIVES VISIT MEREO

 

Rare Disease Organisations

Europe:  EURORDIS – Rare Diseases Europe

USA:  NORD – National Organization for Rare Disorders

 

SCIENTIFIC PUBLICATIONS

  1. Silverman & Sandhaus (2009) Alpha1-Antitrypsin Deficiency. NEJM 360: 2749-2757
  2. Blanco et al (2017) Alpha-1 Antitrypsin Pi*Z Gene Frequency And Pi*ZZ Genotype Numbers Worldwide: An Update. Int J COPD 12: 561-569
  3. Blanco et al (2017) Alpha-1 Antitrypsin Pi*SZ Genotype: Estimated Prevalence And Number Of SZ Subjects Worldwide Int J COPD 12: 1683-1694
  4. Rodriguez-Frias et al (2012) Rare Alpha-1-antitrypsin Variants: Are They Really So Rare? Ther Adv Respir Dis 6: 79-84
  5. Vogelmeier C et al. 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. 2012 Apr;9(2):111-120
  6. Stockley R et al. Phase II Study Of A Neutrophil Elastase Inhibitor (AZD9668) In Patients With Bronchiectasis. Respir Med. 2013 Apr;107(4):524-533
  7. Elborn JS et al. Efficacy, Safety And Effect On Biomarkers Of AZD9668 In Cystic Fibrosis. Eur Respir J. 2012 Oct;40(4):969-976
  8. Nordenmark LH et al. Feasibility of Computed Tomography in a Multicenter COPD Trial: A Study of the Effect of AZD9668 on Structural Airway Changes. Adv Ther. 2015 Jun;32(6):548-566

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