[2015] hcv direct acting antivirals [da as] stumbling

HCV Direct Acting Antivirals [DAAs] Stumbling

Ayman Alsebaey, MD.

Lecturer of Hepatology,

National Liver Institute.

1

from RAVs to newer therapeutic agents

Introduction

About 170 million or more are chronically infected with HCV worldwide.

Chronic HCV infection may progress to cirrhosis, liver decompensation, HCC and ultimately death.

The current concept of HCV treatment is to achieve SVR [SVR 12] as it is associated with permanent eradication of the virus and diminished long term risks of HCV especially HCC.

PegINF/RBV was the SOC for HCV treatment with 50-60% SVR.

About 50% of patients infected with HCV genotype 1 and 20% of patients infected with HCV genotype 2 or 3 still fail to achieve SVR with SOC.

This urged the research of new treatment for the naive, relapsers, non-responders and cases not fit for SOC e.g. cardiac patients, advanced cirrhosis, etc.

2

4

HCV life cycle

HCV Virus binding

and internalization

Cytoplasmic release and uncoating

IRES-mediated translation and

polyprotein processing

RNA replication

Packaging and assembly

Virion maturation and

release.

5

HCV Life Cycle

HCV is a linear, positive-sense, single-stranded RNA virus.

It encodes a single polypeptide of approximately 3000 amino acids.

HCV enters hepatocytes through endocytosis and uncoats in a pH-dependent fashion.

The positive-sense strand RNA within the virion is used as a template for cytoplasmic translation into the single polypeptide.

The polypeptide is cleaved by host and viral proteases into 10 proteins.

Viral replication occurs at an endoplasmic reticulum membrane-derived replication complex, including NS4B and NS5A.

6

HCV Life Cycle cont.

Through the activity of the NS5B RNA-dependent RNA polymerase (RdRp) and the NS3 helicase, positive-sense RNA strands are copied into negative-antisense strands in a cyclophilin A– and microRNA-122–dependent fashion.

The negative-antisense strands act as a replicative intermediate for copies of positive-sense RNA strands.

Newly produced viral RNA genomes are then encapsidated, and are released by the host plasma membrane.

Viral secretion occurs in association with very-low-density lipoproteins.

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Categories of the new treatment

11

NS5B NS5A NS3/4A

RNA-dependent RNA polymerase

Component of HCV replication complex

Serine protease

Nucleoside analogs Covalent (ketoamide)

Sofosbuvir Ledipasvir Daclatasvir Ombitasvir Elbasvir Samatasvir PPI-668

Boceprevir Telaprevir

Nonnucleoside Noncovalent (tripeptide or macrocyclic)

GS-9669 Beclabuvir Dasabuvir

Faldaprevir Simeprevir Paritaprevir Asunaprevir Grazoprevir

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Characteristics of the direct-acting antiviral agents

Potency Genotypic Coverage Barrier to

Resistance

NS3/4 protease inhibitors High Limited Low

NS5A inhibitors High Multigenotypic Low

NS5B nucs Intermediate Pangenotypic High

NS5B Non-nucs Intermediate Limited Low

Mechanism of action of DAAs

[NS3/4A] Protease Inhibitors “…previr”: NS3 has a proteolytic activity. NS4 is a co-factor. NS3/4A PIs disrupt post-translation processing and replication

of HCV. Members: Telaprevir, boceprevir, simprevir, paritaprevir

CYP3A4 and PIs: Telaprevir, boceprevir, paritaprevir are metabolized by liver

CYP3A4. Simprevir is metabolized by liver and intestine CYP3A4. Inhibitors of CYP3A4 affect these drugs.

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• NS5A Inhibitors “….asvir”: Unknown mechanism of action.

Is used in regulating replication, and in the assembly of the viral particle released from the host cell.

Members: Ledipasvir, ombitasvir, daclatasvir.

• NS5B Non-nucleoside Polymerase Inhibitors “…buvir”: NS5B is an RNA-dependent RNA polymerase essential for viral replication.

NS5B has a catalytic site for nucleoside binding and 4 other sites where a non-nucleoside compound may bind, resulting in allosteric alteration.

Genotype specific.

Metabolized by CYP2C8

Members: Dasabuvir.

NS5B Nucleoside Polymerase Inhibitors: NS5B NPIs target the catalytic site and result in chain termination during RNA

replication of the viral genome.

Members: sofosbuvir.

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Clinical Status of DAAs failure

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Mono PIs

Boceprevir and telaprevir are used with PegINF/RBV [PR] for genotype 1 treatment.

Treatment naïve non cirrhotic patients:

Boceprevir SVR: 65%

Telaprevir SVR: 75%.

Treatment experienced and cirrhotic patients [SVR 52%]:

Boceprevir SVR: 56%

Telaprevir SVR: 53%.

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Sofosbuvir [SOF]

NEUTRINO study: SOF + PR + cirrhosis +G1: 92% SVR12

SOF + PR + without cirrhosis +G1: 80% SVR12.

HCV-TARGET: SOF + PR +G1: 85% SVR4.

SOF + PR + cirrhosis +G1: 70% SVR4.

SOF [12w] + R + G2: 90% SVR4.

TRIO Network: SOF [12w] + PR +G1: 78% SVR12.

SOF + R +G2: 90% SVR12.

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SOF + PR SOF+ R

All Oral Treatment

COSMOS (G1): SIM + SOF ±R + G1 + F0-1 Metavir + treatment experienced [non-

responders]: 92% SVR12.

SIM + SOF ±R + G1 + F3-4 Metavir + naïve or non-responders: 92% SVR12.

HCV-TARGET: SOF +SIM ±R : SVR4 [89%; G1a 89%, G1b: 95%].

Prior PIs experienced: SVR4 90%.

TRIO Network: SOF + SIM ±R +G1 + non cirrhosis: 87% SVR12.

SOF + SIM ±R +G1 + cirrhosis: 76% SVR12.

Real-world data: Pending for SOF/LDV and paritaprevir/r/ombitasvir/dasabuvir.

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SIM + SOF ±R SIM + SOF ±R

How does failure to DAAs occur?

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Failure factors

Viral

RAVs Genotype

Prior DAAs experience

Host

IL28B status Prior INF experience

Liver Fibrosis Portal hypertension

Portosystemic shunts Drug compliance

Immune function

Drug

Drug potency Metabolism

DDIs DAAs No [ 2 vs 3]

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Resistance-associated variants (RAVs)

HCV-quasispecies is a result of: High viral replication rate, high error rate of viral RNA-dependent RNA

polymerase,

Lack of overlapping reading frames in the hepatitis C nonstructural region.

The wild type always predominates the quasispecies.

HCV polymorphisms: The quasispecies undergo mutations to be the predominant causing

DAAs resistance.

So HCV SVR in G1b> G1a due to resistant variants at key sites on HCV NS3 protease.

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DEFINITIONS

The genetic barrier to resistance: Is the number of amino acid substitutions, needed for a viral variant to acquire full resistance.

Low genetic barrier e.g. PIs and NNIs: a single mutation is sufficient to confer resistance.

High genetic barrier e.g. NIs and NS5A inhibitors: as some specific RAVs are unlikely to preexist naturally (as it is the case of classical mutations for NI) or because effective resistance requires more than one RAVs.

The in-vivo fitness of the virus: Is the ability to survive and grow in the replicative environment.

Drug exposure: is the drug concentration achieved in vivo relative to the IC50–IC90/EC50–EC90

values of resistant variants.

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PIs RAVs

Telaprevir: G1a: V36M, R155K, and V36M plus R155K

G1b: V36A, T54A/S, and A 156S/T/V.

Boceprevir: G1a: V36M, T54S, and R155K

G1b: T54A/S, V55A, A156S, and I/V170A.

SIM and Paritaprevir: G1a: R155K, D168 A/V/E/T, Q80K [for SIM only; 40%]

G1b: D168 A/V/E/T.

SIM peculiar: G1a: Q80K [40%], R155K, R155K plus V36M, R155K plus Q80L, R155K plus S122R,

R155K plus D168E.

G1b: D168 A/V/E/T, Q80R plus D168E.

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Asunaprevir (BMS-650032): G1a: R155K and D168E.

G1b: D168E/V/Y.

Paritaprevir (ABT-450) G1a: D168A/V/Y.

G1b: Y56H and D168V.

G4d: D168V.

Vaniprevir (MK-7009) G1a: R155K and D168T/V/Y.

G1b: D168H/T/V.

Grazoprevir “MK-5172” [phase II]: V36A/M, T54A/S, R155K/Q/T, A156S, V36M+R155K or T54S+R155K.

C-WORTHY study (grazoprevir/elbasvir ±R) 30% had naturally RAVs.

Despite SVR was not affected (93%).

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Common genotype 1a and 1b RAVs are shown here for approved and soon-to-be approved PIs.

Genotype 1a Genotype 1b

V36M/A

T54S/A

Q80K S122R/G

R155K

R155G

D168V/E/

A

V36M/A

T54A/S

Q80R S122

A R155

Q A156T/G

D168V/E/

A

Boceprevir + + − − + − − + + − − − + −

Telaprevir + + − − + + − + + − − − + −

SIM − − + + + − + − − + + + − +

Paritaprevir − − − − + + + − − − − − − +

Grazoprevir − − − − − − + − − − − − + +

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Cross resistance between 1st and 2nd generation PIs:

G1a: R155K .

G1b: A156 T/V .

Protease-inhibitor-RAVs usually show an impaired fitness. low likeliness of detectable pre-existence as well as a relatively rapid

replacement by wild-type virus after stopping NS3 PI-containing antiviral therapy.

Low natural prevalence: 0.1-3.1% except Q80K that is not associated with decreases fitness

Double (or more) mutants (i.e. R155K/T + V36A/M) improve both fitness and resistance profile.

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Q80K mutation of PIs

It causes only SIM resistance unlike sovaprevir, asunaprevir or faldaprevir. 10 fold decreased susceptibility to SIM. confers ⩽5-fold reduction in the replicon susceptibility to sovaprevir .

Clades: G1a clade I [Americans] have 50% Q80K compared to clade II [Europeans].

Phase II ASPIRE trial: +ve Q80K:

SIM 100mg/day SVR 22%. SIM 150mg/day SVR 61%. SVR G1b > G1a (generally 63% vs. 80%).

QUEST-1 and 2: G1a: SVR of SIM/PR is 58% with mutation vs. 84% wild type.

Faldaprevir SVR: Is not affected with Q80K mutation (75% if wild type vs. 82% if +ve Q80K).

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NS5A RAVs

Naturally NS5A RAVs are commonly seen in naïve patients.

It does not affect the viral fitness.

Daclatasvir: Resistance in G1a >G1b.

G1a: L31V/M, Y93H/N, Q30R/H. G1b: Y93H/N. G4: Q30H/S.

L31M in G2 does not predict treatment failure [daclatasivir/PR]

LDV monotherapy: G1a: Q30R/H, L31 M, and Y93H/C G1b: Y93H. NS5a RAVs causes higher relapse in patients treated with SOF/LDV.

Ombitasvir (ABT-267): G1b: M28T and Q30R. G1b: Y93H. G4: L28V.

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Resistance-associated variants in NS5A

Genotype 1a Genotype 1b

M28T

Q30R

Q30E

Q30H

L31M Y93C

Y93H

Y93N L28T

L31M

L31V/F

Q54H/N

Y93H

Y93N

Ombitasvir + + − − + + + + + − + − + +

LDV + + + + + + + + − + + − + −

Daclatasvir + + + + + + + + − − + + + +

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SOF:

Has high resistance barrier. RAVs have low viral fitness The high-resistance-barrier phenomenon of SOF seems useful in combination with other

DAAs to compensate for resistance patterns of other drugs to achieve higher SVR rates.

S282T mutation: is seen in vitro but not much clinically yet in vivo. When occurs, it causes 7-13 fold decreased susceptibility to SOF (G1a,b) compared to 2 fold

in G2.

G1a; S282T mutation in association with I434M unlike G1b G2a:

Five mutation are found plus S282T mutation S282T together with mutations from both the finger (T179A) and palm (M289L and I293L)

domains was essential to conferring resistance to sofosbuvir, while changes at the surface of the thumb domain (M434T and H479T) act as compensatory

mutations improving the fitness of S282T variants

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NS5B [NUCs] RAVs;

Mericitabine: S282T mutation 3-6 fold reduction in susceptibility to mericitabine in vitro.

Rarely seen clinically. 1 patient INFORM-1 trial G1a [mericitabine/danoprevir/RBV] had S282T

mutation

1 patient PROPEL and JUMP-C trials G1b [mericitabine/PR] had L159F/L320F mutation

Effect of genotype and serotypes: JUMP-C trial [mericitabine/PR] SVR was not affected with Genotype 1 a or b.

INFORM-1 trial G1a [mericitabine/danoprevir/RBV]: SVR was G1a 26% vs 71% G1b. May be related to decreased response to danoprevir.

FDA-approved test is available to assess RAVs in the NS3/4a and NS5A coding region.

Future mapping will be useful in guided therapy especially in relapsers and non-responders.

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Site of the resistance genes:

the thumb (sites 1 and 2) and palm (sites 3, 4 and 5) of a right-hand modeled polymerase enzyme

Overlapping resistance: Palm site; the mutations C316Y/N and Y448H associated with resistance to both

NNI-3 and NNI-4 site inhibitors, respectively, which reduces the activity of site 3 and 5 inhibitors.

Resistance to NNI-site 1 inhibitors [deleobuvir]: P495L or P495S decrease susceptibility to deleobuvir 123–130-fold and 91-fold,

respectively [G1b].

A421V caused 5.8-fold increase resistance to deleobuvir in genotype 1a .

This drug is halted due to low efficacy and increases resistance.

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NS5B [nonNUCs] RAVs

Resistance to NNI-site 2 inhibitors

Filibuvir:

binds to the thumb 2 domain of the NS5B polymerase.

M423I/L/T is the predominant pathway to filibuvir resistance displaying high-level resistance and reduced replicative capacity relative to the wild-type .

VX-222:

NNI-site 2 inhibitor [phase II].

L419, R422, and M423 causes breakthrough.

Beclabuvir (GS-9669):

NNI-site 2 inhibitor in early clinical development,

L419, R422, and A486 [G1a,b] with monotherapy.

Resistance to NNI-site 3 inhibitors

Setrobuvir [phase II]:

is under Phase II investigation.

M414, G554 and D559.

ABT-072 and ABT-333 :

C316, S368, M414, Y448, and S556. 37

Resistance to NNI-site 5 inhibitors Tegobuvir:

binds to the b-hairpin in the thumb domain of NS5B.

Y448H; tegobuvir/PR.

Halted due to severe pancytopenia.

Effect of genotype and serotype: V499A:

is found in most (>96%) NS5B sequences among genotypes 1a, 2, 3, and 4.

only been associated with resistance among genotypes 1b (5.6-fold change).

C316Y/N: 13% of NS5B polymerase sequences belonging to genotype 1b

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RAVs and re-treatment

MEDIAN TIME OF RAV DISAPPEARANCE:

Telaprevir: 10.6 mo Boceprevir: 14 mo Simprevir: 8.3 mo Paritaprevir: 24-48 wk. Ombitasvir: 24-48 week post treatment [95%] NS5A: 1-2 years [85%] SOF: few week

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Telaprevir- and boceprevir-experienced patients: RAVs exist for a median of 30 mo [>85%].

C219 study: 9 patients 5.7 years ago were resistant to telaprevir monotherapy.

On re-treatment with telaprevir/PR: Only 5 patients had SVR.

Opera study: 5 patients 1.5 years ago were resistant to SIM monotherapy.

On re-treatment with SIM/PR: Only 3 patients had SVR. Other 2 continued to form RAVs.

Sofosbuvir/ledipasvir [LONESTAR]: One patient had failed 8w sofosbuvir/ledipasvir. SVR with treatment with sofosbuvir/ledipasvir/RBV

It was despite the presence of mutations associated with resistance to both NS5A inhibitors (Q30L, L31M, and Y93H) and the S282T mutation associated with sofosbuvir resistance at the onset of re-treatment

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RAVs and re-treatment

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Add ribavirin

Extend duration

Change regimen

PIs failure:

If you treat with same class give SIM/SOF/±RBV

SVR4 was 81% compared to 89% naïve.

SOF/LDV/±RBV

SOF/RBV: SOF/LED/RBV is associated with high viral response.

SOF/LDV

NS5A RAVs extend for long period and associated with relapse.

Extend the duration to 24 weeks.

60% SVR with +ve RAVs compared to 100% without.

3Ds [paritaprevir(r), ombitasvir and dasabuvir]: ???? Experimental.

SOF/PR

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VIRAL LOAD: SOF/LDV [8w]:

Viral load <6,000,000 in treatment-naıve, non-cirrhotic patients is associated with higher SVR12.

GENO- AND SEROTYPES: G1:

Resistance in G1a >1b

G1b displayed a higher barrier to resistance than G1a for protease inhibitors, non-nucleosides inhibitors and NS5A inhibitors

Genotypes 4 and 5/6: The SVR rates were up to 96% but small number of patients.

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G3: Lack of efficacy of the majority of protease inhibitors against

genotypes 3 .

Less response to SOF except if duration is extended to 2 4 week.

FISSION, POSITRON and FUSSION trials showed SVR G2>G3.

VALENCE: improved SVR with SOF/RBV for 24w instead of 12w.

LONESTAR-2: improved SVR with addition of PR

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The liver is central to DAAs metabolism. Advanced fibrosis and cirrhosis drug metabolism toxicity and drug-drug

interactions [DDIs].

Ribavirin: Is not affected as metabolized by the nucleated cells. Not related to cytochrome P

enzyme.

SIM, BOC, TLV: Are metabolized by CYP3A4 enzyme DDIs.

SOF: Has no cytochrome P enzyme No DDIs. is activated and metabolized by the kidney. Is a substrate to transporter protein Pglycoprotein (pgP) and breast cancer resistance protein any

drug induces them disturbed therapeutic efficacy

LDV: Minimal CYP enzyme metabolism. Is a substrate of pgP. Acid rich GUT environment is required for activation PPIs e.g. omeprazole decreases the

efficacy.

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IL28B status: With DAAs IL28B CC had slightly higher SVR >CT, TT but powered studies are

needed.

Drug misuse/compliance.

Cirrhosis and Portosystemic shunts: Cirrhosis and Portosystemic shunts drug metabolism changed

pharmacokinetics.

Malnutrition with advanced fibrosis interferon signaling.

The mean plasma drug concentration in CTP C > B, A RBV induced anemia.

A study showed that after 7 days of exposure of SOF, the AUC was 126% and 143% higher in Child-Pugh class B and C, respectively, as compared with patients with normal hepatic function.

Advancing degrees of portal hypertension response rates may decline.

Prior IFN experience:

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Interferon integrated therapy: age, sex, race, alcohol use, obesity, insulin resistance, hepatic steatosis, and

vitamin D and vitamin B12 deficiencies.

Hepatic steatosis:

has been shown in 547 patients treated with telaprevir/PEG/RBV to have lower SVR rates in patients with genotype 1.

Vitamin D status was previously shown to be associated with SVR rates;

The question is “will they have impact on interferon free therapy”

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PIs experienced:

Do RAVs mapping.

It is not recommended to give them 2nd generation PIs due to cross resistance.

CUPIC study: Cirrhotic patients [G1a] that failed PR then PR + PIs [telaprevir or boceprevir]

were treated with:

Placebo [12w] then SOF+LDV+RBV [12w] 96% SVR12

SOF+LDV [24w] 97% SVR12

Improved serum albumin, bilirubin and INR.

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SOF EXPERIENCED:

SOF has a high genetic barrier but some failure were seen with these regimens SOF + PR [3m] or SOF + RBV [6m].

Lam et al., 2012: SOF + RBV [6m] experienced:

14 patients, G1a, African Americans , with advanced fibrosis [F3-4].

Most patients were CT or TT and one had S282T polymorphism.

When treated with SOF+LDV [3m] +ve RVR and 100% SVR12.

ELECTRON-2: 19 patients were retreated with SOF+LDV+RBV [mainly non-cirrhotic, G1a].

+ve RVR and 100% SVR12.

Wyles et al., 2014: 51 patients that were either SOF+PR, SOF+RBV, SOF alone.

RAV mutation was negative. Mainly G1a and some compensated cirrhosis [29%].

Retreatment with SOF+LDV [3m] +ve RVR [98%], SVR12 [98%].

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FISSION, POSITRON, or FUSION: G2 or 3.

They were retreated with:

SOF+PR [12w, n=34]: 4 G2 achieved RVR and SVR12, 91% G3 had SVR12

SOF+RBV [12w, n=73]: 1G2 cured and other relapsed, 63% SVR12.

G3: cirrhosis was a predictor of relapse

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What are the next

regimens and drugs?

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Phase III

Phase II

Phase I

Preclinical agents

Host targeted agents

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Daclatasvir/Asunaprevir/Beclabuvir

UNITY I daclatasvir (30 mg daily),

asunaprevir (200 mg daily), and beclabuvir (75 mg daily) in a twice-daily fixed dose (DCV-TRIO) for 12w.

415 non-cirrhotic patients naïve and PR experienced.

Baseline PCR and IL28B did not affect SVR12

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91%

89%

88%

89%

89%

90%

90%

91%

91%

92%

Naïve Experienced

SVR12

P >0.05

This study did not include RBV.

G1b SVR >G1a.

Adverse effects: headache (26%),

fatigue (17%),

diarrhea (14%),

nausea (13%).

ALT elevation was reported in 5% of patients and led to discontinuation in 2 cases

90%

85%

98% 100%

75%

80%

85%

90%

95%

100%

105%

Naïve Experienced

G1a

G1b

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P <0.05

Daclatasvir/Asunaprevir/Beclabuvir

ALLY-3 daclatasvir (60 mg daily),

sofosbuvir (400 mg daily) 12w.

No RBV

G3. It has low SVR with current

SOF/RBV/24w

Naïve and experienced.

Cirrhotic and non-cirrhotics.

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97%

94%

93%

93%

94%

94%

95%

95%

96%

96%

97%

97%

98%

Naïve Experienced

Non cirrhotic

SVR12

Adverse effects: headache (20%),

fatigue (18%),

nausea (12%),

diarrhea (9%).

61

58%

69%

52%

54%

56%

58%

60%

62%

64%

66%

68%

70%

Naïve Experienced

Cirrhotic

SVR12

Phase II trials

Grazoprevir (MK-5172)/Elbasvir (MK-8742)

Velpatasvir (GS-5816)/Sofosbuvir

ACH-3102

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Grazoprevir: is an NS3/4A protease inhibitor developed by Merk. high antiviral potency with a high barrier to resistance.

Elbasvir is an NS5A inhibitor. C-WORTHY trial

treatment-naïve patients with or without human immunodeficiency virus (HIV) coinfection.

Difficult-to-treat patients Cirrhosis previous null response, with or without cirrhosis.

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C-WORTHY Naïve patients.

G1a: 8w; grazoprevir (100 mg daily), elbasvir (50 mg daily).

G1a, b: 12w; grazoprevir (100 mg daily), elbasvir (50 mg daily) ±RBV.

No numerical advantage to RBV.

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80%

98% 93%

0%

20%

40%

60%

80%

100%

120%

Naïve

8w 12w 12w +RBV

90%

97%

86%

88%

90%

92%

94%

96%

98%

Naïve cirrhotic [12w]

with RBV

without RBV

94%

91%

90%

90%

91%

91%

92%

92%

93%

93%

94%

94%

95%

Experienced cirrhotic [12w]

with RBV

without RBV

65

Grazoprevir + Elbasvir ± RBV [12w, G1, n=125].

97%

94%

93%

93%

94%

94%

95%

95%

96%

96%

97%

97%

98%

Naïve cirrhotic [18w]

with RBV

without RBV

100%

97%

96%

96%

97%

97%

98%

98%

99%

99%

100%

100%

101%

Experienced cirrhotic [18w]

with RBV

without RBV

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No benefit from extending the therapy or adding RBV

93%

98%

90%

91%

92%

93%

94%

95%

96%

97%

98%

99%

Naïve HCV

with RBV

without RBV

97%

87%

82%

84%

86%

88%

90%

92%

94%

96%

98%

Naïve HIV co-infected

with RBV

without RBV

67


HIV co-infection.


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92% 99% 100%

81%

97%

0%

20%

40%

60%

80%

100%

120%

G1a G1b G4 G6 Cirrrhosis

SVR

Grazoprevir (MK-5172)/Sofosbuvir

C-SWIFT Naïve patients, cirrhotic and non-

cirrhotic [G1, n=102].

Sofosbuvir, Grazoprevir and elbasvir

Non-cirrhotic: 4 vs. 6 w.

Cirrhosis: 6 vs 8 w.

C-SWIFT demonstrates that treatment durations as short as 4 weeks are biologically plausible

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39%

87% 80%

95%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Non-cirrhotic Cirhosis

4w 6w 8w

Grazoprevir (MK-5172)/Sofosbuvir

C-SWIFT Naïve patients, cirrhotic and

non-cirrhotic [G3, n=41].

Sofosbuvir, Grazoprevir and elbasvir

8 vs 12 week

70

91%

100%

91%

86%

88%

90%

92%

94%

96%

98%

100%

102%

Non-cirrhotic Cirhosis

8w 12w


Velpatasvir is a pan-genotypic NS5A inhibitor in a fixed dose combination with sofosbuvir.

G1 though G6 [n=154] for 12 w.

25 mg Velpatasvir + 400 mg SOF.

100 mg Velpatasvir + 400 mg SOF.

Overall SVR is 97% across all genotypes.

It is pangenomic.

71

96%

91%

93%

100% 100% 100% 100% 100%

93%

86%

100%

75%

80%

85%

90%

95%

100%

105%

1 2 3 4 5 6

Genotype

25mg GS-5816 100mg GS-5816


When tried for 8 weeks ±RBV: G1 to 3

Lower SVR12.

77% to 90% with 8 weeks of treatment compared to 91%–100% with 12 weeks of treatment.

Adverse effects: fatigue (21%),

headache (19%),

nausea (12%)

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77%

91% 90% 100%

0%

20%

40%

60%

80%

100%

120%

8w 12w

Genotype

SVR SVR2

ACH-3102

ACH-3102 is an NS5A inhibitor.

In vitro potency against multiple RAVs.

8 w trial, G1, non-cirrhotic, naïve [n=12].

50 mg ACH-3102 and 400 mg sofosbuvir .

100% SVR12

• Another 6 w trial [n=12]

• 100% SVR12.

• Not related to the viral load or IL28B status

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Study Regimen Patients Genotype N SVR 12

ACH-3102 ACH 3102

Sofosbuvir

Treatment-naïve

noncirrhotic

1 24 patients 100%

C-SWIFT Grazoprevir

Elbasvir

Sofosbuvir

Treatment-naïve with and

without cirrhosis

1 102 patients SVR 4/8

Non-cirrhotic

4 wk: 38.7%

6 wk: 86.7%

Cirrhosis

6 wk: 80%

8 wk: 94.7%

C-WORTHY –

12 wk

Grazoprevir

Elbasvir ±RBV

Treatment-naïve with

cirrhosis

Treatment-experienced

with and without cirrhosis

1 125 patients Treatment-naïve cirrhosis + RBV: 90%

Treatment-naïve cirrhosis without RBV: 97%

Treatment-experienced + RBV: 94%

Treatment-experienced without RBV: 91%

C-WORTHY –

18 wk

Grazoprevir

Elbasvir

± RBV

Treatment-naïve with

cirrhosis

Treatment-experienced

with and without cirrhosis

1 128 patients Treatment-naïve cirrhosis + RBV: 97%

Treatment-naïve cirrhosis without RBV: 94%



C-WORTHY – HIV

co-infected

Grazoprevir

Elbasvir

Treatment-naïve, non-

cirrhotic monoinfected and

HIV co-infected

1 218 patients HIV coinfected + RBV: 97%

HIV coinfected without RBV: 87%

Monoinfected + RBV: 93%

Monoinfected without RBV: 98%

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Study Regimen Patients Genotype N SVR 12

ALLY-3 Daclatasvir

Sofosbuvir

Treatment-naïve and

treatment-experienced

with and without

cirrhosis

3 152

patients

Treatment-naïve noncirrhotic: 97%

Treatment-naïve cirrhotic: 58%

Treatment-experienced noncirrhotic: 94%

Treatment-experienced cirrhotic patients:

69%

UNITY-1 Daclatasvir

Asunaprevir

Beclabuvir



noncirrhotic patients

1 415

patients

Treatment-naïve: 92%

Treatment-experienced: 89%

UNITY-2 Daclatasvir

Asunaprevir

Beclabuvir

± RBV



with cirrhosis

1 202

patients

Treatment-naïve + RBV: 98%

Treatment-naïve without RBV: 93%



GS-5816 GS-5816

(100 mg)

Sofosbuvir

Treatment-naïve

noncirrhotic

1–6 154

patients

Genotypes 1–2: 100%

Genotype 3: 93%

Genotype 4: 86%

Genotype 5: N/A

Genotype 6: 100%

Phase I

ABT-493/ABT-530

MK-3682 (Formally IDX21437)

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ABT-493/ABT-530

ABT-493 is a second-generation protease inhibitor [AbbVie]

ABT-530 is a second-generation NS5A inhibitor.

Both are potent, pan-genotypic agents with high barriers to resistance.

Both >4 log decline in viral load regardless of the presence or absence of cirrhosis in a 3-day dose-ranging study of 89 G1 patients.

Adverse effects: ABT-493: headache (22%), abdominal discomfort (6%), and diarrhea (6%).

ABT-530: headache (10%) and constipation (5%).

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Lawitz E, O'Riordan WD, Freilich BL, et al. Potent antiviral activity of ABT-493 and ABT-530 with 3-day monotherapy in patients with and without compensated cirrhosis with hepatitis C

virus (HCV) genotype 1 infection [abstract 1956]. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9, 2014.

MK-3682 (Formally IDX21437)

MK-3682 is a nucleotide NS5B polymerase inhibitor.

Pan-genotypic activity.

Phase I testing showed mean maximal viral load reductions of 4.8 and 3.9 log for G1a/1b and 4.6 and 4.1 log reductions in G2/3 with 7-days of 300 mg/d dosing.

Phase II studies: MK-3682 + grazoprevir/elbasvir

MK-3682 + grazoprevir/MK8408 (preclinical NS5A inhibitor).

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Gane EJ, Sicard E, Popa S, et al. A phase I/IIa study assessing 7-day dosing of MK-3682 (formerly IDX21437) in subjects infected with hepatitis C virus

(HCV) [abstract: 1974]. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9, 2014.

Preclinical agents: MK-8408

MK-8408 is a potent pan-genotypic NS5A inhibitor.

High resistance barrier.

It acts against RAVs Q30R and Y93H [NS5A inhibitor associated].

It may be combined with grazoprevir.

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Asante-Appiah E, Liu R, Curry S, et al. MK-8408, A potent and selective NS5A inhibitor with a high genetic barrier to resistance and activity against HCV genotypes 1–6 [abstract:

1979]. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9, 2014.

Lahser F, Bystol K, Curry S, et al. The combination of MK-5172, an NS3 inhibitor, and MK-8408, an NS5A inhibitor, presents a high genetic barrier to resistance in HCV

genotypes [abstract: 1988]. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, November 9, 2014.

Host targeted agents (HTAs)

Miravirsen

RG-101

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Category Target Compounds Stage of Development References

Entry inhibitors

CD81 mAbs Mouse model

SR-BI mAbs Mouse model

ITX-5061 Phase 1

CLDN1 mAbs Mouse model

EGFR Erlotinib Phase 1/2 NCT01835938

NPC1L1 Ezetimide Mouse model

Endocytosis/fusion Silymarin/silibinin Phase 2/3

Chloroquine Phase 4 NCT02058173

Translation inhibitors miR-122 Miravirsen Phase 2

Replication inhibitors

miR-122 Miravirsen Phase 2

HMGCoA reductase Statins Phase 3

Cyclophilin

Alisporivir Phase 2/3

SCY-635 Phase 2

NIM811 Phase 2

Assembly inhibitors

α-glucosidase 1 Celgosivir Phase 2

DGAT-1 LCQ908 Phase 2 NCT01387958

Cyclophilin NIM811 Phase 2

PPARα Naringenin Phase 1

HNF4α Bezafibrate Phase 4

Biological response

modifiers Immune responses

IFN-α FDA-approved

IFN-λ Phase 3 NCT01795911

TLR7 agonist Phase 1

TLR9 agonist Phase 3

Thymosin α1 Phase 3

Nitazoxanide Phase 2

miR-122 is a protective agent to HCV.

binds to 2 highly conserved sites (s1 and s2) of the HCV genome, preventing recognition and degradation by host enzymes.

miR-122 inhibitors: It is pangenomic as is highly conserved.

No reported RAVs.

Given SC.

?? Systemic side effect.

When combined with DAAs, they may shorten the duration of therapy.

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Miravirsen

Miravirsen is complimentary 15-nucleotide chain that binds to and inhibits miR-122.

Dose dependent inhibition of HCV. 3-7 mg/kg SC.

Best results with 7 mg/kg miraversen.

Adverse effects: headache (22%–44%),

fatigue (11%–33%),

injection site reactions.

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RG-101

RG-101 is a miR-122 inhibitor.

Phase IIa:

Results with 4mg [8w] are better than 2 mg.

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[2015] hcv direct acting antivirals [da as] stumbling

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