Sunvepra (asunaprevir) / BMS - LARVOL DELTA

Hepatitis C treatment in arterial hypertension is safe and highly effective: real-world study (EASL 2025) - "The predictors of treatment failure in AH patients included genotype 3 infection, decompensated liver function, cirrhosis, thrombocytopenia, and treatment with asunaprevir+daclatasvir. Although hypertensive patients were more prone to therapy discontinuation, the vast majority of them completed it, with only one-fifth reporting adverse events, mostly fatigue. The study shows that DAAs therapy is safe and effective in hypertensive patients and underscores the need for targeted screening strategies, particularly in hypertensive individuals, to optimize treatment success and reduce the long- term burden of HCV in this population."

Clinical • Real-world • Real-world evidence • Anemia • Cardiovascular • Fatigue • Fibrosis • Genetic Disorders • Hematological Disorders • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Failure • Obesity • Oncology • Pulmonary Arterial Hypertension • Solid Tumor • Thrombocytopenia

SWITCH-1: Switching Regimen in Treating Cirrhotic HCV GT1b Subjects (clinicaltrials.gov) - P2 | N=138 | Completed | Sponsor: Humanity and Health Research Centre | Recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Oct 2024 | Trial primary completion date: Oct 2022 ➔ Oct 2024

Trial completion • Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Development of an OATP1-humanized transchromosomic mouse model for prediction of hepatic drug uptake in humans. (PubMed, Drug Metab Dispos) - "Rifampicin (60 mg/kg orally) increased the area under the plasma concentration-time curves of orally administered pitavastatin and grazoprevir in hOATP1-MAC mice, but not of asunaprevir. SIGNIFICANCE STATEMENT: Transchromosomic technology holds promise for addressing species differences by introducing multiple solute carrier drug transporter genes such as OATP1. Mice OATP1-humanized using a mouse artificial chromosome vector demonstrated enhanced clearance of endogenous OATP1B biomarkers and probe drugs."

Journal • Preclinical • ATP1A1 • SLCO1A2 • SLCO1B3 • SLCO1C1

Drug repositioning and experimental validation for targeting ZZ domain of p62 as a cancer treatment. (PubMed, Comput Biol Med) - "Notable candidates, particularly montelukast and asunaprevir, blocked the p62-RIP1 interaction, establishing a basis for potential therapeutic interventions against chemoresistant cancers. This study highlights the critical role of the ZZ domain of p62 protein in chemotherapy resistance and sheds light on the possibility of repurposing existing drugs for novel applications in cancer treatment. Our findings provide a solid groundwork for preclinical studies."

Journal • Oncology • RIPK1 • SQSTM1

The Role of CYPs and Transporters in the Biotransformation and Transport of the Anti-hepatitis C Antiviral Agents Asunaprevir, Daclatasvir, and Beclabuvir: Impact of Liver Disease, Race and Drug-drug Interactions on Safety and Efficacy. (PubMed, Curr Drug Metab) - "Pharmacokinetic drug-drug interactions, especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • CYP3A4 • SLCO2B1

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

Computer-Aided Prediction of the Interactions of Viral Proteases with Antiviral Drugs: Antiviral Potential of Broad-Spectrum Drugs. (PubMed, Molecules) - "As a result, Compounds 1-2, modified based on the structures of Ray1216 and Asunaprevir, indicate potential inhibition of DENV protease according to our computational simulation results. These studies offer ideas and insights for future research in the design of broad-spectrum antiviral drugs."

Journal • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Potential Target Discovery and Drug Repurposing for Coronaviruses: Study Involving a Knowledge Graph-Based Approach. (PubMed, J Med Internet Res) - "We showed the effectiveness of a knowledge graph-based approach in potential target discovery and drug repurposing for coronaviruses. Our approach can be extended to other viruses or diseases for biomedical knowledge discovery and relevant applications."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. (PubMed, Diagnostics (Basel)) - "L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant...The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats. (PubMed, Pharmaceutics) - "The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes...PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans."

Journal • Preclinical

Going Viral: An Investigation into the Chameleonic Behavior or Antiviral Compounds. (PubMed, Chemistry) - "We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO- d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. No significant differences in size and polar surface area were observed between the DMSO- d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption."

Journal

Hexafluoroisopropanol for the selective deactivation of poisonous nucleophiles enabling catalytic asymmetric cyclopropanation of complex molecules | Poster Board #2420 (ACS-Fall 2022) - "These complex molecules included relevant medicinal compounds including the immunosuppressant FK506, the hepatitis-C therapeutic Asunaprevir, and the procaspase-3-activator PAC-1, as well as natural products like (S)-Cinchonidine.HFIP allows for the selective deactivation of poisonous nucleophiles in dirhodium-catalyzed asymmetric cyclopropanation. The radar plot demonstrates the robustness of the reaction system as a percentage of the nucleophiles tested which can be tolerated under the conditions used (HFIP as solvent). The method is also applicable to the derivatization of complex molecules like (S)-Cinchonidine."

Hepatitis C • Hepatology • Infectious Disease • Inflammation • CASP3

A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice. (PubMed, NAR Cancer) - "SMASh degron-tagged PD-1-mCherry in Jurkat cells and CD3 splenocytes were degraded by the NS3/4A protease inhibitors, asunaprevir (ASV) or grazoprevir (GRV). This is the first study to use a degron tag targeting an endogenous mouse protein in vivo. Our experimental system using the SMASh degron may be employed for treating diseases and characterizing the cellular functions of essential proteins."

Journal • Preclinical • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • Targeted Protein Degradation • Transplantation • PD-1

Early Post-marketing Study of Daclatasvir (Daklinza®) + Asunaprevir (Sunvepra®) in the Treatment of Chronic Hepatitis C (CHC) in Adults (clinicaltrials.gov) - P=N/A | N=0 | Withdrawn | Sponsor: Bristol-Myers Squibb | N=30 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Assessing the Risk of Decrease in Kidney Function in Patients Prescribed Direct-Acting Antivirals for Hepatitis C Utilizing the MID-NET Medical Information Database Network in Japan. (PubMed, Ther Innov Regul Sci) - "Among the 10 patterns, a significant increase in the incidence rate ratio (P < 0.01) was observed in the prescription patterns of concomitant use of telaprevir with peginterferon alpha and ribavirin, concomitant use of daclatasvir hydrochloride with asunaprevir, and ombitasvir hydrate combined with paritaprevir hydrate and ritonavir, which were concomitantly used with ribavirin; such an increase was not observed in the other prescription patterns. The effects of DAAs on kidney function may differ among drugs, suggesting the possibility that the risk of kidney disease is not a class effect of DAAs and should be evaluated individually for each DAA."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Nephrology • Renal Disease

Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing. (PubMed, Hepatol Commun) - "We performed haplotype analysis of HCV mutations in 12 asunaprevir/daclatasvir treatment-failure cases using the Oxford Nanopore sequencer. The combination of various mutations other than the known signature RAS was suggested to influence the kinetics of individual HCV quasispecies in the direct-acting antiviral treatment. HCV haplotype dynamic analysis will provide novel information on the role of HCV diversity within the host, which will be useful for elucidating the pathological mechanism of HCV-related diseases."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models. (PubMed, AAPS J) - "Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters...Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins...Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate..."

Journal • Preclinical • Breast Cancer • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Oncology • Solid Tumor

Evaluation of the Potency of Anti-HIV and Anti-HCV Drugs to Inhibit P-Glycoprotein Mediated Efflux of Digoxin in Caco-2 Cell Line and Human Precision-Cut Intestinal Slices. (PubMed, Pharmaceuticals (Basel)) - "At concentrations of up to 100 µM, asunaprevir, atazanavir, daclatasvir, darunavir, elbasvir, etravirine, grazoprevir, ledipasvir, lopinavir, rilpivirine, ritonavir, saquinavir, and velpatasvir inhibited [H]-digoxin transport in Caco-2 cells and/or in precision-cut intestinal slices prepared from the human jejunum (hPCIS). However, abacavir, dolutegravir, maraviroc, sofosbuvir, tenofovir disoproxil fumarate, and zidovudine had no inhibitory effect...More inhibitors were identified when using digoxin as the ABCB1 probe substrate than when using rhodamine123. However, both approaches had limitations, indicating that inhibitory potency should be tested with at least these two ABCB1 probes."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • ABCB1

Real-world Incidence Proportion of Hepatic Toxicity and All Adverse Drug Reactions (ADRs) in Japanese Patients Receiving Daclatasvir (DCV) Trio Therapy (clinicaltrials.gov) - P=N/A | N=344 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=1000 ➔ 344

Adverse drug reaction • Enrollment change • Real-world evidence • Trial completion • Fibrosis • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation

Hepatitis C Virus NS3/4A Inhibition and Host Immunomodulation by Tannins from Terminalia chebula: A Structural Perspective. (PubMed, Molecules) - "These findings are highly comparable with Asunaprevir (known inhibitor of HCV NS3/4A), which scored a BE of -7.4 kcal/mol with 20 key intermolecular interactions...On overall analysis, this present study predicts that tannins from T. chebula have a potential HCV NS3/4A inhibitory and host immune-modulatory activity. However, further experimental studies are required to confirm the efficacies."

Journal • Hepatitis C • Hepatology • Immune Modulation • Immunology • Infectious Disease • Inflammation

Postmarketing Surveillance of the Safety and Effectiveness of Daclatasvir and Asunaprevir for the Treatment of Chronic HCV Genotype 1B Infection in the Routine Clinical Practice in Korea (clinicaltrials.gov) - P=N/A; N=1941; Completed; Sponsor: Bristol-Myers Squibb; Recruiting ➔ Completed

Trial completion • Hepatitis C • Hepatology • Infectious Disease • Inflammation

A Recurring Chemogenetic Switch for Chimeric Antigen Receptor T Cells. (PubMed, Angew Chem Int Ed Engl) - "By embedding the hepatitis C virus NS3 protease (HCV-NS3) between the single-chain variable fragment (scFv) and the hinge domain, we showed that the display of anti-CD19 scFv on CAR-T cells was positively correlated to the presence of a clinical HCV-NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti-CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically recurring chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR-T activation during cancer treatment."

CAR T-Cell Therapy • Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Oncology

[VIRTUAL] CHANGES IN IMMUNE CELL PROFILES BEFORE AND AFTER TREATMENT WITH DIRECT-ACTING ANTIVIRAL AGENTS IN PATIENTS WITH CHRONIC HEPATITIS C (AASLD 2021) - " Forty-seven and 30 received patients treated by asunaprevir/daclatasvir and ombitasvir / paritaprevir / ritonavir (OBV/PTV/r), respectively, were analyzed in this study. Our study showed that DAAs treatment changes host immune cell profiles and can decrease the frequency of T cells with high expression of PD-1 by eliminating F protein . These results suggest that the strength of immune response against virus or tumor changes after DAAs treatment ."

Clinical • IO biomarker • Hepatitis C • Hepatology • Immune Modulation • Infectious Disease • Inflammation • Oncology • CD8 • CTLA4 • CXCR3 • FOXP3 • IL2RA • PD-1

Effect of sofosbuvir-based DAAs on changes in lower-density lipoprotein in HCV patients: a systematic review and meta-analysis. (PubMed, BMC Infect Dis) - "For HCV patients, SOF-based DAA regimens were associated with rapid and significant increases in LDL during the initial 4 weeks of treatment, and the changes did not sustain after the end of treatment. Potential mechanism might be related to the phosphoramidate side chain of SOF."

Clinical • Journal • Retrospective data • Review • Dyslipidemia • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Asunaprevir, a Potent Hepatitis C Virus Protease Inhibitor, Blocks SARS-CoV-2 Propagation. (PubMed, Mol Cells) - "We found that asunaprevir, but not sofosbuvir and daclatasvir, markedly inhibited SARS-CoV-2-induced cytopathic effects in Vero E6 cells. Furthermore, asunaprevir inhibited SARS-CoV-2 propagation in human lung Calu-3 cells. Collectively, we found that asunaprevir displays broad-spectrum antiviral activity and therefore might be worth developing as a new drug repurposing candidate for COVID-19."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases