Daclatasvir: potential role in hepatitis C

Figures & data

Figure 1 Structure of daclatasvir.

Figure 2 Mechanism of action for daclatasvir.

Abbreviations: DCV, daclatasvir; HCV, hepatitis C virus; NS, nonstructural viral protein; N-term, N terminal; P, phosphate.

Table 1 Summary of the clinical trial results of daclatasvir

Study	Reference	Number of patients	GT	Treatment	Note
DCV-alone regimens
Phase I	Gao et al^Citation27	6	1	Single dose of 1, 10, and 100 mg	aCmin>bEC90 cT1/2 10–14 hr MCAE: headache
	3.3 log10 reduction at 24 hr postdose with 10 and 100 mg of DCV
	A sustained reduction for an additional 120 hr in two GT 1b patients
	A more sustained decline for GT 1b than for GT 1a patients
Phase II	Nettles et al^Citation39	30	1	Once daily dose of 1, 10, 30, 60, or 100 mg or twice daily dose of 30 mg for 14 days	cT1/2 12–15 hr MCAE: headache
	A 2.8 to 4.1 log10 of mean maximum decline
	Viral rebound on or before day 7
	A greater antiviral response for GT 1b than for GT 1a patients
IFN-containing regimens
Phase IIa	Pol et al^Citation28	48	1	Once daily dose of 3, 10, and 60 mg of DCV with PEG-IFNα and RBV for 48 weeks	PEP: eRVR
	8%, 42%, 83%, and 75% of eRVR achieved for patients treated with 0, 3, 10, and 60 mg of DCV with PEG-IFNα and RBV, respectively
Phase IIa	Lok et al^Citation43	21 (all null responders to previous PEG-IFNα and RBV treatment)	1	Once daily dose of 60 mg of DCV and 600 mg of ASV with or without PEG-IFNα and RBV for 24 weeks	PEP: SVR12 MCAE: diarrhea
	36% and 90% of SVR12 achieved for patients treated with PEG-IFNα and RBV alone or together with 60 mg of DCV and 600 mg of ASV, respectively
IFN-free regimens
Phase IIa	Sulkowski et al^Citation45	170	1, 2, 3	Once daily dose of 60 mg of DCV and 400 mg of SOF with or without RBV for 24 weeks	PEP: SVR24
	Cotreatment of DCV and SOF with or without RBV achieved SVR24 in more than 93% of patients with HCV GT 1, 2, or 3
Phase IIa	Sulkowski et al^Citation44	41 (all null responders to previous telaprevir or boceprevir plus PEG-IFNα and RBV treatment)	1	Once daily dose of 60 mg of DCV and 400 mg of SOF with or without RBV for 24 weeks	PEP: SVR12
	The all-oral, once-daily combination of DCV and SOF with or without RBV achieved SVR12 in all 41 HCV GT 1–infected patients who failed prior treatment
Phase IIa	Chayama et al^Citation46	9 (all null responders to previous PEG-IFNα and RBV treatment)	1b	Once daily dose of 60 mg of DCV and twice daily dose of 600 mg of ASV for 24 weeks	PEP: SVR12 MCAEs: diarrhea and headache
	100% of SVR12 achieved, for patients treated with 60 mg of DCV and 600 mg of ASV
	No viral breakthrough or relapse observed during or after treatment
Phase IIa	Suzuki et al^Citation47	21 (all null responders to previous PEG-IFNα and RBV treatment) 22 (all ineligible/intolerant for PEG-IFNα and RBV treatment)	1b	Once daily dose of 60 mg of DCV and twice daily dose of 200 mg of ASV for 24 weeks	PEP: SVR12
		90.5% and 63.6% of SVR12 achieved, for null responders and ineligible/intolerant patients, respectively
	Viral breakthrough for three ineligible/intolerant patients

Notes:

a Minimal plasma concentration

b protein binding–adjusted 90% median effective concentration

c mean plasma elimination half-life.

Abbreviations: ASV, asunaprevir; DCV, daclatasvir; eRVR, extended rapid virologic response at 4 and 12 weeks after start of treatment; GT, genotype; PEP, primary end point; MCAE, most common adverse event; PEG-IFNα, pegylated interferon-α; RBV, ribavirin; SOF, sofosbuvir; SVR₁₂, sustained virologic response at 12 weeks after end of treatment; SVR₂₄, sustained virologic response at 24 weeks after end of treatment; hr, hours.

Gao M Nettles RE Belema M Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010 465 7294 96 100 20410884

 PubMed Web of Science ®Google Scholar

Nettles RE Gao M Bifano M Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1 Hepatology 2011 54 6 1956 1965 21837752

 PubMed Web of Science ®Google Scholar

Pol S Ghalib RH Rustgi VK Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial Lancet Infect Dis 2012 12 9 671 677 22714001

 PubMed Web of Science ®Google Scholar

Lok AS Gardiner DF Lawitz E Preliminary study of two antiviral agents for hepatitis C genotype 1 N Engl J Med 2012 366 3 216 224 22256805

 PubMed Web of Science ®Google Scholar

Sulkowski MS Gardiner DF Rodriguez-Torres M AI444040 Study Group High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 Hepatology 2012 56 1516 1517

 Web of Science ®Google Scholar

Sulkowski MS Gardiner DF Rodriguez-Torres M AI444-040 Study Group Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC) Presented at: 48th Annual Meeting of the European Association for the Study of the Liver April 24–28, 2013 Amsterdam, The Netherlands

 Google Scholar

Chayama K Takahashi S Toyota J Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders Hepatology 2012 55 3 742 748 21987462

 PubMed Web of Science ®Google Scholar

Suzuki Y Ikeda K Suzuki F Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options J Hepatol 2013 58 4 655 662 23183526

 PubMed Web of Science ®Google Scholar