Alvelestat (MPH966) 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).¹ Alvelestat acts to inhibit the neutrophil elastase enzyme which Mereo anticipates has the potential to help reduce further lung damage in individuals with AATD-LD.²  While AATD may affect both the lungs and the liver, alvelestat mechanism of action specifically addresses lung disease, which is the most common effect of AATD in adults.^2,3 Other companies are researching the effects of AATD on the liver.

The only treatment with regulatory approval for AATD-LD is intravenous pooled plasma AAT protein, dosed once weekly. Alvelestat has the potential to offer the convenience of an oral regimen, and the potential benefit of daily dosing for sustained control of neutrophil elastase.  

Alpha-1 Antitrypsin Deficiency-associated Lung Disease

Alpha-1 Antitrypsin Deficiency (AATD) is a rare, genetic condition that results in a deficiency of alpha-1 antitrypsin.^1,3,4 This protein protects the lungs against damage caused by neutrophil elastase, a key enzyme that the body releases during inflammation.³ Without this protein, or with defective proteins, inflammation has both acute and long-term effects.^1,3

People living with Alpha-1 Antitrypsin Deficiency-associated Lung Disease (AATD-LD) experience gradual, irreversible loss of lung function due to the permanent destruction of the lungs’ supportive elastic tissues.¹ This can result in early onset emphysema or chronic obstructive pulmonary disease (COPD), even in the absence of smoking.³ This often starts in early adulthood.

AATD-LD 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 Pi*ZZ or NULL genetic types, which mean that they produce either very low blood levels of abnormal protein or even no protein at all.³ There are an estimated 50,000 people with severe deficiency (i.e. Pi*ZZ or NULL) in North America, and some 60,000 in Europe.³

AATD-LD remains substantially underdiagnosed.⁵ Many patients are misdiagnosed with asthma or chronic obstructive pulmonary disease (COPD), delaying appropriate care.⁶ Awareness and diagnostic rates remain low despite recommendations in the GOLD Guidelines to test all COPD patients for Alpha-1 Antitrypsin Deficiency.^5,6,7

Orphan drug designation for alvelestat

AATD-LD is recognized as an area of high unmet medical need. Alvelestat has received orphan drug designation for the treatment of AATD-LD in the U.S. and Europe, meaning it is officially acknowledged by the regulatory authorities to be targeting a rare and serious condition. ^8,9 Alvelestat also has Fast Track designation from the FDA, a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.¹⁰ 

Clinical study status of alvelestat

The ASTRAEUS study (H3)

The ASTRAEUS study* was a Phase 2 randomized double-blind placebo-controlled study in patients with severe AATD-LD (Pi*ZZ), naïve to augmentation or following a 6-month wash-out period.¹¹ ASTRAEUS evaluated two different doses of alvelestat (120 mg twice daily and 240 mg twice daily) or placebo over a 12-week period, and the effect on three primary biomarker endpoints associated with AATD-LD: blood neutrophil elastase activity, the elastin breakdown product desmosine and Aα-val³⁶⁰.¹¹ A total of 98 patients were enrolled and dosed in the study, across 26 sites in North America, the EU and the U.K.¹¹  

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

 
The ATALANTa trial

The companion Phase 2 investigator-led randomized placebo-controlled 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 twice daily or placebo, 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.^11,12 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).^11,12

^†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.

Alvelestat Phase 3 study design

In the US, following interactions with the FDA, the Division of Pulmonology, Allergy and Critical Care (DPACC), and the Division of Clinical Outcomes Assessment (DCOA), Mereo has aligned on a Phase 3 study design using the St Georges Respiratory Questionnaire (SGRQ) Total Score as the primary endpoint, with a functional assessment as a key secondary endpoint. If successful, this Phase 3 study is expected to support full regulatory approval in the U.S. Mereo has also started the process of validating the SGRQ tool in the AATD-LD population, with the initial results showing the SGRQ is a fit-for-purpose, content valid measure for patients with AATD-LD.⁴

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. 

The unmet need in AATD-LD

The current standard of care includes lifestyle modifications and COPD therapies, which are not specifically approved for AATD-LD.^13,15 The only approved AATD-LD treatment is weekly intravenous infusions of alpha-1 antitrypsin protein, known as augmentation therapy.^13,14

Augmentation therapy

Augmentation therapy is the only disease-specific treatment currently approved for AATD-LD.^15,16 It involves weekly intravenous infusions of purified human alpha-1 antitrypsin, aiming to raise serum and lung levels of the protein to protective thresholds.¹⁵ By restoring the antiprotease shield, the therapy is intended to neutralize excess neutrophil elastase and slow the progression of emphysema.¹⁵ Despite its mechanistic rationale, clinical evidence for augmentation therapy remains mixed.^13,16,17 Two randomized controlled trials, RAPID and EXACTLE, have shown reductions in lung density decline measured by CT densitometry, but failed to demonstrate improvements in FEV₁ or exacerbation rates.^13,16,17  
Access to augmentation therapy, especially in Europe, varies across countries.¹⁸ This inconsistency leads to unequal access to treatment for patients, making it difficult for many to receive the necessary care. While many European countries now reimburse the treatment in line with its approved European label, typically for patients with severe disease, other regions, including the U.K. and Ireland, do not. This inconsistency leads to unequal access to treatment for patients in Europe, making it difficult for many to receive the necessary care, and may further discourage testing and diagnosis, compounding the treatment gap.

Lung transplant

AATD-LD 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.¹⁹ 

Early-stage AATD-LD treatment gaps

There is a critical lack of treatment options for patients in the early stages of AATD-LD. Although early intervention could delay disease progression, the current standard of care does not provide effective solutions for these patients.²⁰ Neither of the pivotal augmentation therapy trials enrolled patients with FEV₁ >80%.^18,19 In Europe, the therapy is approved only for patients with evidence of progressive lung disease (e.g., declining FEV₁), limiting its use in early-stage cases.¹⁶ In contrast, the U.S. label does not impose this restriction, though clinical data in this population remain sparse and the Alpha-1 Foundation Guideline for the diagnosis and management of AATD recommends augmentation therapy in AATD patients within a FEV₁ range of 30-65% predicted.¹⁵ As a result, many patients remain undiagnosed or untreated, underscoring the urgent need for more effective and accessible therapies.

You can find out more about the realities of living with AATD-LD by visiting our patient communities page.