avoralstat (BCX4161) / BioCryst - LARVOL DELTA

Investigation of the Impact of Hereditary Angioedema (HAE) on Health-Related Quality of Life: A Systematic Literature Review (ISPOR-EU 2025) - "From 100 HRQoL references accepted, 31 were full-text journal articles reporting 27 unique studies that assessed treatment with berotralstat (n=4), C1-INH (n=3), donidalorsen (n=3), garadacimab (n=2), avoralstat, danazol, and lanadelumab (n=1 each); ten included a placebo comparator and twelve were non-interventional studies. Only one study was identified that captured HRQoL during and between patients' HAE attacks. There remains difficulty in accurately quantifying the impact of each attack on HRQoL, likely due to the transient and unpredictable nature of attacks. This highlights the need for further research to improve understanding of how to measure patient HRQoL during attacks."

Clinical • HEOR • Review • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

A Study of Avoralstat In Participants With Diabetic Macular Edema (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: BioCryst Pharmaceuticals

New P1 trial • Diabetic Macular Edema • Ophthalmology

BioCryst Reports First Quarter 2025 Financial Results and Provides Business Update (GlobeNewswire) - "The first clinical trial with suprachoroidal delivery of avoralstat, the company’s investigational plasma kallikrein inhibitor for the treatment of diabetic macular edema (DME), has been granted authorization to proceed in Australia. The company expects initial data from DME patients in 2025." "

Clinical data • Diabetic Macular Edema

BioCryst Reports Fourth Quarter and Full Year 2024 Financial Results and Upcoming Key Milestones (GlobeNewswire) - "ORLADEYO net revenue in the fourth quarter of 2024 was $124.2 million (+36.6 percent y-o-y). 73.5 percent of U.S. patients were on paid product at the end of the fourth quarter (up from 71.4 percent at the end of 2023). Sales from outside the U.S. contributed 13.9 percent of global ORLADEYO net revenues in the fourth quarter and 11.8 percent for full year 2024...ORLADEYO is now reimbursed in all major countries in Western Europe, except the Netherlands, which is expected in 1H 2025...The company has advanced BCX17725, its KLK5 inhibitor for the treatment of Netherton syndrome, into clinical trials and expects initial data from the program in 2025...In 2025, the company plans to advance avoralstat, a plasma kallikrein inhibitor, into a clinical trial of patients with diabetic macular edema (DME)."

Commercial • New trial • P1 data • Reimbursement • Diabetic Macular Edema • Genetic Disorders • Hereditary Angioedema • Rare Diseases

Specificity of contact pathway inhibitors with regard to other coagulation and fibrinolysis proteases. (ISTH 2023) - "CTI was very specific for factor XIIa with little inhibition of other factors (Figure). SBTI, ecallantide, and avoralstat were, as expected, very potent inhibitors of kallikrein. Avoralstat, at concentrations well above therapeutic levels, had weak inhibitory effect on many other coagulation enzymes."

Cardiovascular • Hematological Disorders • Thrombosis

Interventions for the long-term prevention of hereditary angioedema attacks. (PubMed, Cochrane Database Syst Rev) - "The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Hepatology • Hereditary Angioedema • Liver Failure • Pain

Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2. (PubMed, Microbiol Spectr) - "Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat...These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid...The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency...We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Microvesicles from Stored Platelets Promote High Molecular Weight Kininogen Cleavage Leading to Bradykinin Generation. (ISTH 2022) - "Following incubation of sPLT-MVs with HK, the HKi concentration gradually decreased, whereas bradykinin levels increased, suggesting that sPLT-MVs generate bradykinin from HK cleavage, independently of PKa, since these effects were not abolished by avoralstat (Fig 1A&B). However, the addition of PK further increased HK cleavage and bradykinin generation, both of which were inhibited by avoralstat (Fig 1C&D), suggesting the contribution of PKa formed by the activation of PK by sPLT-MVs. Separately, the concentration of exogenously added bradykinin decreased following incubation with sPLT-MVs, which was inhibited by the presence of lisinopril (Fig 1E), indicating the presence of angiotensin-converting enzyme activity associated with sPLT-MVs."

Immunology • Inflammation

In silico and in vitro assays reveal potential inhibitors against 3CL main protease of SARS-CoV-2. (PubMed, J Biomol Struct Dyn) - "In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His and Cys, more frequently than avoralstat.Communicated by Ramaswamy H. Sarma."

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

Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice. (PubMed, J Clin Invest) - "Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans."

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

Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition. (PubMed, J Struct Biol) - "Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161...Lack of conservation in surrounding residues explains the ∼10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: the OPUS-2 study. (PubMed, Allergy) - "Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo."

Journal • P3 data