Finally sofosbuvir: an oral anti-HCV drug with wide performance capability

Figures & data

Figure 1 Therapeutic targets of the HCV replication cycle.

Notes: DAA viral target sites in advanced clinical development are numbered 1–3. Reprinted from Clin Gastroenterol Hepatol, 12(5), Schmidt WN, Nelson DR, Pawlotsky JM, et al., Direct acting antiviral agents and the path to interferon independence, 728–737, Copyright 2014, with permission from Elsevier.³⁸
Abbreviations: DAA, direct-acting antiviral agent; ER, endoplasmic reticulum; HCV, Hepatitis C virus; LD, luminal domain.

Table 1 Major direct-acting antiviral drugs

Characteristic	PIs	NIs	NNIs	NS5A inhibitors
Potency	High for GT1 Variable for GT2–4	Moderate to high	Variable among GTs	High; multiple among GT
Barrier to resistance	Low; GT1a<1b	Very high; GT1a=1b	Very low; GT1a<1b	Low; GT1a<1b
Drug interaction	High	Low	Variable	Low to moderate
Toxicity	High for first generation Rash, anemia, hyperbilirubinemia	Variable mitochondrial nuclear interactions	Variable	Variable
Agents approved	Telaprevir, boceprevir, simeprevir	Sofosbuvir	None	None
Examples in pipeline	Faldaprevir (BI-201335) MK-5172 Asunaprevir (BMS-650032) Veruprevir (ABT-450/r) Danoprevir (RG7227/ITMN-191)	VX-135 Mercitabine	ABT-072 Dasabuvir (ABT-333) BMS-791325	Daclatsavir (BMS-790052) Ledipsavir (GS-5885) Samatasvir (IDX21437) Ombitasvir (ABT-267)

Note: Comparisons regarding safety and efficacy between all direct-acting antiviral drug groups, along with their barrier to resistance.

Abbreviations: GT, genotype; NIs, nucleotide polymerase inhibitors; NNIs, non-nucleoside inhibitors; PI, protease inhibitors.

Figure 2 Activation of sofosbuvir.

Table 2 Sofosbuvir (SOF) Phase II trials

Name	Regimen	Genotype (n)	Duration (week)	Treatment history (TN, TE)	SVRa (%)	Reference
ELECTRONb	SOF + RBVc SOF SOF + RBV SOF + RBV	2, 3 (10) 2, 3 (10) 1 (25) 1 (10)	12 12 12 12	TN TN TN TE	100 60 84 10	^Citation31
SPAREd	SOF + RBVc SOF + RBV SOF + ½RBV	1 (10) 1 (25) 1 (25)	24	TN	100 68 48	^Citation50

Notes:

a SVR at week 24 post-treatment

b the ELECTRON trial used a fixed 400 mg daily SOF dosage plus weight-based RBV

c SOF: 400 mg daily plus weight-based RBV as indicated

d SPARE: the majority of subjects (70%) were viral subtype 1a, male (62%), AA (83%), non-CC interleukin-28 genotype (80%), body mass index >30 (48%), and 23% had fibrosis stage F3 or F4, with 62% having high viral loads (Hepatitis C virus ribonucleic acid >800,000 IU/mL). Study arm 1 included 9/10 patients with stage F0–F2 fibrosis, while arms 2 and 3 included 24% and 28% patients with F3–F4 fibrosis.

Abbreviations: AA, African American; RVB, ribavirin; SVR, sustained virologic response; TE, treatment experienced; TN, treatment naïve.

Table 3 Sofosbuvir (SOF) ± ribavirin (RBV) Phase III trials

Namea	Regimenb	Genotype	Duration (week)	Treatment history (TN, TE [n])	SVRc (%)	Test (result)	Reference
FISSION	SOF + RBV PR	2 3 2 3	12 12 24 24	TN (73) TN (145) TN (67) TN (176)	91–98d 34–61 62–82 30–71	Noninferiority (SOF + RBV vs PR) (P<0.001)	^Citation46
POSITRON (intolerant, ineligible, or unwilling to take IFN)	SOF + RBV	2 3	12 12	TN (109) TN (98)	94–92 21–68	Superiority (SOF + RBV vs placebo) (P<0.001)	^Citation45
FUSION	SOF + RBV	2 3 2 3	12 12 16 16	TE (39) TE (64) TE (35) TE (63)	60–90 19–37 78–92 61–63	Superiority (16 weeks vs 12 weeks) (P<0.001)	^Citation45
NEUTRINO	SOF + PR	1 4 5, 6	12 12 12	TN (292) TN (28) TN (7)	89e 96 N/A	Superiority (compared with historical rate PR =60%) (SOF + Peg-IFN + RBV) (P,0.001)	^Citation46
VALENCE	SOF + RBV	2 2 3 3	12 24	TN (32) TE (41) TN (105) TE (145)	97 90 93 79	12 vs 24 weeks (all GT3 extended to 24 weeks)	^Citation51

Notes:

a In the FISSION, POSITRON, FUSION, and NEUTRINO studies, 20%, 16%, 34%, and 17% of patients had cirrhosis, respectively;⁶⁵

b all SOF trials used a fixed 400 mg daily dosage given with weight-based RBV

c SVR at week 12 post-treatment

d the lower SVR interval is for cirrhotics, upper interval for noncirrhotics

e SVR for cirrhotics in NEUTRINO was 80% vs 92% for noncirrhotics.

Abbreviations: GT, genotype; IFN, interferon; PR, pegylated interferon and ribavirin; SVR, sustained virologic response; TE, treatment experienced; TN, treatment naïve; vs, versus.

Table 4 Sofosbuvir (SOF) in combination ± ribavirin (RBV) Phase II–III trials

Name	Regimen	Genotype (n)	Duration (week)	Treatment history	SVR (%)a	Reference
Unnamed	SOF + DCV	1 (15)	24b	TN	93	^Citation53
	SOF + DCV	1 (14)	24	TN	100
	SOF + DCV + RBV	1 (15)	24	TN	100
	SOF + DCV	2, 3 (16)	24	TN	88
	SOF + DCV	2, 3 (14)	24	TN	100
	SOF + DCV + RBV	2, 3 (14)	24	TN	93
	SOF + DCV + RBV	1 (20)	24	TE	95
	SOF + DCV	1 (21)	24	TE	100
LONESTAR Cohort A (no cirrhosis) Cohort B (58%–52% cirrhosis)	SOF + LDV	1 (20)	8	TN	95	^Citation32
	SOF + LDV + RBV	1 (21)	8	TN	100
	SOF + LDV	1 (19)	12	TN	95
	SOF + LDV	1 (19)	12	TE	95
	SOF + LDV + RBV	1 (21)	12	TE	100
COSMOS	SOF + SMV	1 (15)	24	TE (F0–2)c	93	^Citation52
Cohort 1	SOF + SMV + RBV	1 (24)	24	TE (F0–2)	79	^Citation63
	SOF + SMV	1 (14)	12	TE (F0–2)	93
	SOF + SMV + RBV	1 (27)	12	TE (F0–2)	96
Cohort 2	SOF + SMV	1 (7)	12	TN (F3–4)	93	^Citation64
	SOF + SMV + RBV	1 (12)	12	TN (F3–4)	100
	SOF + SMV	1 (7)	12	TE (F3–4)	100
	SOF + SMV + RBV	1 (15)	12	TE (F3–4)	93
ION-1 (16% cirrhosis)	SOF + LDV	1 (214)	12	TN	98	^Citation55
	SOF + LDV + RBV	1 (217)	12	TN	97
	SOF + LDV	1 (217)	24	TN	NA
	SOF + LDV + RBV	1 (217)	24	TN	NA
ION-2 (20% cirrhosis)	SOF + LDV	1 (109)	12	TE	94	^Citation54
	SOF + LDV + RBV	1 (111)	12	TE	96
	SOF + LDV	1 (109)	24	TE	99
	SOF + LDV + RBV	1 (111)	24	TE	99
ION-3 (no cirrhosis)	SOF + LDV	1 (215)	8	TN	94	^Citation56
	SOF + LDV + RBV	1 (216)	8	TN	93
	SOF + LDV	1 (216)	12	TN	95

Notes:

a SVR at week 12 post-treatment

b SOF given alone for 1 week, then SOF + DCV for 23 weeks

c fibrosis (F) stage F0–4.

Abbreviations: DCV, daclatasvir; LDV, ledipasvir; NA, not available; SMV, simeprevir; SVR, sustained virologic response; TE, treatment experienced; TN, treatment naïve.

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