Ximency (daclatasvir/asunaprevir/beclabuvir) / 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

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

A Cost-Effectiveness Analysis of Glecaprevir/Pibrentasvir Versus Existing Direct-Acting Antivirals to Treat Chronic Hepatitis C in Japan. (PubMed, Adv Ther) - "In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio."

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

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-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan. (PubMed, J Gastroenterol) - "Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen."

Clinical • Journal • Real-World Evidence • Hepatitis C Virus • Infectious Disease

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

Safety, Tolerability, and Efficacy of Asunaprevir and Daclatasvir in Subjects Coinfected With HIV-HCV (clinicaltrials.gov) - P2; N=39; Active, not recruiting; Sponsor: National Institutes of Health Clinical Center (CC); Recruiting ➔ Active, not recruiting; N=60 ➔ 39; Trial primary completion date: Jan 2016 ➔ Nov 2016

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

A Phase 3 Study of a Daclatasvir/Asunaprevir/BMS-791325 Fixed Dose Combination (FDC) in Subjects With Chronic Hepatitis C Genotype 1 (clinicaltrials.gov) - P3; N=160; Active, not recruiting; Sponsor: Bristol-Myers Squibb; Suspended -> Active, not recruiting

Enrollment closed • Biosimilar • Hepatitis C Virus

UNITY 4: A Phase 3 Study of a Daclatasvir/Asunaprevir/BMS-791325 Fixed Dose Combination (FDC) in Subjects With Chronic Hepatitis C Genotype 1 (clinicaltrials.gov) - P3; N=169; Completed; Sponsor: Bristol-Myers Squibb; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

Phase 3 UNITY trials demonstrate high cure rates for investigational, all-oral daclatasvir trio fixed-dose combination in genotype 1 hepatitis c patients, including those with cirrhosis (Bristol-Myers Squibb Press Release) - P3, N=102; UNITY-2 (NCT01973049); Sponsor BMS; "Daclatasvir TRIO achieves 98% cure rate in treatment-naïve and 93% cure rate in treatment-experienced genotype 1 patients with cirrhosis when used with ribavirin, as shown in UNITY 2...12-week, all-oral treatment halves current regimen duration for hard-to-manage treatment-experienced genotype 1 patients with cirrhosis...Fixed-dose regimen also demonstrates 91% SVR rates in non-cirrhotic genotype 1 patients without requiring use of ribavirin...The data will be presented at The Liver Meeting® 2014, the Annual Meeting of...(AASLD)...."

P3 data • Hepatitis C Virus

Bristol-Myers Squibb statement about asunaprevir in the U.S. (Bristol-Myers Squibb Press Release) - "...Bristol-Myers Squibb (NYSE:BMY) has decided that it will not pursue U.S. Food and Drug Administration (FDA) approval of the dual regimen of daclatasvir and asunaprevir for the treatment of HCV genotype 1b patients in the United States and has therefore withdrawn its new drug application (NDA) for asunaprevir, an NS3/4A protease inhibitor. The company will continue to pursue FDA approval of daclatasvir....Next month at the annual meeting of The American Association for the Study of Liver Diseases (AASLD), we will present new data from several daclatasvir-based regimens."

Anticipated clinical data • NDA • Hepatitis C Virus

BMS: Q3 2014 Results (Bristol-Myers Squibb) - Anticipated presentation of UNITY-1 P3 trial data for HCV at AASLD (Nov 07-11, 2014); Anticipated presentation of UNITY-2 P3 trial data for HCV at AASLD (Nov 07-11, 2014)

Anticipated P3 data • Hepatitis C Virus

Bristol-Myers Squibb receives complete response letter from U.S. Food and Drug Administration for daclatasvir, an investigational treatment for hepatitis C (Bristol-Myers Squibb Press Release) - "Bristol-Myers Squibb Company (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for daclatasvir...in combination with other agents for the treatment of hepatitis C (HCV)....FDA is requesting additional data for daclatasvir in combination with other antiviral agents for the treatment of HCV....Will continue to collaborate with the FDA to bring daclatasvir to patients in the U.S. as quickly as possible.”

FDA event • Hepatitis C Virus

Bristol-Myers Squibb submits NDAs for daclatasvir and asunaprevir to US FDA for the treatment of hepatitis C (Bristol-Myers Squibb Press Release) - "Bristol-Myers Squibb...announced today that they have submitted new drug applications (NDAs) with the U.S. Food and Drug Administration (FDA) for the investigational products daclatasvir...and asunaprevir (ASV), a NS3 protease inhibitor. The data submitted in the NDAs support the use of DCV+ASV in patients with genotype 1b hepatitis C (HCV). The DCV NDA also seeks approval for use of this compound in combination with other agents for multiple genotypes....In 2013, the investigational all-oral 3DAA Regimen (daclatasvir/asunaprevir/BMS-791325) also received Breakthrough Therapy Designation, and the company anticipates submitting this regimen for FDA review in Q1 2015."

NDA • 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) for 12 weeks for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in non-cirrhotic (clinicaltrials.gov) - P3, N=400; Sponsor: Bristol-Myers Squibb; Not yet recruiting; New P3 trial.

New P3 trial • Hepatitis C Virus

Efficacy and safety of a fixed dose combination tablet of asunaprevir + beclabuvir + daclatasvir for the treatment of Hepatitis C. (PubMed, Expert Opin Pharmacother) - "Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence..."

Clinical • Journal

Favorable outcome of retreatment by direct-acting antivirals for the hepatitis C patients with Daclatasvir plus Asunaprevir combination therapy failure. (PubMed, Hepatol Res) - "AASs were frequently observed in patients with DCV+ASV failure, but most patients achieved an SVR following re-treatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV+ASV failure were overcome with additional treatment."

Clinical • Combination therapy • Journal

Pooled analysis of HCV genotype 1 resistance-associated substitutions in NS5A, NS3 and NS5B pre- and post-treatment with 12 weeks of daclatasvir, asunaprevir and beclabuvir. (PubMed, Antivir Ther) - "DCV+ASV+BCV±RBV was highly efficacious in HCV GT-1 infection, including HCV GT-1b with NS5A RAS. The fitness of treatment-emergent RAS post-treatment was NS5A > NS3 > NS5B; NS3 and NS5B RAS were generally replaced by wild-type sequence within 48 weeks."

Journal • Retrospective data

Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure. (PubMed, J Gen Virol) - "Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed."

Clinical • Journal

Potent viral suppression and improvements in alpha-fetoprotein and measures of fibrosis in Japanese patients receiving a daclatasvir/asunaprevir/beclabuvir fixed-dose combination for the treatment of HCV genotype-1 infection. (PubMed, J Gastroenterol) - "DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis."

Clinical • Journal