Alvelestat (MPH-966): A Comprehensive Profile of an Investigational Oral Neutrophil Elastase Inhibitor for Alpha-1 Antitrypsin Deficiency

I. Executive Summary

Alvelestat, also identified by the development codes AZD-9668 and MPH-966, is an investigational, orally bioavailable, small molecule drug engineered as a selective and reversible inhibitor of human neutrophil elastase (NE).[1] The primary therapeutic focus for alvelestat is the treatment of lung disease associated with severe Alpha-1 Antitrypsin Deficiency (AATD-LD), a rare, genetic condition characterized by progressive lung destruction.[4] By directly targeting the protease-antiprotease imbalance that defines AATD-LD pathophysiology, alvelestat aims to inhibit the enzymatic activity of NE and thereby mitigate the ongoing destruction of lung tissue, offering a potential disease-modifying approach.[3]

The clinical development program, led by Mereo BioPharma, has yielded critical insights from two complementary Phase 2 studies, ASTRAEUS and ATALANTa. These trials demonstrated a clear dose-dependent efficacy profile. The higher dose of 240 mg administered twice daily (BID) resulted in statistically significant reductions in key biomarkers of both NE activity and active elastin degradation, namely Aα-Val360 and desmosine. In contrast, the lower 120 mg BID dose, while effectively suppressing the target enzyme, did not consistently translate this suppression into a significant impact on these downstream markers of disease activity.[5] Furthermore, encouraging signals of clinical benefit were observed in patient-reported outcomes, specifically improvements in the St. George's Respiratory Questionnaire (SGRQ) scores.[4]

The safety profile of alvelestat has been characterized as generally manageable and acceptable for the target patient population. The most frequently reported adverse event is headache, which appears to be dose-dependent but can be effectively managed through a dose-escalation regimen upon treatment initiation.[5] To date, no major safety signals have been identified that would preclude the continued development of the compound.[5]

Originally discovered by AstraZeneca, alvelestat's development is now being advanced by Mereo BioPharma, which has successfully navigated a clear regulatory path forward.[11] The program has garnered significant regulatory support, including Orphan Drug and Fast Track designations from the U.S. Food and Drug Administration (FDA) and Orphan Designation from the European Commission, which provide substantial development and commercial incentives.[4] Alvelestat is now positioned to enter a global pivotal Phase 3 study. Mereo BioPharma is actively exploring strategic partnerships to support this final stage of development and potential commercialization.[12] In conclusion, alvelestat represents a promising, potentially first-in-class oral therapeutic for AATD-LD, with its future success contingent upon the positive outcome of its well-defined Phase 3 program.

II. Therapeutic Rationale: Targeting Neutrophil Elastase in AATD-LD

Pathophysiology of Alpha-1 Antitrypsin Deficiency

Alpha-1 Antitrypsin Deficiency (AATD) is a rare, autosomal co-dominant genetic disorder stemming from mutations in the SERPINA1 gene. These mutations lead to the production of a misfolded alpha-1 antitrypsin (AAT) protein or, in some cases, its complete absence.[4] The primary physiological role of the AAT protein, a serine protease inhibitor (serpin), is to protect bodily tissues from damage caused by proteolytic enzymes, most notably neutrophil elastase (NE).[4] In individuals with severe AATD (e.g., Pi

ZZ, PiNull genotypes), circulating levels of functional AAT are critically low, resulting in a profound protease-antiprotease imbalance, particularly within the lower respiratory tract.[4] This imbalance permits unopposed NE activity, which leads to the progressive and irreversible degradation of elastin and other essential structural proteins in the lung parenchyma. This relentless enzymatic destruction of the lung's elastic matrix is the direct cause of early-onset panacinar emphysema and Chronic Obstructive Pulmonary Disease (COPD), which are the clinical hallmarks of AATD-associated lung disease.[4]

The Central Role of Neutrophil Elastase

Neutrophil elastase (UniProt ID: P08246), the molecular target of alvelestat, is a powerful serine protease stored in the azurophilic granules of neutrophils.[21] It is a key component of the innate immune system, released at sites of inflammation and infection to degrade foreign proteins and assist in pathogen clearance.[3] However, its activity is highly destructive and must be tightly regulated by endogenous inhibitors, primarily AAT.[4] In the context of AATD, or in other neutrophilic inflammatory lung diseases where NE is upregulated, its unchecked activity contributes significantly to pathophysiology. NE degrades a wide array of extracellular matrix components, including elastin, collagen, and fibronectin, directly causing the structural lung damage seen in emphysema.[2] Beyond its direct proteolytic effects, NE also perpetuates the inflammatory cycle by cleaving cell surface receptors, inactivating other protease inhibitors, and acting as a potent secretagogue for mucus, further contributing to the signs and symptoms of chronic lung disease.[2]

Current Standard of Care and Unmet Medical Needs

The only specific therapy currently approved for AATD-LD is augmentation therapy. This treatment involves lifelong, weekly intravenous infusions of pooled, plasma-derived human AAT protein to raise circulating levels into a theoretically protective range.[4] While augmentation therapy has been shown to slow the rate of lung density loss as measured by CT scans, its clinical efficacy is not universally recognized, and it has not definitively been shown to alter the rate of lung function decline (FEV1), reduce exacerbation frequency, or improve survival in a statistically robust manner.[18]

This standard of care carries significant limitations and leaves a substantial unmet medical need. The treatment is exceptionally burdensome for patients, requiring weekly hospital visits or home infusions.[18] It is also extremely expensive.[18] From a pharmacological perspective, the intravenously administered protein has limited penetration into the lung tissue and epithelial lining fluid where NE activity is highest.[19] Furthermore, the AAT protein itself is susceptible to oxidative inactivation at sites of intense inflammation, potentially reducing its efficacy when it is needed most. Finally, the fixed-dose regimen does not allow for titration to cover periods of acute inflammation, such as during respiratory infections, when NE release and subsequent lung damage are likely greatest.[19] These limitations underscore the urgent need for a more convenient, effective, and targeted therapeutic option for patients with AATD-LD.

Alvelestat's Value Proposition

Alvelestat is being developed as a direct response to the shortcomings of augmentation therapy. Its value proposition is rooted in a fundamentally different therapeutic strategy. Instead of replacing the deficient protein, alvelestat is a small molecule designed to directly inhibit the pathogenic enzyme, NE.[3] This approach offers several potential advantages that position it as a disease-modifying therapy rather than a simple replacement. Its oral route of administration would dramatically reduce the treatment burden and improve quality of life compared to weekly infusions.[3] As a small molecule, it is expected to achieve significant lung penetration, delivering the inhibitor directly to the site of tissue damage.[19] Furthermore, alvelestat is not susceptible to oxidative inactivation and is active against both soluble and cell-bound forms of NE, suggesting it may maintain its efficacy even within the harsh inflammatory microenvironment of the AATD lung.[19] By directly targeting the enzymatic driver of lung destruction, alvelestat has the potential to offer a more profound and consistent therapeutic effect, representing a paradigm shift from symptom management and protein replacement toward true disease modification.

III. Molecular and Pharmaceutical Profile

Alvelestat is a synthetically derived small molecule classified as an investigational drug.[11] Its identity and chemical characteristics are well-defined across multiple chemical and pharmacological databases.

Drug Identification

The compound is universally known by its International Nonproprietary Name (INN), Alvelestat.[29] During its development history, it has been referred to by several code names, most notably AZD-9668 and AZD9668 during its initial investigation by AstraZeneca, and subsequently as MPH-966 and MPH966 by Mereo BioPharma.[2] The CAS Registry Number for the free base form of the molecule is 848141-11-7.[21] Different salt forms of the compound have also been synthesized, including a tosylate salt (CAS 1240425-05-1) and a hydrochloride (HCl) salt (CAS 1240425-11-9).[2] Key database identifiers include its DrugBank Accession Number (DB11863), FDA Unique Ingredient Identifier (UNII 6Y5629322X), and ChEMBL ID (CHEMBL3617964).[1]

Chemical Structure and Properties

Alvelestat's chemical formula is , corresponding to an average molecular weight of approximately 545.54 g/mol and a monoisotopic mass of 545.134459871 Da.[21] The molecule is structurally complex, belonging to several chemical classes including amides, pyrazoles, and pyridines.[11] Its formal IUPAC name is N-[(5-methanesulfonylpyridin-2-yl)methyl]-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide.[21] The structure is achiral.[29] The molecule's connectivity can be represented by the SMILES string:

CN1N=CC=C1C1=C(C)N(C2=CC=CC(=C2)C(F)(F)F)C(=O)C(=C1)C(=O)NCC1=NC=C(C=C1)S(C)(=O)=O.[21]

Physical and Formulation Properties

In its solid state, alvelestat presents as a white to light yellow powder.[30] It exhibits very low aqueous solubility, with a calculated water solubility of approximately 0.00275 mg/mL, posing a challenge for aqueous-based formulations.[21] Conversely, it is readily soluble in organic solvents such as dimethyl sulfoxide (DMSO), with reported solubilities exceeding 33 mg/mL.[30] For preclinical research, specific protocols have been developed to create solutions or suspensions using co-solvents and excipients like polyethylene glycol (PEG300, PEG400), Tween-80, and corn oil, which is indicative of its lipophilic nature.[30] Its acid-base properties are characterized by a strongly acidic pKa of 12.17 and a weakly basic pKa of 2.0.[21] For long-term preservation of the solid compound, storage at -20°C is recommended, which ensures stability for up to three years.[30]

Table 1: Alvelestat Identification and Key Physicochemical Properties

Property	Value	Source(s)
Generic Name	Alvelestat	21
Key Synonyms	AZD-9668, MPH-966	2
DrugBank ID	DB11863	21
CAS Number	848141-11-7 (free base)	21
Molecular Formula		21
Average Molecular Weight	545.54 g/mol	21
IUPAC Name	N-[(5-methanesulfonylpyridin-2-yl)methyl]-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide	21
SMILES String	CN1N=CC=C1C1=C(C)N(C2=CC=CC(=C2)C(F)(F)F)C(=O)C(=C1)C(=O)NCC1=NC=C(C=C1)S(C)(=O)=O	21
Physical Appearance	White to light yellow solid powder	30
Water Solubility	0.00275 mg/mL	21

IV. Pharmacological Profile: Mechanism and Activity

Primary Mechanism of Action

The primary mechanism of action of alvelestat is the potent, selective, and reversible inhibition of human neutrophil elastase (NE), a serine protease.[1] Upon administration, alvelestat binds to NE and blocks its enzymatic activity, thereby preventing the degradation of elastin and other matrix proteins in the lung.[3] A key feature of its interaction with NE is its binding kinetics. Alvelestat exhibits a very rapid association rate (

) and a relatively fast dissociation rate (), with the resulting complex having a half-life of only seconds to minutes.[22] This fully reversible binding profile means that the inhibitory effect is non-covalent and is maintained only as long as sufficient plasma concentrations of the drug are present at the site of action.[22] This contrasts with covalent inhibitors, which form a more permanent bond with the enzyme.

Pharmacodynamics: Potency and Selectivity

Alvelestat demonstrates high-affinity binding and potent inhibition of its target enzyme. Multiple in vitro assays have consistently characterized its potency in the low nanomolar range. Key metrics reported include an inhibition constant () of 9.4 nM, a dissociation constant () of 9.5 nM, a half-maximal inhibitory concentration () of 12 nM, and a  (negative logarithm of ) of 7.9.[2]

A critical attribute of alvelestat's pharmacological profile is its high degree of selectivity. It is reported to be at least 600-fold more selective for human NE over other related serine proteases, such as pancreatic elastase and proteinase-3 (Pr-3).[32] This high selectivity is a crucial feature, as it minimizes the potential for off-target effects that could arise from the inhibition of other physiologically important proteases, thereby contributing to a more favorable safety profile.

Table 2: Summary of Alvelestat Potency and Selectivity Data

Parameter	Value	Source(s)
Target	Human Neutrophil Elastase (ELANE)	21
(Inhibition Constant)	9.4 nM	30
	12 nM	33
	7.9	32
Binding Characteristic	Reversible, rapid on/off rate	22
Selectivity	>600-fold vs. other serine proteases	32

Non-Clinical (Preclinical) Evidence

The therapeutic potential of alvelestat was established through a series of non-clinical studies.

• In Vitro Activity: In cell-based assays, alvelestat demonstrated the ability to inhibit NE activity in complex biological environments, such as zymosan-stimulated whole blood, as well as NE released from or bound to the surface of stimulated neutrophils.[2] Furthermore, studies using cultured human bronchial epithelial (HBE) and alveolar epithelial (A549) cells showed that alvelestat treatment could decrease cell death and reduce the secretion of key pro-inflammatory cytokines, including interleukin-1β ( ), interleukin-6 (), and tumor necrosis factor-alpha ().[2] These findings provided early evidence of its cytoprotective and anti-inflammatory properties.
• In Vivo Activity: The efficacy of alvelestat was further confirmed in animal models of inflammatory lung disease. Oral administration of the drug to mice and rats was shown to prevent acute lung injury (measured by lung hemorrhage) induced by the instillation of human NE.[22] In a mouse model of cigarette smoke-induced airway inflammation, oral alvelestat treatment significantly reduced the influx of neutrophils into the lungs and lowered the levels of  in bronchoalveolar lavage (BAL) fluid.[22] These preclinical results provided robust proof-of-concept for the drug's ability to suppress NE-driven inflammation and tissue damage in vivo.

Clinical Pharmacokinetics and Pharmacodynamics (PK/PD)

Human studies have characterized alvelestat's pharmacokinetic (PK) profile, which in turn has been crucial for understanding its clinical pharmacodynamic (PD) effects and for guiding dose selection.

• Absorption and Disposition: Alvelestat is orally bioavailable and exhibits dose-linear pharmacokinetics.[1] Following oral administration, it is rapidly absorbed, with the median time to reach peak plasma concentration ( ) occurring between 0.5 and 1.5 hours.[24]
• Elimination and Dosing Regimen: The drug has a short elimination half-life. This property necessitates a twice-daily (BID) dosing regimen to maintain therapeutic plasma concentrations throughout the dosing interval.[24] With BID dosing, steady-state concentrations are achieved rapidly, typically by the second day of treatment, with negligible drug accumulation over time. This predictable exposure profile simplifies dosing and reduces the risk of unexpected toxicity from accumulation.[24]
• PK/PD Relationship and Dose Justification: The integration of PK and PD data has been fundamental to the successful clinical development of alvelestat. A critical determination from early clinical work was that a sustained plasma concentration of greater than 300 nM is required to achieve a clinically meaningful inhibitory effect on NE activity.[24] Subsequent modeling and clinical trial data established that a minimum oral dose of 240 mg BID is required to consistently achieve and maintain this target concentration in patients.[24] This scientific understanding provides a direct and powerful explanation for the results observed in the Phase 2 clinical program. The ASTRAEUS trial demonstrated that the 240 mg BID dose led to significant reductions in downstream biomarkers of disease activity, whereas the 120 mg BID dose, which would be expected to produce plasma concentrations below the 300 nM threshold for much of the dosing interval, did not.[5] This tight correlation between the scientifically predicted effective dose and the clinically observed effective dose provides a high degree of confidence in the selection of the 240 mg BID regimen for the pivotal Phase 3 study, significantly de-risking a key variable for late-stage development.

V. Clinical Development and Efficacy Analysis

The clinical development path of alvelestat has been one of strategic repositioning, moving from broad respiratory indications to a focused, biomarker-driven approach in a rare disease population.

Early Phase Development and Discontinued Programs

Alvelestat was originally developed by AstraZeneca under the code AZD-9668, with the initial goal of treating common, neutrophil-driven inflammatory lung diseases.[11] Several Phase 2 clinical trials were completed in patients with Chronic Obstructive Pulmonary Disease (COPD), Bronchiectasis, and Cystic Fibrosis.[11] Representative studies in COPD included NCT00949975, a dose-ranging study, and NCT00703391, a tolerability study.[37] Despite demonstrating target engagement, these studies ultimately did not show sufficient clinical efficacy on relevant endpoints to warrant continuation.[34] Consequently, AstraZeneca discontinued development for these indications, and the compound was subsequently made available through an open innovation platform for potential repurposing.[34] This led to its acquisition by Mereo BioPharma, which identified AATD-LD as a mechanistically appropriate and commercially viable orphan indication.

Pivotal Indication: Alpha-1 Antitrypsin Deficiency-associated Lung Disease (AATD-LD)

Under Mereo BioPharma, alvelestat's development was re-focused on AATD-LD, culminating in two complementary Phase 2 proof-of-concept studies: ASTRAEUS and ATALANTa.

The ASTRAEUS Trial (NCT03636347)

The ASTRAEUS study was designed to evaluate the mechanistic effect, safety, and tolerability of alvelestat in a well-defined population of patients with severe AATD-LD.

• Design: This was a 12-week, multicenter, double-blind, randomized, placebo-controlled trial that enrolled 99 patients, of whom 98 were dosed.[4] Participants had confirmed severe AATD (e.g., Pi ZZ, PiNull genotypes) and CT evidence of emphysema. A key inclusion criterion was that patients were either naïve to augmentation therapy or had undergone a washout period of at least six months, ensuring that the observed effects were attributable to alvelestat alone.[6] The study randomized patients to one of three arms: placebo, alvelestat 120 mg BID (low dose), or alvelestat 240 mg BID (high dose).[5]
• Endpoints: The trial's design was strategically focused on biomarkers that directly reflect the pathogenic pathway of AATD-LD. The three co-primary endpoints were the change from baseline in: 1) blood NE activity (target engagement), 2) plasma Aα-Val360 (a specific product of NE-mediated fibrinogen cleavage), and 3) plasma desmosine/isodesmosine (a durable marker of elastin breakdown).[6]
• Efficacy Results: The results from ASTRAEUS provided a clear and compelling demonstration of dose-dependent efficacy. Both the 120 mg and 240 mg doses achieved the first objective of target engagement, producing statistically significant and sustained suppression of blood NE activity throughout the 12-week treatment period, with the high dose achieving over 90% suppression.[5] However, a critical differentiation was seen in the downstream biomarkers of disease activity. Only the high dose (240 mg BID) demonstrated a statistically significant reduction in both Aα-Val360 and desmosine compared to placebo. The low dose (120 mg BID) failed to show a significant effect on these key markers of tissue damage.[5] Post-hoc analyses also revealed an important correlation: the degree of biomarker reduction in patients treated with alvelestat was significantly associated with improvements in how they felt and functioned, as measured by the SGRQ-Activity domain score—a link not observed in the placebo group.[4]

Table 3: Key Efficacy Results of the Phase 2 ASTRAEUS Trial (NCT03636347) at Week 12

Endpoint (% Change from Baseline, LSM)	Placebo (n≈39)	Alvelestat 120 mg BID (n≈20)	Alvelestat 240 mg BID (n≈39)	Source(s)
Blood NE Activity	-18.1%	-83.5% (p=0.001 vs. Placebo)	-93.3% (p<0.001 vs. Placebo)	39
Plasma Aα-Val360	+11.7%	Not Significant	-22.7% (p=0.001 vs. Placebo)	39
Plasma Desmosine	+18.1%	Not Significant	-13.2% (p=0.041 vs. Placebo)	39

LSM: Least Squared Means

The ATALANTa Trial (NCT03679598)

The ATALANTa study was an investigator-led trial designed to complement ASTRAEUS by evaluating alvelestat in a broader AATD population.

• Design: This was a 12-week, multicenter, double-blind, randomized (1:1), placebo-controlled study that enrolled 63 participants.[5] Unlike ASTRAEUS, ATALANTa included patients with various severe genotypes (Pi ZZ, PiSZ, Pi*Null) and, importantly, allowed for the inclusion of patients who were on stable, concurrent augmentation therapy (approximately 46% of the cohort).[5] The trial evaluated a single dose of alvelestat, 120 mg BID, against placebo.[5]
• Endpoints: The primary objectives were to evaluate safety and the effect on blood biomarkers of NE activity.[8]
• Efficacy Results: The findings from ATALANTa strongly reinforced the conclusions drawn from ASTRAEUS. The 120 mg BID dose of alvelestat again demonstrated significant suppression of blood NE activity compared to placebo (-58.3% reduction from baseline, p=0.0059 vs. placebo).[8] However, also consistent with ASTRAEUS, this dose failed to produce a statistically significant reduction in the key downstream biomarkers of tissue damage (Aα-Val360 and desmosine) when compared to placebo.[8] A particularly noteworthy finding emerged from the patient-reported outcomes. In the prespecified subgroup of patients who were not receiving background augmentation therapy, treatment with alvelestat led to a statistically significant and clinically meaningful improvement in the SGRQ-Activity score compared to placebo (a -10.2 point difference, p=0.0106).[4]

The combined results of these two trials provide an exceptionally clear and consistent picture of alvelestat's dose-response relationship. The repeated failure of the 120 mg dose to impact key biomarkers of disease progression in two independent studies, contrasted with the robust and significant effect of the 240 mg dose, provides an unambiguous and scientifically rigorous justification for selecting the 240 mg BID dose for the pivotal Phase 3 program. This clarity significantly de-risks the late-stage development plan from a dose-selection standpoint, a common point of failure for many investigational drugs.

Table 4: Key Efficacy Results of the Phase 2 ATALANTa Trial (NCT03679598) at Week 12

Endpoint (Change from Baseline)	Placebo (n=31)	Alvelestat 120 mg BID (n=32)	Source(s)
Blood NE Activity	-3.9 ng/mL (approx.)	-18.9 ng/mL (p=0.0059 vs. Placebo)	8
Plasma Aα-Val360	Not Significant	-1.7 nM (p=0.23 vs. Placebo)	8
Plasma Desmosine	No Significant Change	No Significant Change	8
SGRQ-Activity Score (Non-Augmentation Subgroup)	+2.7 (worsening)	-7.5 (improvement) (p=0.0106 vs. Placebo)	8

Exploratory Indication: Bronchiolitis Obliterans Syndrome (BOS)

Alvelestat is also being explored in an investigator-sponsored Phase 1b/2 trial (NCT02669251) for the treatment of Bronchiolitis Obliterans Syndrome (BOS), a rare and life-threatening complication of allogeneic hematopoietic stem cell transplantation characterized by neutrophilic inflammation.[23] The Phase 1b portion of the study evaluated the safety and pharmacodynamics of intra-patient dose escalation from 60 mg BID up to 240 mg BID in seven patients.[23] The drug was well-tolerated, and the maximum tolerated dose was not reached.[43] Interim data showed encouraging signals of biological activity, including a progressive reduction in plasma desmosine and stimulated NE activity with increasing doses. Clinically, six of the seven patients experienced stable or improved lung function (FEV1), and four reported symptomatic improvement.[4] While very early, these results suggest that alvelestat's mechanism may have utility in other severe, neutrophil-driven rare lung diseases.

VI. Comprehensive Safety and Tolerability Assessment

The safety and tolerability of alvelestat have been evaluated across multiple clinical trials, including early studies in COPD and the more recent Phase 2 program in AATD-LD. The overall assessment indicates a manageable safety profile, with most adverse events (AEs) being mild to moderate in severity.[5]

Common Adverse Events

Across the AATD-LD clinical program, the most frequently reported treatment-emergent adverse event associated with alvelestat is headache or migraine.[5] This AE was observed more frequently in the alvelestat arms compared to placebo and appears to be dose-dependent, with a higher incidence noted in the 240 mg BID group in the ASTRAEUS trial.[5] In the ATALANTa trial, which used the 120 mg BID dose, two participants withdrew from the study due to headache.[8] To mitigate this tolerability issue, a dose-escalation strategy during treatment initiation was successfully implemented in the ASTRAEUS study and is planned for the upcoming Phase 3 trial.[6] In the ATALANTa study, the most common AE in the placebo group was a worsening of COPD symptoms.[8]

Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)

While the overall safety profile is favorable, a few serious or notable adverse events have been reported and are being carefully monitored.

• Liver Function: In the ASTRAEUS trial, a single case of clinically significant liver enzyme elevation was reported in the high-dose (240 mg BID) arm. The event involved an increase in alanine aminotransferase (ALT) to more than five times the upper limit of normal (>5x ULN) and aspartate aminotransferase (AST) to >2x ULN, without a concurrent rise in bilirubin. This event met predefined study drug stopping criteria, and the liver enzyme levels returned to normal following discontinuation of alvelestat.[6]
• Cardiac Effects: One case of QT interval prolongation (prolonged QTcF) was observed in the high-dose arm of ASTRAEUS. The subject had a prior history of this condition and was taking a concomitant medication known to affect the QT interval. The study drug was discontinued as a precaution.[6]
• Infections: Given that NE is part of the innate immune system's defense against pathogens, infections were monitored as an adverse event of special interest (AESI) to assess whether NE inhibition might compromise host defense. A pooled analysis of the 161 patients from both the ASTRAEUS and ATALANTa trials was conducted. The results showed that the frequency and severity of infections requiring antimicrobial therapy were similar across the alvelestat and placebo groups. This provides reassuring evidence that selective NE inhibition with alvelestat over a 12-week period does not appear to increase the risk of infection in patients with AATD.[6]

Overall Risk-Benefit Assessment

The safety data gathered to date suggest an acceptable risk-benefit profile for alvelestat in the context of AATD-LD, a progressive and life-threatening rare disease with limited therapeutic options. The primary tolerability concern, headache, appears to be manageable through dose titration. The isolated instances of more serious events, such as liver enzyme elevation and QTc prolongation, warrant careful monitoring in future larger trials but have not indicated a systemic or frequent safety signal that would impede further development. The lack of an increased infection risk is a particularly important finding that supports the safety of the drug's mechanism of action.

Table 5: Summary of Key Treatment-Emergent Adverse Events Across Phase 2 AATD-LD Studies (Pooled ASTRAEUS & ATALANTa)

Adverse Event Category	Placebo (N=67) n (%)	Alvelestat 120 mg BID (N=54) n (%)	Alvelestat 240 mg BID (N=40) n (%)	Source(s)
Headache/Migraine	Data not specified	Data not specified; common	Data not specified; most common	5
Infections (AESI)	18 (26.9%)	10 (18.5%)*	9 (22.5%)	46
AEs Leading to Discontinuation	Data not specified	2 (3.7%)**	2 (5.0%)***	8
Serious AEs (SAEs)	Data not specified	Data not specified	3 (7.5%)****	40

*Combines ATALANTa (5/32) and ASTRAEUS (5/22). **Both due to headache in ATALANTa. ***One due to LFT elevation, one due to QTc prolongation in ASTRAEUS. ***All three were treatment-related headaches in ASTRAEUS.

VII. Regulatory and Strategic Outlook

Developers and Corporate History

Alvelestat was originally discovered and developed by AstraZeneca under the identifier AZD-9668.[11] Following the discontinuation of its development for broader respiratory indications like COPD, the asset was licensed by

Mereo BioPharma Group plc, a clinical-stage biopharmaceutical company focused on rare diseases.[9] Mereo is now leading the global development of alvelestat (as MPH-966) for its primary indication of AATD-LD and other rare diseases.[12] Other organizations, such as the National Cancer Institute (NCI), are involved as sponsors for investigator-led studies in exploratory indications like BOS.[11]

Regulatory Status and Pathway

Alvelestat has achieved a favorable regulatory standing in key global markets, which has significantly de-risked its development pathway and enhanced its commercial potential.

• U.S. Food and Drug Administration (FDA):
• Orphan Drug Designation: The FDA granted Orphan Drug Designation to alvelestat for the treatment of Alpha-1 Antitrypsin Deficiency on October 25, 2021. This status provides incentives such as tax credits for clinical trials, exemption from user fees, and seven years of market exclusivity upon approval.[4]
• Fast Track Designation: In October 2022, the FDA granted Fast Track designation for alvelestat in AATD-LD. This designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need, allowing for more frequent meetings with the FDA and eligibility for Accelerated Approval and Priority Review.[4]
• Phase 3 Regulatory Alignment: Following extensive End-of-Phase 2 meetings with the FDA's Division of Pulmonology, Allergy, and Critical Care (DPACC) and Division of Clinical Outcome Assessment (DCOA), Mereo has successfully aligned on a pivotal Phase 3 trial design. The FDA has agreed that the St. George's Respiratory Questionnaire (SGRQ) Total Score, a patient-reported outcome (PRO) that measures health-related quality of life, can serve as the primary endpoint. If this study is successful, it is expected to be sufficient to support a submission for full regulatory approval in the U.S..[4]
• European Medicines Agency (EMA):
• Orphan Designation: The European Commission granted Orphan Designation for alvelestat in the treatment of AATD in early 2025. This provides benefits including protocol assistance, fee reductions, and 10 years of market exclusivity in the EU upon marketing authorization.[4]
• Phase 3 Regulatory Alignment: Mereo has also received scientific advice from the EMA regarding the path to approval in Europe. The EMA has indicated that a primary endpoint based on the change in lung density as measured by computed tomography (CT) scan, with a relaxed statistical threshold for significance (), may be sufficient to support a full marketing authorization.[4]

This dual-track regulatory alignment is a significant strategic achievement. It reflects a sophisticated understanding of the differing evidentiary philosophies of the two main regulatory bodies—the FDA's emphasis on direct patient-reported benefit and the EMA's acceptance of objective, structural endpoints. By designing a single global study capable of capturing both of these endpoints, Mereo has created a capital-efficient strategy to pursue simultaneous approvals in the two largest pharmaceutical markets.

Developer Strategy

Mereo BioPharma's forward-looking strategy for alvelestat is clear and focused.

• Pivotal Trial Execution: The company is actively preparing to initiate a single, global Phase 3 pivotal study. This trial will evaluate the efficacy and safety of alvelestat at the 240 mg BID dose compared to placebo in patients with AATD-LD.[4] The study will be designed to meet the primary endpoint requirements of both the FDA (SGRQ Total Score) and the EMA (CT lung density).
• Strategic Partnership: A core component of Mereo's strategy is to secure a strategic partner to co-fund and support the execution of the costly Phase 3 trial and subsequent global commercialization.[12] The company is actively engaged in partnership discussions, and the clarity on the regulatory pathway is a key asset in these negotiations.[12]
• Financial Management: Mereo has reported a cash runway projected to fund its operations into 2026 or 2027, providing financial stability to advance the alvelestat program through key preparatory milestones while it secures a partnership.[13]

VIII. Concluding Analysis and Future Perspectives

Alvelestat has emerged as a highly promising, late-stage clinical asset for the treatment of lung disease associated with severe Alpha-1 Antitrypsin Deficiency. Its development journey, from a repurposed compound to a lead candidate in a rare disease with a clearly defined regulatory path, highlights a successful strategic pivot grounded in strong scientific rationale. A balanced assessment reveals a profile with significant strengths alongside manageable risks and challenges.

Summary of Strengths

• Novel, Targeted Mechanism: Alvelestat has the potential to be a first-in-class oral, selective inhibitor of neutrophil elastase. Its mechanism directly targets the central enzymatic driver of lung destruction in AATD, offering a true disease-modifying approach rather than a protein replacement strategy.
• Convenience of Administration: As an oral, twice-daily medication, alvelestat would offer a transformative improvement in convenience and quality of life for patients currently dependent on weekly intravenous infusions of augmentation therapy.
• Robust Clinical Data: The Phase 2 program delivered unambiguous results, demonstrating a clear dose-response relationship. The strong, statistically significant effects of the 240 mg BID dose on validated biomarkers of target engagement (NE activity) and tissue destruction (Aα-Val360, desmosine) provide a powerful foundation for late-stage development.
• Clear and De-risked Regulatory Pathway: Mereo BioPharma has achieved alignment with both the FDA and EMA on pivotal Phase 3 trial designs. This dual-endpoint strategy, while complex, significantly de-risks the path to market in the world's two largest pharmaceutical territories.
• Favorable Regulatory Designations: The attainment of Orphan Drug and Fast Track designations in the U.S. and Orphan Designation in the EU provides significant regulatory, financial, and commercial advantages that will support its final development and market entry.

Summary of Weaknesses and Challenges

• Tolerability Profile: While generally manageable, headache is a notable and frequent adverse event. Ensuring patient adherence and managing tolerability through strategies like dose titration will be important for long-term treatment success.
• Phase 3 Execution Risk: The ultimate success of alvelestat now hinges entirely on the execution and positive outcome of a large, complex, and expensive global Phase 3 trial. Clinical development at this stage carries inherent risks, regardless of the strength of Phase 2 data.
• Partnership Dependency: As a clinical-stage biopharmaceutical company, Mereo's ability to fully fund and execute the global Phase 3 program and subsequent commercial launch is likely dependent on securing a well-resourced strategic partner. The timing and terms of such a partnership are a key variable.
• Translation to Long-Term Clinical Benefit: The Phase 2 program successfully demonstrated an effect on biomarkers and promising signals in patient-reported outcomes over a 12-week period. The critical challenge for the Phase 3 trial will be to demonstrate that these effects translate into a sustained, long-term clinical benefit on endpoints such as the rate of lung function decline or reduction in exacerbation frequency, which has historically been difficult to prove in this disease area.

Final Perspective

Alvelestat stands as a compelling example of successful drug repurposing, having been skillfully navigated from discontinuation in broad indications to a lead candidate in a high-unmet-need orphan disease. The confluence of a strong scientific rationale, a convenient oral formulation, unambiguous dose-finding data from Phase 2, and a well-defined global regulatory strategy makes alvelestat a formidable late-stage asset. Its potential to become the first oral, disease-modifying therapy for AATD-LD is substantial and could fundamentally alter the treatment landscape for this devastating condition. The primary hurdles remaining are not scientific but rather operational and financial: successfully executing the pivotal Phase 3 study and securing the right corporate partner to deliver this promising therapy to the patients who await a more effective and convenient treatment option.

Works cited

1. Alvelestat | C25H22F3N5O4S | CID 46861623 - PubChem, accessed October 1, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Alvelestat
2. Alvelestat | CAS#848141-11-7 | NE inhibitor - MedKoo Biosciences, accessed October 1, 2025, https://www.medkoo.com/products/6553
3. Definition of alvelestat - NCI Drug Dictionary, accessed October 1, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/alvelestat
4. Alvelestat | Mereo BioPharma, accessed October 1, 2025, https://www.mereobiopharma.com/our-pipeline/alvelestat-mph966/
5. Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency - PubMed, accessed October 1, 2025, https://pubmed.ncbi.nlm.nih.gov/40967767/
6. Mereo BioPharma announces Positive Top-Line Efficacy and Safety ..., accessed October 1, 2025, https://www.mereobiopharma.com/news-and-events/news/2022/may/mereo-biopharma-announces-positive-top-line-efficacy-and-safety-data-from-astraeus-phase-2-trial-of-alvelestat-in-alpha-1-antitrypsin-deficiency-associated-emphysema/
7. Two randomized controlled Phase 2 studies of the oral neutrophil ..., accessed October 1, 2025, https://www.researchgate.net/publication/395655038_Two_randomized_controlled_Phase_2_studies_of_the_oral_neutrophil_elastase_inhibitor_alvelestat_in_alpha-1_antitrypsin_deficiency
8. Alvelestat (MPH966) for the Treatment of Alpha-1 ... - ATS Journals, accessed October 1, 2025, https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A1211?download=true
9. Mereo Reports Positive Data from Phase 2 Study of Alvelestat in AATD-related Emphysema, accessed October 1, 2025, https://globalgenes.org/raredaily/mereo-reports-positive-data-from-phase-2-study-of-alvelestat-in-aatd-related-emphysema/
10. Alvelestat, an Oral Neutrophil Elastase Inhibitor in Alpha-1 Antitrypsin Deficiency (AATD): Results of a Phase II Trial - ATS Journals, accessed October 1, 2025, https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A4493
11. Alvelestat - Mereo BioPharma - AdisInsight - Springer, accessed October 1, 2025, https://adisinsight.springer.com/drugs/800026715
12. Mereo BioPharma Provides Regulatory Updates on Alvelestat for the Treatment of Alpha-1-Antitrypsin Deficiency-Associated Lung Disease, accessed October 1, 2025, https://www.mereobiopharma.com/news-and-events/news/2023/march/mereo-biopharma-provides-regulatory-updates-on-alvelestat-for-the-treatment-of-alpha-1-antitrypsin-deficiency-associated-lung-disease/
13. EX-99.1 - SEC.gov, accessed October 1, 2025, https://www.sec.gov/Archives/edgar/data/1719714/000095017025044783/mreo-ex99_1.htm
14. Search Orphan Drug Designations and Approvals - FDA, accessed October 1, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=804020
15. FDA Grants Mereo Fast Track Designation for Alvelestat for Treatment AATD-associated Lung Disease - Global Genes, accessed October 1, 2025, https://globalgenes.org/raredaily/fda-grants-mereo-fast-track-designation-for-alvelestat-for-treatment-aatd-associated-lung-disease/
16. Mereo BioPharma Provides Update on Pipeline Progress and Corporate Developments, accessed October 1, 2025, https://www.biospace.com/mereo-biopharma-provides-update-on-pipeline-progress-and-corporate-developments
17. Mereo BioPharma Reports Q2 2025 Financial Results and Updates on Setrusumab Phase 3 Studies for Osteogenesis Imperfecta - Quiver Quantitative, accessed October 1, 2025, https://www.quiverquant.com/news/Mereo+BioPharma+Reports+Q2+2025+Financial+Results+and+Updates+on+Setrusumab+Phase+3+Studies+for+Osteogenesis+Imperfecta
18. Study Details | NCT03679598 | Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency | ClinicalTrials.gov, accessed October 1, 2025, https://clinicaltrials.gov/study/NCT03679598
19. Alvelestat (MPH966) R&D Day - Mereo BioPharma, accessed October 1, 2025, https://www.mereobiopharma.com/media/e34lpivx/mereo-r-and-d-day-14mar2022.pdf
20. Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency, accessed October 1, 2025, https://publications.ersnet.org/content/erj/early/2025/09/04/13993003.01019-2025.full.pdf
21. Alvelestat: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 1, 2025, https://go.drugbank.com/drugs/DB11863
22. AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase, accessed October 1, 2025, https://www.researchgate.net/publication/51523436_AZD9668_Pharmacological_Characterization_of_a_Novel_Oral_Inhibitor_of_Neutrophil_Elastase
23. Study Details | NCT02669251 | Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation | ClinicalTrials.gov, accessed October 1, 2025, https://clinicaltrials.gov/study/NCT02669251
24. Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD | Request PDF - ResearchGate, accessed October 1, 2025, https://www.researchgate.net/publication/235421419_Pharmacokinetics_and_safety_of_AZD9668_an_oral_neutrophil_elastase_inhibitor_in_healthy_volunteers_and_patients_with_COPD
25. Alpha-1 Antitrypsin Deficiency - MedlinePlus, accessed October 1, 2025, https://medlineplus.gov/alpha1antitrypsindeficiency.html
26. Alpha-1 Antitrypsin Deficiency Treatment Options - Temple Health, accessed October 1, 2025, https://www.templehealth.org/services/conditions/alpha-1-antitrypsin-deficiency/treatment-options
27. Alpha-1 Antitrypsin Deficiency (AATD) - Takeda U.S. Medical, accessed October 1, 2025, https://www.takedamedconnect.com/diseases-and-conditions/rare-immunology/alpha-1-antitrypsin-deficiency
28. Patient-Focused Drug Development for Alpha-1 Antitrypsin Deficiency - FDA, accessed October 1, 2025, https://www.fda.gov/media/136516/download
29. ALVELESTAT - precisionFDA, accessed October 1, 2025, https://precision.fda.gov/ginas/app/ui/substances/6Y5629322X
30. Alvelestat (AZD9668) | Elastase Inhibitor - MedchemExpress.com, accessed October 1, 2025, https://www.medchemexpress.com/Alvelestat.html
31. alvelestat | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed October 1, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6476
32. Alvelestat | CAS:848141-11-7 | NE inhibitor | High Purity | Manufacturer BioCrick, accessed October 1, 2025, https://www.biocrick.com/Alvelestat-BCC4058.html
33. Alvelestat (AZD9668) | Serine Protease inhibitor | Mechanism | Concentration, accessed October 1, 2025, https://www.selleckchem.com/products/avelestat-azd9668.html
34. alvelestat | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed October 1, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=6476
35. Compound: ALVELESTAT (CHEMBL3617964) - ChEMBL - EMBL-EBI, accessed October 1, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL3617964
36. Chronic Obstructive Pulmonary Disease (COPD) Completed Phase 2 Trials for Alvelestat (DB11863) | DrugBank Online, accessed October 1, 2025, https://go.drugbank.com/indications/DBCOND0031289/clinical_trials/DB11863?phase=2&status=completed
37. Alvelestat Completed Phase 2 Trials for Chronic Obstructive Pulmonary Disease (COPD) Basic Science - DrugBank, accessed October 1, 2025, https://go.drugbank.com/drugs/DB11863/clinical_trials?conditions=DBCOND0031289&phase=2&purpose=basic_science&status=completed
38. NCT03636347 | A 12-week Study Treating Participants Who Have alpha1-antitrypsin-related COPD With Alvelestat (MPH966) or Placebo. | ClinicalTrials.gov, accessed October 1, 2025, https://www.clinicaltrials.gov/study/NCT03636347
39. Alvelestat for AATD meets primary endpoints in phase 2 trial - Medical Conferences, accessed October 1, 2025, https://conferences.medicom-publishers.com/content/roundup/alvelestat-for-aatd-meets-primary-endpoints-in-phase-2-trial-2/
40. Phase 2 Data from “ASTRAEUS” Trial of Mereo BioPharma's Alvelestat in Alpha-1 Antitrypsin Deficiency-associated Lung Disease Presented at the 2023 American Thoracic Society International Conference - GlobeNewswire, accessed October 1, 2025, https://www.globenewswire.com/news-release/2023/05/23/2674716/0/en/Phase-2-Data-from-ASTRAEUS-Trial-of-Mereo-BioPharma-s-Alvelestat-in-Alpha-1-Antitrypsin-Deficiency-associated-Lung-Disease-Presented-at-the-2023-American-Thoracic-Society-Internati.html
41. Study Results | Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency, accessed October 1, 2025, https://clinicaltrials.gov/ct2/show/results/NCT03679598
42. Bronchiolitis Obliterans Syndrome (BOS) Active Not Recruiting Phase 1 Trials for Alvelestat (DB11863) - DrugBank, accessed October 1, 2025, https://go.drugbank.com/indications/DBCOND0071683/clinical_trials/DB11863?phase=1&status=active_not_recruiting
43. Phase 1 Study of Alvelestat, an Oral Neutrophil Elastase Inhibitor, in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation | Request PDF - ResearchGate, accessed October 1, 2025, https://www.researchgate.net/publication/368063080_Phase_1_Study_of_Alvelestat_an_Oral_Neutrophil_Elastase_Inhibitor_in_Patients_with_Bronchiolitis_Obliterans_Syndrome_after_Hematopoietic_Cell_Transplantation
44. Phase 1 Study of Alvelestat, an Oral Neutrophil Elastase Inhibitor, in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation | Blood | American Society of Hematology, accessed October 1, 2025, https://ashpublications.org/blood/article/136/Supplement%201/18/472978/Phase-1-Study-of-Alvelestat-an-Oral-Neutrophil
45. Effects of Alvelestat, an Oral Neutrophil Elastase Inhibitor, on Elevated Elastase and Collagen Turnover Biomarkers in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation - American Society of Hematology, accessed October 1, 2025, https://ashpublications.org/blood/article/138/Supplement%201/1815/480724/Effects-of-Alvelestat-an-Oral-Neutrophil-Elastase
46. No infection risk with alvelestat in patients with AATD in two phase 2 trials., accessed October 1, 2025, https://publications.ersnet.org/content/erj/64/suppl68/pa1776
47. EX-99.1 - SEC.gov, accessed October 1, 2025, https://www.sec.gov/Archives/edgar/data/1719714/000119312521307471/d227135dex991.htm
48. Mereo BioPharma Receives FDA Fast Track Designation for Alvelestat to Treat AATD-associated Lung Disease | American Pharmaceutical Review, accessed October 1, 2025, https://www.americanpharmaceuticalreview.com/1315-News/591003-Mereo-BioPharma-Receives-FDA-Fast-Track-Designation-for-Alvelestat-to-Treat-AATD-associated-Lung-Disease/?catid=26940
49. Mereo BioPharma Receives FDA Fast Track Designation for Alvelestat for Treatment of Alpha-1 Antitrypsin Deficiency (AATD)-associated Lung Disease - GlobeNewswire, accessed October 1, 2025, https://www.globenewswire.com/news-release/2022/10/17/2535304/0/en/Mereo-BioPharma-Receives-FDA-Fast-Track-Designation-for-Alvelestat-for-Treatment-of-Alpha-1-Antitrypsin-Deficiency-AATD-associated-Lung-Disease.html
50. Mereo BioPharma Provides Update on Pipeline Progress and Corporate Developments, accessed October 1, 2025, https://www.mereobiopharma.com/news-and-events/news/2024/january/corporate-update/
51. Mereo BioPharma Updates on Phase 3 Study of Setrusumab and Positive EMA Opinion for Alvelestat in Rare Diseases - Quiver Quantitative, accessed October 1, 2025, https://www.quiverquant.com/news/Mereo+BioPharma+Updates+on+Phase+3+Study+of+Setrusumab+and+Positive+EMA+Opinion+for+Alvelestat+in+Rare+Diseases
52. Mereo BioPharma Updates on Phase 3 Study of Setrusumab and Positive EMA Opinion for Alvelestat in Rare Diseases | Nasdaq, accessed October 1, 2025, https://www.nasdaq.com/articles/mereo-biopharma-updates-phase-3-study-setrusumab-and-positive-ema-opinion-alvelestat-rare