beclabuvir (BMS-791325) / BMS - LARVOL DELTA

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

Novel pseudonucleosides and sulfamoyl-oxazolidinone β-D-glucosamine derivative as anti-COVID-19: design, synthesis, and in silico study. (PubMed, J Biomol Struct Dyn) - "Interesting molecular docking of the prepared pseudonucleosides and (Beclabuvir, Remdesivir) drugs with SARS-CoV-2/M (PDB:5R80) was conducted using the same parameters for a fair comparison. After the motivating results of molecular docking study, the complex between the SARS-CoV-2 M and compound 7 was subjected to 100 ns molecular dynamics (MD) simulation using Desmond module of Schrodinger suite, during which the receptor-ligand complex showed substantial stability after 10 ns of MD simulation. Also, we studied the prediction of absorption, distribution, properties of metabolism, excretion, and toxicity (ADMET) of the synthesized compounds.Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

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

Re-Purposing of Hepatitis C Virus FDA Approved Direct Acting Antivirals as Potential SARS-CoV-2 Protease Inhibitors. (PubMed, J Mol Struct) - "The docked structures were examined and resulted in the identification of six highly promising DAAs i.e. beclabuvir, elbasvir, paritaprevir, grazoprevir, simeprevir, and asunapevir exhibiting high theoretical binding affinity to Mpro from SARS-CoV-2 in comparison to other DAAs. Furthermore, the correlation between binding energies were found in accord with the results from the reported ICs for some DAAs. Overall, the current study provides insight to combat COVID-19 using FDA-approved DAAs as repurposed drugs."

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

Potential inhibitors for the novel coronavirus (SARS-CoV-2). (PubMed, Brief Bioinform) - "In this study, we use the ligand-protein docking program and molecular dynamic simulation to ab initio investigate the binding mechanism and inhibitory ability of seven clinically approved drugs (Chloroquine, Hydroxychloroquine, Remdesivir, Ritonavir, Beclabuvir, Indinavir and Favipiravir) and a recently designed α-ketoamide inhibitor (13b) at the molecular level. We further calculate the important binding site residues at the active site and demonstrate that the MET 165 and HIE 163 contribute the most for 13b, while the MET 165 and GLN 189 for Chloroquine, based on residual energy decomposition analysis. The proposed work offers a higher research priority for 13b to treat the infection of SARS-CoV-2 and provides theoretical basis for further design of effective drug molecules with stronger inhibition."

Journal • Infectious Disease • Novel Coronavirus Disease

Molecular Docking and Virtual Screening based prediction of drugs for COVID-19. (PubMed, Comb Chem High Throughput Screen) - "Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. (PubMed, JHEP Rep) - "Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir...S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures...We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs."

Journal • Fibrosis • Hepatitis C Virus • Hepatology • Immunology • Infectious Disease

Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking Screening. (PubMed, Comb Chem High Throughput Screen) - "These promising drugs could inhibit the replication of the virus; hence, we suggest the repurposing of these compounds for thetreatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs involves further in vivo tests for these drugs."

Journal • Gene Therapies • Hepatitis B • Hepatitis C Virus • Human Immunodeficiency Virus • Immunology • Infectious Disease • Novel Coronavirus Disease

Exposure-Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Patients. (PubMed, Clin Pharmacol Drug Dev) - "With the exception of the NS5A-Q30 substitution in genotype-1a subjects, statistically significant covariate effects had little impact on SVR12 rates. Overall, the E-R model was developed that captured the high SVR12 rates and the effect of covariates for the 3DAA regimen in HCV-infected patients."

Clinical • Journal • Fibrosis • Hepatitis C Virus • Hepatology • Immunology • Infectious Disease

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV-Infected Subjects. (PubMed, Clin Pharmacol Drug Dev) - "The effects of all covariates on daclatasvir PK were modest and not considered clinically significant. With the exception of race on asunaprevir and beclabuvir PK, no other parameters for daclatasvir, asunaprevir and beclabuvir population PK models were meaningfully impacted during the refinement with Japanese subjects."

Clinical • Journal • PK/PD data • Fibrosis • Hepatitis C Virus • Hepatology • Immunology • Infectious Disease

Real-word efficacy of sofosbuvir, velpatasvir plus ribavirin therapy for chronic hepatitis patients who failed to prior DAA therapy with NS5A-P32 deletion mutated HCV infection. (PubMed, Clin J Gastroenterol) - "The patients developed HCV NS5A-P32del, L31F + P32del, or L31V + P32del variants following failure of daclatasvir plus asunaprevir (DCV/ASV) therapy. One of the patients failed to respond to subsequent DCV/ASV and beclabuvir therapy, and the remaining two patients failed to respond to subsequent glecaprevir and pibrentasvir therapy...Direct sequence analysis detected no additional variants within either the NS5A or NS5B regions at the time of relapse. In conclusion, three patients with prior NS5A-P32del-associated DAA treatment failure received 24 weeks of SOF/VEL + RBV therapy, and two of the patients achieved SVR12."

Clinical • Journal • Hepatitis C Virus • Infectious Disease

Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir. (PubMed, J Hum Genet) - "To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms."

Journal

Safety Exposure-Response Analysis for Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Subjects. (PubMed, J Clin Pharmacol) - "Subjects with F4 fibrosis score had a higher rate of Grade 3 or 4 Tbili elevation compared to subjects with F0 to F3 fibrosis score. Higher asunaprevir exposure was associated with increases in Grade 3 or 4 ALT and Tbili elevation rates; however, the impact on the ALT elevation was not clinically relevant and the effect on Tbili elevation was smaller than the other significant covariates."

Clinical • Journal • Fibrosis • Hepatitis C Virus • Immunology

Effect of DAAs therapy for chronic hepatitis C on lipid levels (AASLD 2017) - "A total of 315 pts received daclatasvir and asunaprevir, 102 received sofosbuvir and ledipasvir, 49 received ombitasvir and paritaprevir, 13 received elbasvir and grazoprevir, 18 received daclatasvir, asunaprevir and beclabuvir, and 168 received sofosbuvir and ribavirin [median age, 66 years; 287 men(43%); 182 pts(27%)with cirrhosis, and 497(75%) with genotype(Gt)1]. [Conclusion] Lipid levels significantly increase in patients with successful eradication of HCV through DAAs therapy."

Clinical • Biosimilar • Fibrosis • Hepatitis C Virus

Study to determine the effect of BMS-791325 on the ECG QTcF interval in healthy subjects (clinicaltrials.gov) - P1, N=60; Sponsor: Bristol-Myers Squibb; Not yet recruiting; New P1 trial.

New P1 trial • Hepatitis C Virus

Safety, Tolerability, and Efficacy of Asunaprevir and Daclatasvir in Subjects Coinfected With HIV-HCV (clinicaltrials.gov) - P2; N=39; Completed; Sponsor: National Institutes of Health Clinical Center (CC); Active, not recruiting ➔ Completed; Trial primary completion date: Nov 2016 ➔ Mar 2016

Trial completion • Trial primary completion date • Biosimilar • Gene Therapies • Hepatitis C Virus • Human Immunodeficiency Virus

Bristol-Myers Squibb to present new data demonstrating company’s continuing commitment to research and development in liver disease at the American Association for the Study of Liver Diseases (AASLD) annual meeting (Business Wire) - "Late breaker oral presentation...first report of SVR4 results from an interferon- and ribavirin-free, 12-week, triple DAA...daclatasvir, asunaprevir and BMS-791325 in hepatitis C (HCV)...Oral presentations on...daclatasvir, asunaprevir and peginterferon lambda-1a (Lambda) demonstrate diversity of portfolio"

Anticipated clinical data • Hepatitis C Virus

A study of an investigational treatment regimen of daclatasvir (DCV) + asunaprevir (ASV) + BMS-791325 in a fixed dose combination (the triple regimen) with or without ribavirin (RBV) for 12 weeks for the treatment of chronic hepatitis C virus (HCV)... (clinicaltrials.gov) - P3, N=200; Sponsor: Bristol-Myers Squibb; Not yet recruiting; New P3 trial.

New P3 trial • Hepatitis C Virus

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=1000; Recruiting; Sponsor: Bristol-Myers Squibb

New trial • Biosimilar • Fibrosis • Hepatitis C Virus • Immunology

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects. (PubMed, Drugs R D) - "No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended."

Clinical • Journal • Biosimilar • Hepatitis C Virus • Immunology • Infectious Disease

Daclatasvir present and future DAA combinations (HepDART 2013) - Abstract 29; P3, N=222; NCT01497834; Sponsor: Bristol-Myers Squibb; P2b, N=166; "In the phase 3 study of daclatasvir + asunaprevir, SVR24 was achieved by 84.7% of patients overall....In the phase 2b study of the DCV-based 3-DAA regimen, SVR12 was achieved by 92.2% or 91.7% of patients in the arms receiving BMS-791325 75 mg or 150 mg, respectively, without apparent differences associated with GT1 subtype or presence of cirrhosis."

P2 data • P3 data • Hepatitis C Virus

Broad-spectrum non-nucleoside inhibitors for caliciviruses. (PubMed, Antiviral Res) - "These NNIs included JTK-109 (RdRp inhibition range: IC50 4.3-16.6 μM), TMC-647055 (IC50 range: 18.8-45.4 μM) and Beclabuvir (IC50 range: 23.8->100 μM). Together, this study demonstrates the potential for de novo development of broad-spectrum antivirals that target the highly-conserved RdRp thumb pocket, Site-B. We also revealed three broad-spectrum HCV NNIs that could be used as antiviral scaffolds for further development against caliciviruses and other viruses."

Journal • Biosimilar • Hepatitis C Virus • Immunology • Infectious Disease

Robust HCV Genotype 3a Infectious Cell Culture System Permits Identification of Escape Variants With Resistance to Sofosbuvir. (PubMed) - Gastroenterology - "We developed a system for highly efficient culture of HCV genotype 3a. Genotype 1a has a high genetic barrier to resistance for sofosbuvir, whereas resistance to this DAA can be induced in genotype 3a. We therefore isolated HCV genotype 3a variants with reduced sensitivity to sofosbuvir, with increased fitness and with cross-resistance to other NS5B inhibitors. These findings indicate that sofosbuvir escape variants could compromise the effectiveness of nucleotide analogs against HCV. GenBank accession numbers: KX280712-KX280716."

Journal • Biosimilar • Hepatitis C Virus • Immunology • Infectious Disease

Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes (Antimicrob Agents Chemother) - P=NA, N=NA; "To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a, 3a-6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest."

Clinical • Hepatitis C Virus

Multi-Target DAA Therapy is associated with resolution of T cell suppression marked by reduced T regulatory cells and Myeloid derived suppressor cells in HIV/HCV CoInfected Patients (AASLD 2017) - " We analyzed PBMC, at baseline and at the time of sustained viral response (SVR), from subjects treated with three different combination DAA regimens: daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks (CONQUER 2 DAA), DCV/ASV/beclabuvir (BCV) for 12 weeks (CONQUER 3 DAA), and sofosbuvir (SOF) and ledipasvir (LDV) for 12 weeks (ERADICATE study). Thus this study demonstrates that treatment with 3 DAA regimens is associated with superior recovery in terms of resolution of immunosuppressive cells. This is consistent with our previous finding that showed treatment with 3 DAA therapy (DCV/ASV/BCV) resulted in greater restoration of the T cell impairments and perturbations associated with HIV/HCV co-infection compare to the two-drug regimen. Thus our results strongly suggest that DAA-based therapies targeting at three points of the viral life cycle rather than two are associated with greater normalization of immune responses."

Clinical • Myeloid-derived suppressor cells • Biosimilar • Gene Therapies • Hepatitis C Virus • Immunology • Infectious Disease