glecaprevir (ABT-493) / AbbVie - LARVOL DELTA

Protocol for HIV-1 budding control by inducible inhibition of ESCRT-III. (PubMed, STAR Protoc) - "These fusion proteins function like wild-type ESCRT-III but convert into dominant-negative inhibitors upon addition of the NS3 inhibitor Glecaprevir...Steps for protein expression analysis, VLP quantification by immunoblotting, and live-cell imaging of VLP release kinetics are included. For complete details on the use and execution of this protocol, please refer to Wang et al.1."

Journal • Hepatitis C • Human Immunodeficiency Virus • Infectious Disease • Inflammation

Discovery of TRPV4-Targeting Small Molecules with Anti-Influenza Effects Through Machine Learning and Experimental Validation. (PubMed, Int J Mol Sci) - "Notably, glecaprevir and everolimus demonstrated significant inhibitory effects on the influenza virus, markedly improving survival rates in influenza-infected mice (protection rates of 80% and 100%, respectively). In summary, our study presents the first predictive model for identifying TRPV4 inhibitors, underscoring TRPV4 inhibition as a promising strategy for antiviral drug development against influenza. This pioneering approach lays the groundwork for future clinical research targeting the TRPV4 channel in antiviral therapies."

Journal • Infectious Disease • Influenza • Respiratory Diseases

Systematic Reevaluation of Repurposed Drugs Against the Main Protease of SARS-CoV-2 via Combined Experiments. (PubMed, J Med Virol) - "Our results from a set of in vitro assays revealed that boceprevir is a potential Mpro inhibitor, but other repurposed drugs, including atazanavir, dipyridamole, entrectinib, ethacridine, glecaprevir, hydroxychloroquine, ivermectin, meisoindigo, pelitinib, raloxifene, roxatidine acetate, saquinavir, teicoplanin, thonzonium bromide, and valacyclovir, are not. Our research highlights that the use of candidate Mpro inhibitors from primary screening warrants further comprehensive studies before the reporting of new findings."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Coproporphyrin-I as a Selective OATP1B Biomarker Can Be Used to Delineate the Mechanisms of Complex Drug-Drug Interactions: Cedirogant Case Study. (PubMed, Clin Pharmacol Ther) - "Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUCtau) by 141% and 55%, respectively when co-administered, whereas atorvastatin Cmax increased by 40% with no effect on its AUCtau compared with administration of rosuvastatin/atorvastatin alone. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [Cmax,u]/[OATP1B1 IC50] of > 0.1 are associated with > 1.25-fold increase in CP-I Cmax ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions."

Biomarker • Journal • Breast Cancer • Dermatology • Immunology • Oncology • Psoriasis • Solid Tumor • CYP3A4

Extended 6-month stability data in blister packs demonstrated for hepatitis C medications (BSG 2024) - "Quantitative The stability of in-date originally packed sofosbuvir 400mg/velpatasvir 100mg (S/V) and glecaprevir 100mg/pibrentasvir 40mg (G/P) tablets were assessed in BP at room temperature, monthly over six months for:Tablet weightUltraviolet-visible spectroscopy (measuring absorbance to determine active-ingredient concentration variations)Infra-red spectroscopy (to observe composition variations)Control measurements were obtained of both S/V and G/P.Qualitative We surveyed HCV operation delivery networks (ODN) on BP use.View this table:View inline View popup 48 Table 1 Changes of S/V and G/P in BP over six months compared to controlQuantitativeData reported as mean ± standard deviation with *p<0.05, **p<0.01, ***p<0.001Qualitative: 11 responses were received, but 2 ODN responded twice. Composition variances were observed, but all below 10% and not related to the actives; these could be due to water absorbance, excipient changes and/or machine/operator..."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

SHERPA: Study of Hepatitis Eradication Receiving Protease Inhibitor Administration (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: Sentara Norfolk General Hospital | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Cardiovascular • Coronary Artery Disease • Hepatology • Inflammation

Preclinical Pharmacokinetic Assessment of a Hepatitis C Virus Long-Acting Injectable Formulation (CROI 2024) - "Background: Eight weeks of daily, oral glecaprevir (G) and pibrentasvir (P) cures 98% of people with chronic Hepatitis C Virus (HCV) infection. Preclinical data for a novel G/P LAI demonstrate sustained therapeutic concentrations in rats over a period of 13 weeks, exceeding the 8-week human target duration. Parenteral administration did not adversely affect hepatic penetration in comparison to the oral route. Further work is required to optimise drug ratios and confirm safety through GLP toxicology assessments to support first-in-human evaluation."

PK/PD data • Preclinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation

In silico strategies for identifying therapeutic candidates against Acinetobacter baumannii: spotlight on the UDP-N-acetylmuramoyl-L-alanine-D-glutamate:meso-diaminopimelate ligase (MurE). (PubMed, J Biomol Struct Dyn) - "Out of 500 drug molecules, two were selected based on estimated binding affinity, interaction pattern, interacting residues, etc. The selected drug molecules are DB12887 (Tazemetostat) and DB13879 (Glecaprevir). All the analysis performed on MD trajectories for the complexes of these ligands with protein provided plenty of dependable evidences to consider these molecules for inhibition of MurE enzyme from A. baumannii. Communicated by Ramaswamy H. Sarma."

Journal • CNS Disorders • Infectious Disease • Nephrology • Pneumonia • Respiratory Diseases

Development of a long-acting injectable formulation for the treatment of hepatitis C (ACS-Sp 2024) - "Long-acting injectable SDN formulations of two antiviral drugs, glecaprevir (GLE) and pibrentasvir (PIB), have been developed both as single formulations and fixed dose combinations (FDC), using emulsion-templated spray drying (ETSD)...In vivo pharmacokinetic studies of GLE and PIB formulations, and a FDC of 1:1 GLE:PIB have been when re-dispersed in water for injection showed a prolonged release over a period of 3 months for the FDC and the single PIB formulation. The SDN formulation comprising solely of GLE saw the API release quicker over the course of 1 month, whilst within the FDC the release profile of GLE was comparable to PIB in terms of release duration. The data presented demonstrates the feasibility of a long-acting injectable formulations of GLE and PIB, which the offers the potential opportunity to treat hepatitis C using a single injection at the point of diagnosis."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

The role of SARS-CoV-2 ORF7a in autophagy flux disruption: implications for viral infection and pathogenesis. (PubMed, Autophagy) - "Furthermore, our study highlights that ORF7a can be a therapeutic target, and glecaprevir may hold potential as a drug against SARS-CoV-2 by targeting ORF7a. The key observations revealed in this study also contribute to a growing understanding of the function of SARS-CoV-2 ORF7a and the mechanisms underlying COVID-2019 treatment."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation. (PubMed, Drug Metab Dispos) - "Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10-20 µM, which is physiologically relevant in comparison to the K of DHEA-S oxidation (reported to be between 5 to 20 µM). We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CYP3A7

An Inducible ESCRT-III Inhibition Tool to Control HIV-1 Budding. (PubMed, Viruses) - "We characterized the CHMP-NS3 fusion proteins in the absence and presence of protease inhibitor Glecaprevir with regard to expression, stability, localization, and HIV-1 Gag VLP budding...Through the combined use of transmission electron microscopy and video-microscopy, we unveiled drug-dependent accumulation of CHMP2A-NS3 and CHMP4B-NS3, causing a delay in HIV-1 Gag-VLP release. Our findings provide novel insight into the functional consequences of inhibiting ESCRT-III during HIV-1 budding and establish new tools to decipher the role of ESCRT-III at HIV-1 budding sites and other ESCRT-catalyzed cellular processes."

Journal • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation

VIDEO: ‘Unique’ protocol expands transplant pool to include HCV-infected donors (Healio) - "In this video, Norah Terrault, MD, MPH, FAASLD, spoke with Healio about a presentation from The Liver Meeting on 'The Toronto Protocol,' an ultra-short course of glecaprevir/pibrentasvir with ezetimibe."

Video

SARS-CoV-2 ORF7a blocked autophagy flux by intervening in the fusion between autophagosome and lysosome to promote viral infection and pathogenesis. (PubMed, J Med Virol) - "This study demonstrated that ORF7a could be a therapeutic target, and Glecaprevir may be a potential drug against SARS-CoV-2 by targeting ORF7a. A comprehensive understanding of ORF7a's functions may contribute to developing novel therapies and clinical drugs against COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Preemptive antiviral therapy in lung transplantation from hepatitis C donors results in a rapid and sustained virologic response. (PubMed, JTCVS Open) - "Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission."

Clinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Transplantation

Process development for glecaprevir (ACS-Fall 2023) - "The key steps in the amino acid synthesis were a Knoevenagel condensation, a Corey-Chaykovsky cyclopropanation, a Curtius rearrangement, and a chiral resolution. Subsequent coupling of the macrocycle to the amino acid containing sidechain produced glecaprevir in 16% overall yield."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

Scale up of clinical candidates and key intermediates for cystic fibrosis and hepatitis C (ACS-Fall 2023) - "In this talk, we profile two case studies from a 20+ year career at AbbVie that spans work in Discovery, Process, and a dedicated synthesis group. These case studies will focus on the scale up of clinical candidate ABBV-3221 from the Cystic Fibrosis program and ABT-493 for the treatment of HCV."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases

A Simplified Algorithm for the Management of Hepatitis C Infection. (PubMed, Gastroenterol Hepatol (N Y)) - "The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. This algorithm provides guidance for management of uncomplicated cases of HCV by frontline HCPs and indicates when referral to an HCV specialist is warranted. The algorithm was created to enable more HCPs to screen for and manage HCV infection, and thus contribute to its elimination."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Oncology • Solid Tumor

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors. (PubMed, Int J Mol Sci) - "A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing."

Journal • Hematological Disorders • Infectious Disease

SHERPA: Study of Hepatitis Eradication Receiving Protease Inhibitor Administration (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: Sentara Norfolk General Hospital | Trial completion date: Mar 2023 ➔ Mar 2024 | Trial primary completion date: Mar 2023 ➔ Mar 2024

Trial completion date • Trial primary completion date • Cardiovascular • Coronary Artery Disease • Hepatology • Inflammation

Challenges and synthetic opportunities of macrocyclization as a tool for the development of highly selective kinase inhibitors (ACS-Sp 2023) - "Recent drug approvals such as Lorlatinib, Pacritinib, Glecaprevir, or Voxilaprevir underline the clinical relevance of drug-like macrocycles. Thus, the orthosteric binding pocket of protein kinases is highly conserved and the development of macrocyclic kinase inhibitors is one strategy to overcome this problem. Here I will discuss the challenges and synthetic opportunities for the development of highly selective macrocyclic kinase inhibitors."

An exploratory study evaluating the 30 medications most commonly associated with headaches in the FDA Adverse Event Reporting System. (PubMed, Headache) - "Our study offers a potential list of the medication classes commonly associated with iatrogenic headaches."

Adverse events • Journal • Cardiovascular • Hypertension • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Prospects for Long-Acting Treatments for Hepatitis C. (PubMed, Clin Infect Dis) - "One such tool could be long-acting parenteral formulations of HCV treatments, which may allow PLWHC to be diagnosed and cured in a single encounter. Although existing highly effective oral medications might be formulated as long-acting parenteral treatments, pharmacological, regulatory, patent, and medical challenges have to be overcome; this requires the concerted efforts of PLWHC, researchers, funding agencies, industry, the World Health Organization, and other stakeholders."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Hard-to-Treat HCV - An Approach to Retreatment With Extended Duration: A Case Report (ACG 2022) - "Among his previous salvage courses included glecaprevir-pibrentasivir-sofosbuvir-ribavirin (SOF/G/P) for 24 weeks (with relapse) followed by 24 weeks of sofosbuvir-velpatasvir-voxilaprevir-ribavirin (SOF/VEL/VOX) for 24 weeks (with relapse). We then elected to initiate a protracted course of antiviral therapy SOF/daclatasvir followed by SOF/velpatasvir (SOF/VEL), SOF/G/P, and SOF/VEL for a total duration of 56 weeks...Our patient despite a history of failing to achieve SVR, was finally able to achieve SVR12 after roughly 13 months of continuous DAAs coupled with RBV and IFN as tolerated. It is possible, therefore, that extending treatment length beyond current recommendations may be necessary to successfully induce a durable response among patients with multiple RASs and previous treatment failures."

Clinical • Fibrosis • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation

A Hepatitis C (HCV) Infection Treatment Dilemma (ACG 2022) - "Carbamazepine (CBZ) is contraindicated with all available DAAs...An initial plan for daclatasvir (DAC)-sofosbuvir (SOF)-ribavirin (RBV) was proposed, but DAC is no longer available in the US...Given worsening liver condition, shared decision-making was performed, and patient completed 16 weeks of Glecaprevir (GLE)/pibrentasvir (PIB) + SOF 400mg with 4 weeks of ezetimibe 10mg stopping when the viral load was undetectable. Patient was instructed to start the ezetimibe with the GLE/PIB + SOF but was hesitant to take it due to adverse reaction to statins in the past...HCV relies on cell-to-cell transmission, so we chose to add ezetimibe 10mg daily until HCV not detected. There is a need for larger studies to determine the applicability of this case study to other patients."

Anemia • Fibrosis • Hematological Disorders • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Neuralgia • Pain • Thrombocytopenia