MPH-966 (alvelestat) is an oral neutrophil elastase inhibitor being explored for the potential treatment of alpha-1 antitrypsin deficiency (AATD). AATD is a rare, genetic disease that results in a deficiency of alpha-1 antitrypsin. The loss of the normally protective effect of alpha-1 antitrypsin against damaging enzymes, specifically neutrophil elastase, released during inflammation, leads to lung damage because of the irreversible destruction of the lungs’ supportive elastic tissues.
AATD can, as a result, cause pulmonary emphysema, a life-threatening lung disease, resulting in severe shortness of breath, wheezing, chronic cough and sputum production, as well as recurring chest colds, pneumonia, year-round allergies and bronchiectasis – permanent enlargement of parts of the lungs airways. People with Alpha-1 lung disease very often need to progress to oxygen use to perform normal daily tasks, significantly impacting quality of life from an early age. People with Alpha-1 liver disease may experience jaundice, swelling of the abdomen as the liver damage progresses due to the build-up of abnormal alpha-1 antitrypsin enzyme in the liver. People might also experience panniculitis, a painful swelling of the panniculus, the layer of tissue under the skin.
The most severe form of this genetic disease is found in patients who have the PiZZ or NULL genotypes, producing either very low levels of abnormal protein or no protein at all. This can be determined via genetic testing. There are an estimated 50,000 severe PiZZ or Null patients in North America and 60,000 patients in Europe. Mereo believes that by inhibiting neutrophil elastase activity MPH-966 (alvelestat) has the potential to protect AATD patients from further lung damage. It is not expected to impact the liver disease, however, other companies are researching in this area. 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 3% of emphysema, but often the diagnosis is overlooked.
We have commenced a Phase 2, 12-week randomized, placebo-controlled, trial evaluating two doses of MPH-966 versus placebo that is expected to enroll approximately 165 patients with the PiZZ or NULL genetic mutations. The primary endpoint of the study is the change from baseline of desmosine/isodesmosine which are biomarkers of neutrophil elastase activity. Desmosine has been shown to correlate with deterioration of lung tissue as determined by CT scans in previous studies in AATD patients. Mereo expects to report top line data in mid-2020 and if the results are positive, will seek regulatory advice on the design of a pivotal trial. A total of 12 clinical studies have been completed to date in over 1,100 patients in a range of lung diseases demonstrating safety and good tolerability.
Bringing the patient perspective into our work
Nothing about us without usAlastair 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:
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 medicinesEURORDIS 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
Rare Disease Organisations
- Silverman & Sandhaus (2009) Alpha1-Antitrypsin Deficiency. NEJM 360: 2749-2757
- 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
- Blanco et al (2017) Alpha-1 Antitrypsin Pi*SZ Genotype: Estimated Prevalence And Number Of SZ Subjects Worldwide Int J COPD 12: 1683-1694
- 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. 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
- 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
- Elborn JS et al. Efficacy, Safety And Effect On Biomarkers Of AZD9668 In Cystic Fibrosis. Eur Respir J. 2012 Oct;40(4):969-976
- 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