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

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

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) | Phase classification: P1b/2 ➔ P1/2

Phase classification • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation

Neutrophil elastase remodels mammary tumors to facilitate lung metastasis. (PubMed, Mol Cancer Ther) - "To evaluate whether pharmacological inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE-/- mice, we utilized AZD9668, a clinically available and specific NE inhibitor...Lastly, we identified a NE-specific signature that predicts recurrence and metastasis in breast cancer patients. Collectively, our studies suggest that genetic ablation and pharmacological inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of metastatic breast cancer patients."

Journal • Breast Cancer • Oncology • Solid Tumor • ELANE

ATALANTa: Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Trial completion date: Aug 2023 ➔ Nov 2023 | Trial primary completion date: Aug 2023 ➔ Nov 2023

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

"$MREO how much is Alvelestat phase 3 ready in #AATD worth ? @VertexPharma should acquire Alvelestat for $1Bn $WVE landed $3.3Bn partnership deal with $GSK for WVE-006 preclinical asset $XBI $IBB $VRTX" (@ej23ny)

Licensing / partnership • P3 data

"Alvelestat worth 1b? Damn" (@Cryptos_Tales)

Promising Results of Setrusumab in the Treatment of Osteogenesis Imperfecta (Best Stocks) - "The company also announced that it had completed patient enrollment in a Phase 2 trial of its drug alvelestat for the treatment of alpha-1 antitrypsin deficiency..."

Enrollment closed • Alpha-1 Antitrypsin Deficiency

ATALANTa: Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency (clinicaltrials.gov) - P2 | N=63 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Trial primary completion date: Jun 2023 ➔ Aug 2023

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

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) - "Mereo is completing preparatory work for a single pivotal Phase 3 study evaluating the high dose of alvelestat (240mg), which, if successful, is expected to support submissions for full regulatory approvals in both the U.S. and EU. The planned study will have two independent primary endpoints, based on the recommendations of the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA)...Mereo is continuing to explore potential partnerships to fund the Phase 3 development of alvelestat....'We look forward to sharing further updates on the progress of the alvelestat program, including the results of the investigator-led Phase 2 ATALANTA study evaluating alvelestat in combination with augmentation therapy, which is expected to read out in Q3 2023.'"

New P3 trial • P2 data • Alpha-1 Antitrypsin Deficiency

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) - P2 | N=99 | ASTRAEUS (NCT03636347) | Sponsor: JMereo BioPharma | "Mereo BioPharma Group...today announced that data from the Phase 2 'ASTRAEUS' trial of alvelestat for the treatment of Alpha-1 Antitrypsin Deficiency-associated Lung Disease (AATD-LD), as well as post-hoc analyses demonstrating the association between biomarker reductions with alvelestat and improvements in SGRQ, a key Patient-Reported Outcome (PRO) measure...Low - and high-dose alvelestat significantly suppressed NE activity compared to baseline (-83.5% and -93.3%, p=0.023 and p<0.001 respectively) and versus placebo (p=0.001 and p<0.001). In the high dose arm, Aα-val360 and desmosine progressively decreased from baseline, -22.7% (p=0.004) and -13.2% (p=0.045) respectively, with significant reductions compared to placebo as well (p=0.001 and p=0.041)."

P2 data • Retrospective data • Alpha-1 Antitrypsin Deficiency

Alvelestat, an Oral Neutrophil Elastase Inhibitor in Alpha-1 Antitrypsin Deficiency (AATD): Results of a Phase II Trial (ATS 2023) - "CONCLUSIONS Alvelestat demonstrated significant and consistent reduction in all 3 biomarkers related to AATD disease activity, with an acceptable safety profile. The magnitude of changes in desmosine and Aα-val360 at the high dose were comparable to effects in placebo-controlled augmentation studies1,2 and support progression to Phase 3."

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