Advancing the understanding and treatment of lung pathologies associated with alpha 1 antitrypsin deficiency

Abstract

Alpha 1 antitrypsin deficiency (AATD) is a genetic disorder that alters the functionality and/or serum levels of alpha 1 antitrypsin (AAT). Dysfunctional forms of AAT, or low levels of serum AAT, predispose affected individuals to pulmonary complications. When AATD-associated lung disease develops, the most common pulmonary pathology is emphysema. The development of emphysema and decline in lung function varies by AATD genotype and is accelerated by risk factors, such as smoking. To improve the understanding and treatment of AATD, emerging knowledge and unresolved questions need to be discussed. Here we focus on developments in the areas of disease pathogenesis, biomarkers, and clinical endpoints for trials in AATD, as well as barriers to treatment. The clinical impact of AATD on lung function is highly variable and highlights the complexity of AATD pathogenesis, in which multiple underlying processes are involved. Reduced levels of functional AAT disrupt the protease-antiprotease homeostasis, leading to a loss of neutrophil elastase inhibition and the breakdown of elastin within the lung interstitium. Inflammatory processes also play a critical role in the development of AATD-associated lung disease, which is not yet fully understood. Biomarkers associated with the disease and its complications may have an important role in helping to address AATD underdiagnosis and evaluating response to treatment. To improve access to treatment, the problem of underdiagnosis needs to be addressed and the provision of therapeutic options needs to become uniform. Patients should also be empowered to play a key role in the self-management of the disease. Advancing our understanding of the disease will ultimately improve the life expectancy and quality of life for patients affected by AATD.

Keywords

AAT AATD alpha 1 antitrypsin alpha 1 antitrypsin deficiency barriers to treatment biomarkers clinical endpoints COPD disease management disease pathogenesis emphysema genetic variants rare disease

Introduction

Alpha 1 antitrypsin deficiency (AATD) is a genetic disorder first identified in 1963.¹ The underlying cause of AATD is a result of genetic mutations in the highly polymorphic SERPINA1, which can result in changes to the functionality and/or serum levels of alpha 1 antitrypsin (AAT).² There are in excess of 200 genetic variants of SERPINA1, which accounts for some of the variability observed in the clinical presentation of patients with AATD.^2,3 In the general population, the three most common SERPINA1 protease inhibitor (Pi) alleles are M, which results in normal levels of functional AAT, and S and Z, which are associated with reduced AAT serum levels.⁴ The most prevalent severe genotype is homozygous Pi*ZZ³; however, 85%–95% of individuals have the homozygous Pi*MM genotype, which results in normal levels (>20 µmol/L) of functional AAT.⁵

The prevalence of the genotype that confers a high risk of developing AATD-related diseases, Pi*ZZ, is approximately 180,000 people worldwide, predominantly in Caucasian individuals in Western and Central Europe, while Pi*SZ and Pi*MZ, which confer more moderate risk, are estimated to be present in approximately 1.3 and 42.6 million people worldwide, respectively.⁵ Dysfunctional forms of AAT, or low levels of serum AAT, predispose individuals to pulmonary complications, including chronic obstructive pulmonary disease (COPD), bronchiectasis, and early-onset emphysema. Individuals may also develop liver disease, panniculitis, and vasculitis.⁶

The general epidemiology and pathology of AATD is well characterized.⁶ In individuals with normal AAT levels, AAT inhibits neutrophil serine proteases, specifically neutrophil elastase (NE), to maintain protease-antiprotease homeostasis. When AAT is defective, absent, or also present at reduced levels, NE is uninhibited and breaks down elastin, which is a key component of the lung interstitium, contributing to the development of lung disease.⁴ Some SERPINA1 mutations lead to polymerization of defective AAT proteins, and as a result of hepatocytes being the primary source of AAT, polymerized/defective AAT proteins can accumulate within the liver. This accumulation can lead to the development of liver diseases, such as cirrhosis.^4,7,8 Other extrapulmonary manifestations, such as panniculitis and vasculitis, are thought to be caused by subcutaneous proteolytic and inflammatory mechanisms, respectively.⁴

Due to the relatively rare nature of AATD and the fact that cases can often be asymptomatic for many years, the condition is significantly underdiagnosed, and AATD is often misdiagnosed as standard asthma or COPD.^4,9
–11 Among AATD-associated lung diseases, the most common pulmonary pathology is emphysema, which is irreversible and accelerated by smoking, and the risk of emphysema development relative to the general population varies depending on the patients’ AATD genotype.⁴ Clinically, manifestations of AATD are similar to nonhereditary emphysema.¹² Most commonly, patients with AATD initially present with emphysema at a relatively young age and have a greater likelihood of panlobular emphysema than most patients with COPD.^3,4,13 In patients with the Pi*ZZ genotype in the European AATD Research Collaboration (EARCO) international registry, diagnoses of emphysema and COPD (defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) <70%)^14,15 were the most frequently reported lung diseases and were observed at similar frequencies in these patients.¹⁶ However, there are a range of lung diseases associated with AATD, including bronchiectasis and asthma,¹⁶ leading to the concept of different phenotypes of the disease.¹⁷ There is also increasing evidence that both lung tissue damage and inflammatory disequilibrium contribute to the respiratory dysfunction experienced by patients with AATD.¹⁷ Therefore, the clinical presentations of AATD may be diverse.¹⁷

AATD may also share common mechanisms with other respiratory diseases. Epidemiological studies during the coronavirus disease 2019 (COVID-19) pandemic identified geographical overlap in cases of patients with AATD and COVID-19, along with shared pathogenic pathways.^18
–20 AAT can also bind to and inhibit proteases, like transmembrane protease 2, important to the pathophysiology of COVID-19.^18,21,22 These associations with COVID-19 further demonstrate the breadth of consequences associated with SERPINA1 mutations observed in AATD.

Currently, lung disease associated with AATD is the only approved use for the intravenous administration of plasma-derived AAT (AAT therapy); however, its use in the treatment of AATD-associated panniculitis is also recommended.²³ In addition, due to the anti-inflammatory/immunomodulatory properties of AAT, AAT therapy is also being explored in autoimmune and other inflammatory conditions.^24,25 AAT therapy is a well-established and approved treatment for patients with severe AATD that can restore AAT levels to within the normal range.^26
–33 However, despite this, access to AAT therapy and therapy reimbursement can vary by country and demographic.³⁴

To improve the diagnosis and access to effective therapies for AATD, it is essential to increase awareness and knowledge of the condition among clinicians and other healthcare professionals. In particular, there are several areas where emerging knowledge or unresolved questions will contribute to the improved understanding and treatment of this rare condition. These areas of focus include disease pathogenesis, biomarkers, and clinical endpoints for trials in AATD, and barriers to treatment, all of which are discussed in this review and are outlined in Figure 1.

Figure 1.

An overview of disease processes in AATD and the areas of focus required to improve diagnosis and treatment.

Disease pathogenesis in AATD

Pathogenic processes

The clinical impact of AATD on lung function is highly variable,³ which may be due to a greater complexity to the pathogenesis of AATD than was at first apparent. The absence of functional AAT leading to excess uninhibited NE breaking down lung tissue elastin is a well-established core mechanism underlying AATD.⁴ NE is an inflammatory protease released by neutrophils, and as part of its role in the immune response, NE clears Gram-negative bacteria by disrupting the bacterial membrane.³⁵ When NE is dysregulated and is present in abundance within the lung, it degrades elastin in the extracellular matrix of the lung tissue.³⁵ In addition to this degradation, when NE is dysregulated there are also multiple inflammatory processes instigated, and normal innate immune processes become impaired.³⁵ These immune-related actions initiated by NE must also be considered in the pathogenesis of AATD and may require additional therapeutic interventions separate from treatments targeting the protease-antiprotease imbalance.³⁵

A direct link also exists between serine proteases and inflammation mediated by cytokines and chemokines.^36,37 Many of these inflammatory mediators are activated when cleaved by serine proteases, particularly NE.^36,37 NE should not be the only elastase to consider when understanding this mechanism of action in AATD; other neutrophil-serine proteases, such as proteinase 3 (PR3) and cathepsin G (CG) should also be considered since the action of these proteases are also regulated by AAT and they play roles in inflammation.^35
–37 For instance, PR3 may have a greater role than NE in the secretion of the highly inflammatory cytokine, interleukin-1β.³⁷ AAT also has anti-inflammatory and immunomodulating properties, independent of NE inhibition, which may contribute to the diverse clinical presentations in AATD.^4,38 Aside from the three serine proteases (NE, PR3, and CG), AAT has also been shown to be biologically connected to a network of cytokines, chemokines, and growth factors and may modulate anti-inflammatory/immune-regulatory pathways via interactions with colony-stimulating factor 1, also known as macrophage colony-stimulating factor, and protects against neutrophilic inflammation.^37,39 Cell surface modification of acute phase proteins via glycosylation, which usually occurs during inflammation, may also be absent or changed in AATD.⁴⁰ As AAT is an acute-phase protein, changes in glycosylation may also affect how this protein acts as a modulator of the immune system.⁴⁰ Together, these immune-related processes indicate that the link between AAT and NE in AATD is highly complex.

The strategy of treating the multiple immunological consequences of dysregulated NE in AATD is still under investigation and is further complicated by the fact that AAT is not the only protein to inhibit NE. The effect of decreased functional AAT in regulating NE may be compensated by other proteins in the network, such as secretory leukocyte peptidase inhibitor, elafin, and α2-macroglobulin.^36,41 Therefore, the core mechanism of dysregulated NE elastase breakdown, caused by a decrease in functional AAT, is only part of the immunological story of AATD. Treatment pathways for AATD that include specific adjustments for inflammation need to be considered, as inflammation plays a large role in AATD pathogenesis. This is also demonstrated by the diverse clinical presentations of AATD beyond lung pathologies, such as inflammation of the vasculature caused by autoimmune antibodies to NE, which presents as vasculitis.⁴

Clinically variable disease presentation

The patient’s genotype determines the levels of serum AAT and also the likely rate of lung function decline.⁵ In extreme circumstances, in patients with Null/Null genotypes, which result in no AAT being present, patients may experience a rapid decline in lung function, but Null/Null cases are relatively rare.⁵ Of the deficient variants, the Z allele is associated with greater AAT deficiency than the S allele,⁴ and of the patients with clinical manifestations of AATD, approximately 95% have the Pi*ZZ genotype.⁴² The Z allele results in abnormally forming AAT proteins, which may polymerize as Z-AAT and be retained intracellularly in hepatocytes, resulting in liver disease.^7,43 However, Z-AAT polymers are also found extracellularly in the lung interstitium, where they promote neutrophilic inflammation associated with increased degradation of lung tissue and progression of emphysema.^43,44 Therefore, in patients with the Pi*ZZ genotype, serum AAT levels are low (5–6 μmol/L) and their risk of emphysema development is high.^4,42 Although basal panlobular emphysema is the usual pattern of lung disease with Pi*ZZ, heterogeneity of lung disease is also observed with this genotype. In the EARCO international registry, of patients with the Pi*ZZ genotype, 22.0% have a diagnosis of bronchiectasis and 14.1% have asthma.¹⁶ There are also differences in pulmonary manifestations between sexes in these patients, with more diagnoses of bronchiectasis in women, and more chronic bronchitis, COPD, and emphysema in men.⁴⁵

For patients with AATD, the risk of lung disease may be dependent on additional environmental risk factors, such as cigarette smoke exposure.⁴⁶ Smoking is a crucial modifiable risk factor for AATD since the neutrophilic inflammation induced by smoking is less inhibited than in Pi*MM individuals, thus resulting in protease imbalance, but also because cigarette smoke can inactivate AAT by oxidation.^46
–48 In all AAT-deficient genotypes, even milder combinations such as patients with the Pi*SZ and Pi*MZ heterozygous genotypes, the risk of lung disease is increased in relation to smoke exposure.^49,50 With the Pi*SZ genotype, ever-smokers have been shown to be at a greater risk of lung disease than ever-smoking control individuals (Pi*MM or Pi*MS genotypes); however, the degree to which former smoking status is a risk for lung disease development is unclear.

Former smoking status and AAT levels alone were, however, not a predictor of disease risk in a family-based analysis of patients with the Pi*SZ genotype; here, it is likely that the decline in lung function, post-smoking cessation, is dependent on the presence or absence of airway obstruction at the time of cessation.⁴⁹ Higher degrees of ex-smoking, with a possible threshold effect at higher pack years exposure than patients with the Pi*ZZ genotype, also related to worse lung disease in a British cohort of patients with the Pi*SZ genotype.⁴⁸ Therefore, it seems likely that patients with the Pi*SZ genotype are at risk in the context of significant environmental influences, but may well remain lung-disease-free in its absence. In patients with the Pi*MZ genotype, the risk of lung disease is also strongly influenced by cigarette smoke exposure, with a greater risk in patients with the Pi*MZ genotype who have ever smoked compared with individuals with the Pi*MM genotype who have ever smoked.⁵⁰ For patients with the Pi*MZ genotype who have never smoked, there is no increased risk relative to individuals with the Pi*MM genotype who had never smoked, again indicating that the interaction between smoking and genotype may be more important for lung disease risk than absolute AAT levels alone.⁵⁰ However, there may be an increased risk of liver disease due to the intracellular retention of Z-AAT in Pi*MZ individuals.⁵¹ The relative risk of lung disease in different genotypes versus smoking status is summarized in Table 1.

Table 1.

Probable relative risk of lung disease in different AATD genotypes who have either smoked or never smoked.

No risk means the probable relative risk is no higher than Pi*MM genotype. Colours indicate degree of risk, with green being no risk and shades progressing through orange to red indicating progressively higher risk.

AATD, alpha 1 antitrypsin deficiency.

There are multiple factors involved in the regulation of AAT expression/secretion besides cigarette smoke exposure, including tissue-specific promoter regions in the SERPINA1 transcript and alternative splicing events during transcription that result in different AAT isoforms.⁵³ It has been demonstrated that transcript expression is affected in deficient or Null SERPINA1 variants, which indicates further levels of potential variation in deficient genotypes that may potentially have clinical significance.⁵³

Biomarkers and clinical endpoints in AATD

Biomarkers of disease activity and treatment efficacy

Biomarkers associated with the consequences of AATD will have an important role in furthering the understanding of the condition, helping to address underdiagnosis and indicating treatment efficacy.^33,54 As highlighted in the previous section, AATD can have complex and diverse presentations, leading to the concept of there being different disease phenotypes.⁵⁵ If biomarkers can be identified that characterize different phenotypes, this may be a means to a greater understanding of AATD pathology and a step toward personalized medicine.^54
–56 Biomarkers of this specificity have not yet been characterized for AATD, but for lung conditions in general that have diverse etiologies, such as asthma, COPD, and bronchiectasis, these types of personalized medicine approaches are becoming increasingly important.^56,57

Fibrinopeptides are products of the acute phase protein fibrinogen when cleaved by NE and are potential biomarkers for AATD. Fibrinopeptide Aα-VaL³⁶⁰ is an NE neoepitope and a marker of NE activity and is generated at the point NE is released by neutrophils. The relationship between pre-inhibitory NE activity, as quantified by Aα-VaL³⁶⁰, and the total amount of NE differs in those with AATD compared to those without AATD, demonstrating the specificity of Aα-VaL³⁶⁰ as a candidate AATD biomarker.⁵⁸ Levels of Aα-VaL³⁶⁰ have also been shown to be reduced after 6 months of treatment with AAT therapy in a cohort of 77 patients with the Pi*ZZ genotype.⁵⁸ In addition to Aα-VaL³⁶⁰, plasma levels of the fibrinopeptide Aα-VaL⁵⁴¹, a PR3 neoepitope, have been shown to be reduced with AAT therapy, indicating that Aα-VaL⁵⁴¹ may be a useful biomarker to assess PR3 activity in AATD.⁵⁹

Other biomarkers of interest are desmosine and isodesmosine. Desmosine and isodesmosine are cross-linked elastin peptides released when elastin is broken down,⁵⁴ and levels may be measured in urine, plasma, or induced sputum.⁶⁰ Levels of desmosine and isodesmosine were measured in plasma samples from patients receiving AAT therapy in the RAPID randomized controlled trial (RAPID-RCT; NCT00261833) and RAPID open-label extension (RAPID-OLE; NCT00670007), and were found to be reduced in patients receiving AAT, from month 3 through month 48, indicating reduced elastin degradation.⁶¹ Reduced levels of desmosine and isodesmosine have also been demonstrated in bronchoalveolar lavage fluid (BALF) from patients receiving AAT therapy.⁶² Together, these studies demonstrate how desmosine and isodesmosine can be useful biomarkers to assess the efficacy of AAT therapy in patients with AATD. However, caution should be exercised with using desmosine as a urinary biomarker. Despite elevated levels of urinary desmosine being associated with exacerbation status in patients with usual (Pi*MM) COPD,⁶³ in a recent cohort of patients with severe AATD, half of all urinary desmosine measurements were at the upper limit of the desmosine assay and so a meaningful analysis in these patients could not be performed.⁶⁴

The efficacy of AAT therapy was further explored in a single-/double-dosing study that analyzed the presence of Aα-VaL³⁶⁰ in plasma, and desmosine and isodesmosine in BALF and plasma.⁶⁵ Double-dosing of AAT (120 mg/mL/week) restored AAT to normal levels in patients with AATD and also significantly reduced Aα-VaL³⁶⁰ levels, as well as desmosine and isodesmosine levels in plasma, along with serine protease activity (NE and CG) in BALF.⁶⁵ Measuring elastase levels in BALF may also be a useful biomarker of disease activity, although it may be less specific than Aα-VaL³⁶⁰ or desmosine and isodesmosine. These observed changes indicate the potential for use of such biomarkers in future clinical trials to assess AAT therapy efficacy.

C-reactive protein (CRP) is a clinical marker of systemic inflammation, with its levels significantly elevated during inflammatory episodes.^66,67 Chronic systemic inflammation may persist in patients with AATD and can be further exacerbated during acute phase reactions to inflammation/infection.^66,67 Since AAT is an acute phase reactant, its levels transiently increase, alongside CRP levels in response to infection.^66,68 In patients with AATD-related COPD, treatment with AAT therapy has been shown to reduce CRP levels, indicating that AAT therapy effectively decreases systemic inflammation.⁶⁷

The measurement of CRP levels during the diagnosis of AATD can help determine whether AAT levels are transiently elevated. This is particularly important if AAT levels are being used to assess whether they fall within the normal range and require no further diagnostic evaluation.^3,68 Adjusted AAT levels can be calculated based on the level of CRP elevation, and the AAT level can be reassessed once CRP levels have normalized.^3,68 However, if genotyping is performed concurrently with AAT level measurement, CRP measurements may not be necessary.⁶⁹

Biomarkers of disease genotype

The candidate biomarkers Aα-VaL³⁶⁰ or desmosine and isodesmosine are markers of disease activity; however, other specific markers of disease may also be valuable in AATD. The circulating polymer, Z-AAT, may be such a biomarker as it is present in patients with the Pi*ZZ and Pi*SZ genotype, as well as any other genotype that has the Z allele. A cohort study of Dutch patients with the Pi*ZZ genotype demonstrated a correlation between plasma levels of Z-AAT and multiple markers of liver injury: gamma-glutamyltransferase, a marker of metabolic liver disease (and possibly of lung disease)⁷⁰; glutamate dehydrogenase, which reflects leakage from damaged hepatocytes; and triglycerides, which may be indicative of endoplasmic reticulum stress.⁷¹ This may be expected given that the majority of AAT is synthesized in hepatocytes. In this study, there was no observed relationship between Z-AAT polymers and FEV₁ or the carbon monoxide transfer coefficient, leading to the conclusion that levels of circulating Z-AAT polymers may not reflect levels of lung disease.⁷¹ However, the opposite was found in a more recent study, where Z-AAT polymers correlated with lung function, at least in the absence of AAT therapy.⁷² Further studies are needed though, as blood samples taken at random points in the disease course may not reflect preceding lung damage.⁷¹ It should also be noted that FEV₁ is a poor surrogate measure for emphysema; therefore, these lung function measures may not be the most sensitive measures of lung disease.³

Imaging as a clinical endpoint

Biological biomarkers may not be the only biomarkers of value in AATD; imaging biomarkers may also be useful. Computed tomography (CT) densitometry is sensitive to changes in lung density and may be a better indicator of emphysema than FEV₁, which is a measure of lung function, and therefore, only a surrogate measure of emphysema.^3,73,74 CT densitometry has been demonstrated to be related to the progression of decline in FEV₁ and a surrogate outcome measure for survival in AATD.^75,76 In clinical trials, a reduction in the progression of emphysema with AAT therapy has been shown using CT densitometry.^77,78 For dose adjustment trials, such as determining the efficacy of higher doses of AAT (SPARTA clinical trial, NCT01983241), a more direct metric such as CT densitometry, may be more sensitive to changes than functional FEV₁ endpoints.⁷⁹

However, as the methods associated with these biomarkers become more established, standardization will be required to enable their use as clinical trial endpoints. For imaging biomarkers associated with CT densitometry, this may be less straightforward than for biomarkers measured using laboratory assays. Variability in the functional characteristics of CT scanners between sites makes repeatability and reliability challenging, as the ability to optimize scanning parameters reduces conformity.⁸⁰ This should not be inferred as a weakness of CT; the ability to optimize protocols for clinical need is valuable in clinical use but does present a challenge when making population comparisons between different imaging centers.⁸⁰ There are also ionizing radiation exposure risks associated with recurrent CT imaging, which places ethical considerations on scanning normal populations and performing sequential scans on patients.^74,81 Costs and accessibility to CT scanners are also a consideration, particularly with the large number of products in development for AATD, which collectively will require large numbers of patients, and thus many centers to participate.

Clinical trials in AATD

FEV₁ as a primary endpoint

The design of clinical trials for AATD has been largely influenced by observations in 1997,⁸² and 1998,⁸³ where AAT therapy demonstrated a beneficial effect on slowing the rate of FEV₁ decline in subsets of patients with AATD, and by trials in COPD unrelated to AATD, where FEV₁ is a standard endpoint with an established minimal clinically important difference.^84,85 As a result, traditionally, guidelines have indicated that FEV₁ should be the standard endpoint in evaluating AATD, and FEV₁ has become the key metric of evaluating lung function in patients with AATD.²³ However, the original studies on the effects of AAT therapy only observed an effect in patients with either an FEV₁ predicted of 31%–65%,⁸² or 35%–49%,⁸³ which correlates with subsequent guidance on indicative FEV₁ values for recommending AAT therapy.²³

The use of FEV₁ as an endpoint is predicated on a pathological association between a lack of functional AAT and dysregulated NE breaking down elastin. It is established that low serum AAT levels are associated with an increased risk of emphysema.⁷ However, FEV₁ as a measure of lung function is a poor surrogate of emphysema.³

In patients referred for AATD testing due to specific respiratory reasons, or who demonstrated airflow obstruction during initial spirometry, FEV₁ showed an initial rapid decline between the ages of 20 and 50 years old, followed by a plateau from 50 years and older.⁸⁶ In these latter patients, AATD diagnosis may have occurred once lung function had already declined.⁸⁶ Once the decline in lung function has reached a plateau, it is less likely that treatment effects will be observed using FEV₁. However, in this same cohort, a survival advantage was demonstrated from AAT therapy that was decoupled from FEV₁ decline.⁸⁶ This indicates that clinical trial design should consider the population enrolled; if the population has already reached a plateau in lung function, FEV₁ decline is unlikely to be a sensitive metric.

As a consequence of FEV₁ only being a functional surrogate of emphysema, and the decline in FEV₁ plateauing as the decline in lung function progresses, effects in clinical trials may be attenuated in the full population and so sub-analyses are required to see an effect.^82,83 The importance of sub-analyses is demonstrated by the studies in 1997 and 1998 that showed a decrease in FEV₁ decline in a subset of the population treated with AAT therapy,^82,83 and the decline in FEV₁ observed in GOLD stage 2 lung-indexed patients receiving AAT in a recent multinational registry analysis.⁸⁶ Comparisons between analyses may also be difficult to resolve, or seem contradictory, due to the limitations of the FEV₁ endpoint. For instance, a retrospective study on the long-term effect of AAT therapy on FEV₁ did not detect a significant difference in the annual decline of FEV₁ over a mean AAT treatment period of 8.6 years.⁸⁷ Projections of the number of patients required to detect a difference in FEV₁ also suggest that the sample size would be prohibitive in this rare disease.⁸⁸

Alternative endpoints to FEV₁

Trials that have shown a population-level benefit for AAT therapy have used an alternative metric to FEV₁. The RAPID-RCT and RAPID-OLE showed a decrease in lung density loss using CT densitometry at total lung capacity in patients with serum AAT levels <11 µM and receiving AAT therapy when compared with placebo.^77,78 CT densitometry, a more direct measure of emphysema progression than FEV₁, showed greater sensitivity to lung injury than FEV₁, which was also measured in these trials and was not significantly different between the AAT therapy and placebo groups.⁷⁷ This does, however, raise ethical questions for clinical trials going forward regarding the inclusion of placebo populations using CT densitometry; if efficacy has been demonstrated with AAT therapy, are placebo populations justified?^74,86

In addition to showing an effect on the rate of lung density loss, if AAT therapy acts on the causal pathway of AATD, then an effect on mortality would also be expected. This is not because AAT therapy has a reparatory effect on lung function, but because it delays lung function decline. Effects on survival have been observed with AAT therapy, which in one study was demonstrated to be decoupled from FEV₁ decline.^83,86 In contrast, in a 7-year longitudinal study that was powered to explore a survival effect from AAT therapy, an improvement in mortality was not reliably demonstrated.⁸⁹ However, this study did demonstrate a difference in the rate of quality of life (QoL) decline, with patients who received AAT therapy having a slower decline in QoL versus patients who did not receive AAT therapy.⁸⁹ Powering clinical trials for important measures such as survival and QoL is more complex in rare diseases, where sample sizes are limited, but would be beneficial to expand disease understanding.

Another potential alternative endpoint to FEV₁ is the lung clearance index (LCI). The LCI has been used as a primary endpoint in trials of patients with cystic fibrosis and is derived from the multiple breath nitrogen-washout test.^90
–92 It serves as an indicator of ventilation inhomogeneity and is particularly sensitive to early lung disease.⁹² The LCI has been shown to detect early lung changes in younger AATD individuals more frequently than traditional spirometry measures such as FEV1.⁹² The reliability and responsiveness of the LCI as a potential endpoint for bronchiectasis clinical trials have been evaluated, with mixed recommendations.^93,94 However, the LCI is not currently an established endpoint in AATD studies.

Going forward, clinical trials in AATD would benefit from the development of further biomarkers, such as the biological biomarkers outlined previously. However, standardization of collection methods, handling, and storage will all be necessary with biological samples for reliable conclusions to be drawn and for the use of these biomarkers as clinical trial endpoints. Further standardization may be achieved by pharmaceutical and/or diagnostic companies providing validated enzyme-linked immunosorbent assays for measuring levels of such biomarkers.

Unlocking patient access to treatment

Improving AATD diagnosis

One of the major barriers to treating AATD is the underdiagnosis of the condition. Worldwide estimates indicate that as little as 0.35% of expected AATD cases are actually detected.⁹⁵ However, in Europe, estimates from a survey of physicians treating AATD indicated that most physicians believed the diagnosis rate was higher, at approximately 15%.^96,97 A key reason why it is important to improve the rate of diagnosis is that diagnosis of AATD can often occur after the patient has already experienced a substantial decline in lung function.⁸⁶

Guidance from the World Health Organization recommends testing all patients diagnosed with COPD or adult-onset asthma for AATD,^3,98 which should be implemented. However, at present, there are barriers to the universal testing of these patients, including low disease awareness, and insufficient familiarity with and implementation of guidelines.^4,99 A consequence of this is a low referral rate to specialists for further diagnosis.¹⁰⁰ A recent European-wide survey of physicians identified heterogeneity in approaches to AATD testing, including in the methods used for genetic testing of patients with pulmonary presentations.¹⁰⁰ However, the survey also showed that genetic testing was reported to be widely available, often by sending samples to specialist laboratories.¹⁰⁰ The lack of standardization in protocols and awareness of genetic testing requirements indicate a need for education and standardization in order to improve diagnosis rates.¹⁰⁰

AATD symptoms, being consistent with other lung conditions such as emphysema, chronic bronchitis, or asthma, results in AATD often being under-recognized.⁴ Furthermore, individuals may be symptomatic for >5 years before diagnosis, which can result in a greater symptom burden prior to treatment.^4,6,99 Detection of AATD, therefore, needs to improve; where guidelines for testing exist, they need to be implemented.⁹ Enhancing detection rates may also involve educating clinicians and the use of reminder tools to prompt physicians, or patients, to test for AATD.^9,101

Benefits in detection may also come from the large number of lung CT scans increasingly being performed, internationally, for lung cancer screening and CT coronary angiography. These scans may be able to incidentally detect early stages of emphysema, which can then be referred to for specific AATD diagnostics. Although the inclusion criteria for lung cancer screening and CT coronary angiography do not allow for very early detection of AATD, the increased detection of AATD cases in smoking populations can provide valuable information for the understanding of the disease and potentially for individual therapy and family screening.

AATD incidence and access to AATD-specific treatment is often variable between countries and by demography.^5,34 In Europe, where healthcare provision is local, there is variability in the provision of AAT therapy in countries both inside and outside of the European Union.³ However, it is recommended that AATD reference centers of excellence should supervise patient management and European initiatives such as the European Reference Network for Rare Lung Diseases (ERN-LUNG) will hopefully widen access to AATD programs.^3,6 National and international registries can also improve patient management and access to therapy.³

A key consideration in all these points regarding access to treatment is the fact that AATD is a rare disease.³ Patient groups are therefore small, and with geographical variability in treatment and management, population data within international registries may be too variable to be conclusive without standardization.⁸⁹ Standardization may also improve the accuracy and reliability of AATD diagnosis.^6,102 Initiatives such as the EARCO Registry and ERN-LUNG’s AATD Core Network are important for such standardization and cross border cooperation.^3,6,103

Understanding available treatment options

Treatment options for AATD should consider the relative benefits of all available treatments for AATD, not exclusively AAT therapy, in order to maximize the benefits to patients. The first consideration may be the removal of known risk factors such as smoking and exposure to mineral dust or smoke and fumes, which can lead to poorer outcomes and lung function in patients with AATD.^{4,46,49,50,104} As cigarette smoke has an oxidative effect of inactivating AAT,⁴⁶ cessation of smoking should be considered as a primary intervention that can improve outcomes.¹⁰⁵

The removal of risk factors may also include non-environmental factors. Progression of AATD is also impacted by the frequency with which symptom exacerbations are experienced, and therefore, treatment of exacerbations should be an integral aspect of disease management.^106,107 Prompt intervention with antibiotics for infections, when necessary, is an important consideration with AATD, as NE activity increases at exacerbation onset, causing potential for disease progression.¹⁰⁷ AAT therapy can reduce exacerbation severity but does not affect their frequency.^107,108 Some vaccinations are also recommended as a preventative measure for AATD and should follow local guidelines for people with COPD; these may include interventions for influenza, COVID-19, respiratory syncytial virus, pneumococci, pertussis, and shingles.^104,109 Therefore, treatments other than AAT therapy may also be necessary for patients with AATD.

As well as managing specific disease exacerbations, general disease management can also impact a patient’s health outcomes.^104,110 Patient-focused education and other initiatives provided by the Alpha-1 Disease Management and Prevention Program can make patients more informed of AATD, as well as improve medication usage and QoL.^104,110,111 Specific exercise interventions such as the impact of pulmonary rehabilitation in AATD have also been studied.^107,112 Patients have been demonstrated to experience increased exercise capacity and QoL improvements with pulmonary rehabilitation exercises, but less so than those with non-AATD COPD.¹¹² Therefore, further optimization is needed for such interventions to improve the outcomes for patients and the quantifiable evidence of an effect in patients with AATD.¹¹²

In advanced and severe AATD, when respiratory failure is encountered at the latter stages of the disease, lung transplantation (single or bilateral) is the only effective treatment available.¹¹³ Data suggests survival rates for patients who have had a lung transplant are higher for COPD patients with AATD than those without AATD, although the relative mortality risk due to post-transplant infection or associated liver disease is greater for COPD patients with AATD.¹¹³ Lung volume reduction surgery and endobronchial lung volume reduction are also potential options for treatment prior to lung transplantation, but further evidence is needed to provide a sound basis for recommending these treatments.¹⁰⁴ As part of the considerations for unlocking access to treatment, the relative value of these non-pharmacological interventions needs to be understood, alongside the value of AAT therapy, so that access can be advised where appropriate. AATD reference centers of excellence supervising patient management and ERN-LUNG initiatives may be integral in sharing this advice.^3,6

Enhancing efficacy of AAT therapy

Where AAT therapy is indicated in patients with severe AATD (i.e., with serum AAT <11 μM, evidence of lung impairment, including emphysema, and an FEV₁ ⩽65%),¹⁰⁴ there may be scope to improve the impact of AAT therapy. AAT therapy has been demonstrated to be beneficial with no safety concerns in relevant patient cohorts,^77,78,114 and standardizing access to AAT therapy, where indicated, will make treatment more internationally equitable.³ In Europe, reimbursement for AAT therapy is decided at the national level.³ To enable wider access to AAT therapy, patients may need to be involved with regulatory access for AATD treatment; in countries where there is no reimbursement for AAT therapy, patients can be central to policy making. Patients’ understanding of disease burden is important to the regulatory processes and can communicate the beneficial effects of treatment to payers. Similarly, disease foundations and patient organizations can empower patients to be active during regulatory approval. Examples of where this approach has been successful, and in particular where patient organizations have been involved with the development of therapies, can be seen in the field of cystic fibrosis.^115
–117

Dose optimization may be another area where the efficacy of AAT therapy can be enhanced. At present, the standard dose is 60 mg/kg/week; however, the greater benefit was noted in the RAPID trial where serum concentrations of AAT were higher.⁷⁷ Here, the rate of lung function decline was inversely related to AAT serum concentration, leading to questions of whether dosing should be individualized to serum trough levels of AAT.^3,77 There are also questions regarding whether the threshold for AAT therapy should be set at serum levels of 11 μM, or whether other clinical indicators should be used as evidence, since knowledge in the field has advanced since this putative protective threshold was first suggested in 1987.^105,118 Additionally, a double-dosing study found that increasing AAT levels into the normal range through higher dosing (120 mg/kg/week) was shown to have a more robust impact on the clinical outcomes of patients with AATD.⁶⁵ Therefore, there may be scope to improving and personalizing the doses received during AAT therapy.

Although the RAPID clinical trial program demonstrated a disease-modifying effect of AAT therapy on AATD progression,^77,78 improvements in lung function, QoL, and exacerbation incidence/severity were not demonstrated.^77,78 To advance our understanding of the optimal treatment strategy, endpoints and protocols need to be improved in clinical trials using AAT therapy. Alternative surrogate outcome measures of lung injury and function need to be developed. The previously discussed progress using biomarkers may be valuable in this regard. Reimbursement for AAT therapy may also increase if the cost-effectiveness of the clinical intervention can be demonstrated.

Patient experience of AAT therapy

For patients already receiving AAT therapy, the quality of their experience is also important. For patients who need frequent access to an infusion therapy center, commitment to AAT therapy can be challenging.^96,107 Self-administration of AAT therapy may improve the convenience of treatment in such instances, particularly for those in employment,^6,96,107 and has proved to be particularly useful during the COVID-19 pandemic, both for patient convenience and to avoid the risk of COVID infection.¹¹⁹ Although relatively few patients self-administer at present, a patient satisfaction survey in the United States reported that all self-infusing patients were either “satisfied” or “very satisfied” with the process, with very few adverse events reported.⁶ Self-administration offers an additional level of treatment flexibility that may benefit a selection of patients for whom this is suitable, providing they receive the appropriate support and education to do so.⁶ Methods of AAT delivery using inhalation are also being investigated and may provide an additional method of self-administration if trials prove to be successful.¹⁰⁴

Therapies in development

Future therapeutic interventions have the potential to change the treatment landscape and further unlock access to treatment for patients with AATD. Synthetic forms of AAT, referred to as recombinant AAT, are in development as an alternative to the currently approved human-derived AAT therapies.^120,121 In addition, understanding the pathological significance of circulating Z-AAT and reliably measuring it may provide opportunities for innovative personalized medicine. Interventions using RNA interference methods are feasible in instances like AATD where there is a known genetic mechanism. Potential treatments with small interfering RNA molecules that interfere with the production of the pathogenic Z-AAT proteins and polymers are being trialed and developed with promising results.^122
–124 RNA-based approaches that both reduce Z-AAT polymers and improve M-AAT protein production are also in development, with an early-phase human trial currently in progress, which is due for completion in July, 2025.^125,126 Other gene therapy techniques, including gene repair, also provide a mechanism to edit the mutant variants of the SERPINA1 gene.^127,128 However, the applications of these gene editing tools are still in development in the field of AATD.^33,128

Conclusion

Although much is known about AATD, and the general epidemiology and pathology is well established, advancements are still needed to fully understand the disease pathogenesis. The heterogeneity of symptoms and the emergence of disease phenotypes indicates more needs to be understood about the multiple underlying pathogenic processes involved in AATD. The role of inflammatory processes in the development of lung disease, alongside the breakdown of elastin, is increasingly becoming evident as being critical to understanding. For therapeutic interventions to provide maximal benefit, improved endpoints, metrics of disease progression, and treatment efficacy need to be determined. Standardization of protocols and processes is required to ensure there is consistency across AATD studies, testing, diagnosis, and disease management. This is particularly relevant where data is limited due to AATD being a rare disease. Implementation of widespread testing and greater disease awareness are also needed to help identify individuals at risk who may benefit from specific treatment. Ultimately, overcoming barriers to treatment is crucial for improving patient outcomes and patients should be empowered to play a key role in gaining greater access to AATD therapies.

Footnotes

Acknowledgements

Medical writing assistance and editorial support were provided by Michael Simpson and Ben McDermott of Bioscript Group Ltd., Macclesfield, UK.

Declarations

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Advancing the understanding and treatment of lung pathologies associated with alpha 1 antitrypsin deficiency

Abstract

Keywords

Introduction

Disease pathogenesis in AATD

Pathogenic processes

Clinically variable disease presentation

Biomarkers and clinical endpoints in AATD

Biomarkers of disease activity and treatment efficacy

Biomarkers of disease genotype

Imaging as a clinical endpoint

Clinical trials in AATD

FEV1 as a primary endpoint

Alternative endpoints to FEV1

Unlocking patient access to treatment

Improving AATD diagnosis

Understanding available treatment options

Enhancing efficacy of AAT therapy

Patient experience of AAT therapy

Therapies in development

Conclusion

Footnotes

Acknowledgements

Declarations

References

FEV₁ as a primary endpoint

Alternative endpoints to FEV₁