alvelestat (MPH966) / AstraZeneca, Mereo Biopharma - LARVOL DELTA

Mereo recently announced an option and license agreement with Sentynl Therapeutics, Inc. (Sentynl), a wholly owned subsidiary of Zydus Lifesciences Limited (GlobeNewswire) - "Sentynl has the right to acquire a license for the U.S. commercial and global manufacturing rights to alvelestat for AATD-LD....Under the agreement, the companies will collaborate to refine the design of the planned global Phase 3 trial of alvelestat and to advance the manufacturing during the short option period. Mereo will receive a non-refundable option fee and, on option exercise, would also be eligible to receive $40 million in upfront and R&D payments, up to $435 million in regulatory and commercial milestone payments, as well as double-digit tiered royalties on U.S. net sales of alvelestat. Mereo will lead the global Phase 3 study and regulatory interactions until study completion and will retain rest-of-world commercial rights for alvelestat. On exercise of the option by Sentynl, the agreement provides funding for the global Phase 3 study, which could be initiated early in 2027."

Licensing / partnership • New P3 trial • Alpha-1 Antitrypsin Deficiency

The Differential Redox Resilience of Alvelestat and Sivelestat: A Mechanistic Hypothesis for Inhibitor Performance Under Oxidative Stress. (PubMed, Molecules) - "Oxidation-induced remodeling of the S1 pocket disrupts the near-attack configuration required for covalent bond formation, thereby impairing inhibition. Overall, these findings indicate that oxidative stress may selectively compromise covalent inhibition while preserving enzymatic activity, and suggest that context-dependent redox-related structural effects may represent a consideration for the design of next-generation HNE inhibitors."

Journal • Inflammation • Pulmonary Disease • Respiratory Diseases • ELANE

Neutrophil Elastase Regulates both Innate and Adaptive Immunity in SARS-CoV-2-Infected Mice (IMMUNOLOGY 2026) - "These findings identify NE as a critical regulator of host immunity and viral replication during SARS-CoV-2 infection. Ongoing single-cell RNA sequencing of infected lungs will further define NE-dependent programs governing the protective versus pathogenic immunity seen."

Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • ELANE

Alvelestat for alpha-1 antitrypsin deficiency-associated emphysema: the hope for an oral treatment. (PubMed, Eur Respir J) - No abstract available

Journal • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Pulmonary Disease • Respiratory Diseases

Two randomized controlled Phase 2 studies of the oral neutrophil elastase inhibitor alvelestat in alpha-1 antitrypsin deficiency. (PubMed, Eur Respir J) - "Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice daily dose into a clinical endpoint study."

Journal • P2 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Pain • Pulmonary Disease • Respiratory Diseases • ELANE

Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1/2 | N=14 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting

Enrollment closed • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

AZD 9668, a neutrophil elastase inhibitor, promotes wound healing in the irradiated skin by inhibiting NET-derived vascular dysfunction. (PubMed, Int Immunopharmacol) - "AZD9668 effectively mitigated radiation-induced damage by preventing NET formation, preserving tight junction integrity, and reducing inflammation. These findings underscore the therapeutic potential of NET and NET-derived NE in the management of radiation-induced vascular and skin injuries."

Journal • Inflammation • ELANE

First Quarter 2025 Financial Results (GlobeNewswire) - "Total research and development ('R&D') expenses decreased by $0.1 million from $4.0 million in the first quarter of 2024 to $3.9 million in the first quarter of 2025. The decrease was primarily due to decreases of $1.2 million and $0.1 million in R&D expenses for alvelestat and etigilimab, offset by an increase of $1.3 million in R&D expenses for setrusumab. The decrease in program expenses for alvelestat was primarily due to undertaking reduced drug formulation and manufacturing activities in preparation for the Phase 3 study in the first quarter of 2025, compared to the first quarter of 2024."

Commercial • Alpha-1 Antitrypsin Deficiency • Graft versus Host Disease • Ovarian Cancer • Solid Tumor

Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting | N=14 ➔ 34

Enrollment change • Enrollment open • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1/2 | N=14 | Suspended | Sponsor: National Cancer Institute (NCI) | N=34 ➔ 14 | Recruiting ➔ Suspended

Enrollment change • Trial suspension • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

Mereo BioPharma’s SWOT analysis: setrusumab, alvelestat drive rare disease stock potential (Investing.com) - "Mereo’s lead candidate, setrusumab, an anti-sclerostin monoclonal antibody, is currently in a Phase 3 study for the treatment of osteogenesis imperfecta (OI), commonly known as brittle bone disorder. The company is anticipating the second interim analysis (IA2) of this study in mid-2025...The company is nearing finalization of the Phase 3 trial design for alvelestat, a crucial step in securing a potential partnership....Mereo is actively engaged in discussions with potential partners for alvelestat, with a partnership potentially materializing in 2025."

Clinical protocol • Commercial • P3 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Mereo BioPharma Reports Full Year 2024 Financial Results and Provides Corporate Highlights (GlobeNewswire) - "Setrusumab (UX143): The Phase 3 portion of the Orbit Study is continuing to dose pediatric and young adult patients, with the second interim analysis expected mid-2025 and potential final analysis in the fourth quarter of 2025....Alvelestat (MPH-966): In the first quarter of 2025, the European Commission granted Orphan Designation to alvelestat for the treatment of AATD-LD. This designation followed a positive recommendation from the EMA Committee for Orphan Medicinal Products in January 2025....Total research and development ('R&D') expenses increased by $3.5 million from $17.4 million in 2023 to $20.9 million in 2024. The increase was primarily due to increases of $6.2 million and $2.6 million in R&D expenses for alvelestat and setrusumab, respectively..."

Commercial • Orphan drug • P3 data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders

Neutrophil Extracellular Trap Formation Model Induced by Monosodium Urate and Phorbol Myristate Acetate: Involvement in MAPK Signaling Pathways. (PubMed, Int J Mol Sci) - "They include the Ras inhibitor Salirasib, Raf inhibitor Vemurafenib, ERK inhibitor PD98059, and p38 MAPK inhibitor SB203580, as well as NADPH oxidase inhibitor DPI and neutrophil elastase inhibitor Alvelestat. These data indicated that the activation of a signaling pathway involving Ras-Raf-ERK, which is dependent on ROS, is crucial for the induction of NET formation by MSU and PMA. Given the involvement of NETs in multiple pathologies, our findings could potentially serve as molecular targets for the intervention and treatment of crystal-related diseases, especially for gout."

Journal • Gout • Inflammation • Inflammatory Arthritis • Rheumatology • CXCL8 • ELANE

Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Dec 2027 | Trial primary completion date: Dec 2024 ➔ Dec 2027

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

HSYA ameliorates venous thromboembolism by depleting the formation of TLR4/NF-κB pathway-dependent neutrophil extracellular traps. (PubMed, Int Immunopharmacol) - "Depletion of NETs using the NE inhibitor Alvelestat significantly alleviated ferroptosis in VTE mice...Additionally, we found that HSYA exerted protective effects against ferroptosis in NETs-induced HUVECs and VTE mice. In summary, HSYA ameliorates VTE by depleting neutrophil extracellular traps through the inhibition of the TLR4/NF-κB pathway, thus providing a novel therapeutic strategy for treating VTE."

Journal • Cardiovascular • Venous Thromboembolism • METTL3

Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD. (PubMed, Cells) - "Calcineurin Inhibitors (CNI) with either Methotrexate (MTX) or Mycophenolate (MMF) still represent the standard prophylaxis in HLA-matched allogeneic stem cell transplantation (HSCT); other strategies focused on ATG, Post-Transplant Cyclophosphamide (PTCy), Abatacept and graft manipulation...For Ruxolitinib-refractory cGVHD, Belumosudil and Axatilimab represent the most promising agents. Bronchiolitis obliterans syndrome (BOS) still represents a challenge; among the compounds targeting non-immune effectors, Alvelestat, a Neutrophil elastase inhibitor, seems promising in BOS. Finally, in both aGVHD and cGVHD, the association of biological markers with specific disease manifestations could help refine risk stratification and the availability of reliable biomarkers for specific treatments."

Journal • Review • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation • ELANE

Efficacy of alvelestat on SGRQ in patients with alpha-1 antitrypsin deficiency and mild airflow limitation: A pooled analysis from two Phase 2 studies (ERS 2024) - "Between group changes for both scores were numerically superior with alvelestat vs. placebo but not significant. Conclusions In a pooled analysis, alvelestat for 12 weeks was associated with improvement in SGRQ scores in patients with AATD and GOLD 1 airflow limitation."

P2 data • Retrospective data • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases

No infection risk with alvelestat in patients with AATD in two phase 2 trials. (ERS 2024) - "Consistent with studies in COPD, bronchiectasis and cystic fibrosis, selective inhibition of NE in patients with AATD with alvelestat was not associated with increased frequency or severity of infection over the course of 12 weeks, including at the 240 mg bid proposed clinical dose. AESI ATALANTA Alvelestat 120 mg bid (N = 32) n (%) ASTRAEUS Alvelestat 120 mg bid (N = 22) n (%) ASTRAEUS Alvelestat 240 mg bid (N = 40) n (%) Placebo (N = 67) n (%) Infections 5 (15.6) 5 (22.7) 9 (22.5) 18 (26.9)"

Clinical • P2 data • Alpha-1 Antitrypsin Deficiency • Bronchiectasis • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • ELANE

Robustaflavone as a novel scaffold for inhibitors of native and auto-proteolysed human neutrophil elastase. (PubMed, SAR QSAR Environ Res) - "The robustaflavone scaffold likely inhibits both tcHNE and scHNE. It is potentially superior to sivelestat and alvelestat and can aid in developing therapeutics targeting both forms of HNE."

Journal • Inflammation • Targeted Protein Degradation • ELANE

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency. (PubMed, Front Pharmacol) - "The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint... Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management."

Journal • Preclinical • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hepatology • Pulmonary Disease • Respiratory Diseases • ELANE

Alvelestat (MPH966) for the Treatment of Alpha-1 Antitrypsin Deficiency (ATALANTa): A Phase 2, Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate Efficacy, Safety, and Tolerability of Alvelestat in Alpha-1 Antitrypsin Deficiency (ATS 2024) - "The oral NE inhibitor alvelestat was safe and well-tolerated, and its use led to a significant and sustained reduction in NE activity and the NE-specific fibrinogen cleavage product A-alpha-Val360 in AATD. These findings support further testing of alvelestat in severe AATD in Phase 3 clinical trials."

Clinical • P2 data • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • CNS Disorders • Genetic Disorders • Hematological Disorders • Hepatology • Immunology • Inflammation • Migraine • Neutropenia • Pain • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE

Association of Biomarker Suppression With St George'S Respiratory Questionnaire and COPD Assessment Test in Patients With Alpha-1 Antitrypsin Deficiency Treated With Alvelestat: Results From the Treatment of Alpha-1-antitrypsin Deficiency (Atalanta) Study (ATS 2024) - P2 | "The previous association of biomarker response to alvelestat with improvement in respiratory health status (SGRQ-Activity Domain) has been substantiated by the ATALANTa data, within a broader patient population and extended to a second PRO (CAT)."

Biomarker • Clinical • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • ELANE

Alvelestat: Expiry of patents related to dosing regimens, methods of treatment and dosage forms of alvelestat between 2040 and 2044 (Mereo BioPharma) - Annual Report 2023: Expiry of patents directed to 2-pyridone derivatives as NE inhibitors and their uses as well as claims to polymorphs of the tosylate salt of a 5-pyrazolyl-2-pyridone derivative between 2024 and 2030

Patent • Bronchiectasis

Alvelestat (MPH966), an Oral Neutrophil Elastase Inhibitor, in Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2024 ➔ Dec 2024 | Trial primary completion date: Jan 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

ATALANTa: Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (clinicaltrials.gov) - P2 | N=63 | Completed | Sponsor: University of Alabama at Birmingham | Active, not recruiting ➔ Completed

Trial completion • Alpha-1 Antitrypsin Deficiency • Chronic Obstructive Pulmonary Disease • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • ELANE