New Treatment for HCV G4Towards an End to HCV Epidemic in Egypt

1. Rehman S, et al. Genet Vaccines Ther 2011;9:11. 2. http://clinicaltrials.gov/ct2/show/NCT01464827. 3. http://ir.achillion.com/releasedetail.cfm?releaseid=6989383. 4. Gish R & Meanwell NA. Clin Liver Dis 2011;15:627–39. 5. Coelmont L, et al. PLoS One 2010;5:e13678. 6. http://clinicaltrials.gov/ct2/show/NCT01448200. 7. Miller DM, et al. Ann N Y Acad Sci 2009;1182:807. 8. http://clinicaltrials.gov/show/NCT01309932. 9.Poordad F, et al. AASLD 2012, abstract 83. 10. Gane E, et al. EASL 2012, poster 1113. 11. http://clinicaltrials.gov/ct2/show/NCT01030432. 12 . Delang L, et al. Viruses 2010;2:826–66. 13. http://www.gilead.com/research. 14. http://clinicaltrials.gov/ct2/show/NCT01353911. 15. Wedemeyer H, et al. Hepatology 2013 January 24. [Epub ahead of print]. doi: 10.1002/hep.26274. 16. http://www.pipelinereport.org/browse/hcv-treatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/NCT01193361. 19. http://www.vrtx.com/research-development/pipeline. 20. http://news.bms.com/press-release/financial-news/bristol-myers-squibbpresent-new-data-hepatitis-c-and-hepatitis-b-compo. [Accessed April 10, 2013].

NS3/4A NS5A NS5BA serine protease, essential for post-translational processing of HCV polyproteins

Multifunctional membrane-associated phosphoprotein, essential component of the HCV-RNA replication complex

An HCV-specific, RNA-dependent RNA polymerase

Boceprevir1

Telaprevir1

ABT-450/r2

Sovaprevir3

Asunaprevir11

Simeprevir9

Faldaprevir12

Danoprevir12

GS-945113

MK-517214

ACH-806/GS-91321

Daclatasvir4

Ledipasvir4

ABT-2672

PPI-6686

AZ-6894

BMS-8243934

PPI-4614

Nucleos(t)ide analogueSofosbuvir10

Mericitabine15

VX-13520

Non-nucleoside analogueBI-20712716 ABT-3332

ABT-07217

BMS-79132518

Tegobuvir12

Setrobuvir12

VX-22219

Filibuvir12

Several potential innovative drug targets in HCV

*On clinical hold, Novartis press release

IFN-lambdaA type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7

BMS-9141438

Cyclophilin AHost protein involved in HCV replication through interaction with NS5A and the HCV polymerase

Alisporivir5,*SCY-6351

c

E1 E2

NS5A NS5BNS3NS2

Characteristics of DAA

Schinazi, et al. Liver Int 2014;34 Suppl 1:69-78

DAA

PI 1st generation

PI 2nd generation

NS5A Inh. 1st generation

NS5A Inh. 2nd generation

NS5Bnucleos(t)ide

inh.

NS5B non nucleos(t)ide

inh.

Efficacy

Resistance profile

Pangenotypic efficacy

Adverse events

Drug-drug interaction

Good profile Average profile Least favorable profile

Many studies have looked at different ways of combining these compounds

This slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible

In different patient types• Different genotypes

• Treatment-naive

• Null-responders to prior therapy

• Intolerant to previous therapy

NS5B(nuc inhibitor)RBV

Alfa RBV

NS5A

NS5A

NS3/4A

RBV

Alfa

NS3/4A

NS5ANS3/4A

NS5B

(non-nuc

inhibitor)

Lambda

RBV

NS3/4ALambda

RBV

Lambda

RBV

NS5A

NS5A

AlfaRBV

NS3/4A

Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin

Sofo+RBV

Response Duration Regimen Patients Study

SVR 24Non cirrhotic: 90%Wight based RBV: 68%Low dose RBV: 48%

12 weeks A: 10 non cirrhoticB: 50 All stages of fibrosis:25 (weight based RBV)25 (low dose RBV: 600)

No: 60 treatment-naive patients genotype 1with bad predictors: (African-American, high BMI, low frequency ofIL28B CC, viral load and advanced fibrosis)

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment CharacteristicsOsinusi (2013)JAMA

12 weeks SVR12 68%24 weeks SVR12 93%:

12 weeks Or 24 weeks

Sofosbuvir + RBV 60 patientsEgyptiansG4 Treatment naive and -experienced

Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in Egyptian patientsRuane (2013)Hepatology

12 weeks SVR12 77%24 weeks SVR12 90%

12 weeks Or 24 weeks

Sofosbuvir + RBV G4 100 patients Treatment naive and -experienced

Egyptian study

Sofo+IFN+RBVResponse Duration Regimen Patients Study

SVR 24A: 89%B: 89%C: 87%

12 w24 weeks24 weeks (12 +12)

A (N:52): sofosbuvir +P+RB (N: 109, with 11 of them genotype 4): sofosbuvir +P+RC (N: 155): 12 weeks of sofosbuvir +P+R followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir +R

316 naïve genotype-1

ATOMICSofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentrephase 2 trialKowdley et al (2013)Lancet

Total 90% (295/327)G1a 92% (206/225)G1b 82% (54/66)G4 96% (27/28)G5/6 100% (7/7)Cirrhosis 80% (43/54)

12 weeks Sofosbuvir + PegIFN+ RBV

G1, 4, 5, 6Naïven = 327(G1 79%)

NEUTRINOSofosbuvir for previously untreated chronic hepatitis C infectionLawitz (2013)NEJM

Sofo and other DAA combination trials

Study Patients Regimen Duration Response

Electron (1)

Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin

G1 prior null responders with compensated cirrhosisand in naive, noncirrhotic patients

Sofosbuvir+ ledipasvirWith or without RBV

12 weeks Cirrhotic TTT failure: With RBV: 100% SVR12Without RBV: 70% SVR 12Non cirrhotic naïve: 6 weeks ttt: 68% SVR 128 weeks ttt; 100% SVR 12

LONESTAR (2)

Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial

G 1treatment-naive, noncirrhotic

Sofosbuvir+ ledipasvirWith or without RBV

8 weeks 8 weeks with RBV: 100%8 weeks without RBV: 95%12 without RBV: 95%

COSMOS (3)

SVR results of a oncedailyregimen of simeprevir (TM435) plus sofosbuvir (GS-7977) with of without ribavirin in cirrhotic and noncirrhotic HCV genotype 1 treatment naıve and prior null responder patients

G1 Noncirrhotic and cirrhotic, treatment-naıve and prior null responder

Sofosbuvir+simeprevirwith or without RBV

for 12 or 24 weeks

SVR12 in prior null responders with F0-F2 fibrosis were 93% (in both 12 and 24 weeks).In cirrhotics: SVR 4: 100% (in both null responders and naïve) 24 weeks.

1) Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology

SOF + RBV: In genotype 4

Ruane PJ, et al. EASL 2014. P1243Ruane PJ, et al. AASLD 2013. Abstract 1090 Ruane PJ, et al. EASL 2014. P1243

12 WeekSOF + RBV

24 WeekSOF + RBV

12 WeekSOF + RBV

SV

R12

(%

)

24 WeekSOF + RBV

Treatment naïve

Treatment experienced

13/1511/14 10/1714/14

This study done on 60 Egyptians (G4) living in USA 20% of them are cirrhotics.

All

12 WeekSOF + RBV

24 WeekSOF + RBV

21/31 27/29

Sofosbuvir+ Ribavirin in G4 (Egypt)

9

Naïve84%

Exper70%

100 patients(20% C, 3 centers)

Arm 1 (12 wks)

Arm 2 (24 wks) Naïve

92%

Exper89%

Overall

77%

Overall90%

(Esmat, et al AASLD.2014)

• In 51 patients GT4, received SOF + RBV for 12 weeks, SVR in 39 (77%)

–Pts who were treatment naïve, Fibrosis stage<F3, and baseline viremia <600,000 IU were 9 pts. All showed SVR (100%)

–Pts who were either treatment experienced, and/or fibrosis stage >F2 and viremia level >600,000 IU showed SVR (71%) (12 pts of whom 8 were treatment experienced)

–P value 0.01 (S)

0= naïve, Fibrosis <F3, viremial<600,000 IU 1= treatment experienced, and/or fibrosis ≥F3, viremial >600,000 IU

SOF STUDIES

OV

ER

AL

L

NA

ÏVE

TE

NA

ÏVE

TE

NA

ÏVE

TE

NA

ÏVE

TE

SOF/PR1 NEUTRINO

SOF/RBV2 12 WK SOF/RBV2 24WK SOF/RBV 12W SOF/RBV 24WK

0

10

20

30

40

50

60

70

80

90

100 96

79

59

100

87 84

70

92 89

SV

R 1

2 %

1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242. 3. Esmat et al,AASLD. 2014

EGYPTIAN

Non invasive detection of hepatic fibrosis

Fib-4 Formula

13

http://gihep.com/calculators/hepatology/fibrosis-4-score/

Non invasive detection of hepatic fibrosis

Fibroscan

14

Non invasive diagnosis of Advanced hepatic fibrosis(>F2)

AUCNo of

patientsBest

cutoffsensitivity specificity PPV NPV accuracy LR+ LR-

*Fib-4 0.71 36841 1.45 0.69 0.63 0.28 0.90 0.63 1.9 0.49

♠Fibroscan 0.82 231 9.5 0.82 0.87 0.68 0.93 0.86 6.52 0.20

Fib-4 Fibroscan

>1.45 ≤1.45

Wait or Do liver biopsy

Do not treat ≤9.5

Treat Wait or Do liver biopsy

>9.5

*National Committee for control of viral hepatitis, NNTC data , Jan 2014♠ Esmat et al, Arab Journal of Gastroenterology 14 (2013) 109–112

PEARL 1 INTERFERON-FREE REGIMENS OF ABT-450/R + ABT-267 WITH OR WITHOUT

RIBAVIRIN In 135 Ch HCV GENOTYPE 4 Patients

Treatment-naive and Peginterferon/RBV-

experienced patients with chronic HCV GT4 infection

were enrolled. Treatment-naive patients received

ABT-450/r (150/100mg QD) + ABT-267 (25mg QD) ±

weight-based RBV for 12 weeks. Experienced

patients received the RBV-containing regimen for 12

weeks.

Hezode EASL 2014 Ab 58

Current and future regimens containing the new DAAs for genotype 4 patients

1. Lawitz et al. DDW 2013. 2. Ruane et al. EAS L2014. Poster 1242. 3. Moreno et al. EASL 2014. Poster 1319.4.Hézode et al.EASL2014. 4. Hézode et al. AASLD 2012. Poster 755.

SOF/PR1

NEUTRINO SMV/PR*3

RESTORE

Experienced

12/1241/7229/3527/28

NaiveNaive Naive

DCV 60 mg/PR*5

COMMAND-1

SOF/RBV2

12 wk

Naive

11/14 10/17

SV

R (

%)

Naive ExperiencedExperiencedExperienced

SOF/RBV2

24 wk

14/14 13/15

No data for

DCV/PR

ABT-450/r + Ombitasvir

+RBV*4

PEARL-I(SVR4 only in experienced)

100 100Naive

Experienced

Phase IIbPhase III

12/1242/42 37/37

EASL Guidelines: Treatment of HCV GT 4 infection

Treatment Options

Recommendation status: Regimen Comments by authors

Option 1 B1: PR + SOF 12 wks „appears the most efficacious and the easiest to use “Evaluated in TN Neutrino SVR 96% 27/28No data in TE

Option 2 B1: PR+ SMV 12 wks + additional PR for either 12 or 36 wks (12 wks SMV + PR; 24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis)

TN: SVR 89% 31/35Prior Relapsers: SVR 86% 19/22Non Responders 57% 41/72

Option 3 B1: PR + DAC 60mg 24 wksB2: 12 wks TT + additional PR for either 12 or 36 wks: (24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis)

Theoretically effective, few data available SVR 100% in 12/12 COMMAND 1 trial

Option 4IFN intolerant or ineligible

C2:R + SOF 24 wks „only preliminary data is available in Egyptian pts“TN 12 wks treatment: SVR 79% 11/14 TN 24 wks treatment: SVR 100% 14/14TE 12 wks treatment: SVR 59% 10/17TE 24 wks treatment: SVR 93% 14/15

Option 5 B2: SOF+SMV 12 wks Consider adding RBV in patients with predictors of poor response or in pts with cirrhosis

„no data with this combination- it is likely that data from Cosmos can be extrapolated“

Option 6 B2: SOF +DAC (60mg) 12 wks TN or 24wks TEConsider adding RBV in patients with predictors of poor response or in pts with cirrhosis

„no data with this combination- it is likely that data can be extrapolated“

COST EFFECTIVENESS CHART

P/R 48 P/R/SOF 12 WK R/SOF 24 WK *R/SOF 12 WK0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

120,000 L.E

12,000 L.E 9600 L.E 12,600 L.E 6600 L.ECOST/PT

*NAÏVE, NON CIRRHOTIC, LOW VIREMIA,

SVR %

Eradication of HCV in EgyptOvercoming the Barriers

Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

Overcome the Barriers

•Ideal drug

•Decrease incidence

•Mass treatment

Ideal Drug

It is important for patients treatment but more important for control and eradication of any infectious disease

Decrease incidence

•Blood safety.

•Avoid unneeded injection.

•Auto destructive syringes.

•Infection control.

•Media awareness.

•Case detection and treatment by Ideal drug

HCV in EGYPTfrom Control to Eradication

To decrease HCV prevalence to< 2 % in Egypt

in 10 years(Mathematical modeling)

Effective treatment SVR > 90%

Annual treatment of 250.000 to 300.000 patients

Decrease incidence by prioritize treatment to most frequent injectors

J.viral hepatitis,2014

HCV Treatment guidelines(Draft)

• Priority for treatment will be directed towards patients with F3 and F4.

• No differentiation in treatment priority will be established based on the previous treatment experience.

• Assessment of fibrosis stage will be performed by using a combination of both Fibroscan results and FIB 4 score. F3-4 stage will be considered if both Fibroscan result is more than 9.5 and FIB4 score is more than 1.45. If both results are below these cut-off values, patient will not be assigned as a treatment priority . If one of these two methods is above the cut-off value while the other is below, performing liver biopsy or re-assessment after one year is recommended to rule out the fibrosis stage of the patient.

• Upper GI endoscopy is mandatory in the following circumstances:

a. Histological evidence of cirrhosis by liver biopsyb. Fibroscan > 19.2 K.Pac. Platelet count < 100,000

• Patients who are eligible to receive Interferon (according to the currently used inclusion/exclusion criteria for combined IFN/RBV treatment)will be treated with daily Sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks.

• Recommended regimen for patients who are not eligible to receive IFN is daily Sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks

• Inclusion criteria for treatment will be expanded to adapt for more advanced liver fibrosis patients (who will be treated with Interferon free regimen) as defined with the presence of one or more of the following;– Child score up to 8– Total bilirubin ≤ 3– Albumin ≥ 2.5– Platelet count ≥ 50,000– Prtothrombin concentration ≥ 50%– Hemoglobin concentration ≥ 10 mg

• Otherwise, waiting for new DAAs combination is advised.

• Patients with more decompensated liver disease will be excluded from treatment until enough data will be available and this will be applied to: – Child C patients with scores ≥ 9– Presence of ascites (except after control)– Patients with HCC except after successful radical

curative intervention (4 months after resection or successful local ablation) evident by triphasic CT.

– Presence of large risky esophageal varices (except after prophylactic management)

• Age limits for treatment legibility will be above 18 years and below 70 years for all patients while BMI will be accepted up to 35.

• The same rules will be applied for all patients regardless the source of payment and there will be no role for patients' preferences in deciding the treatment regimen.

• For special population groups; priority for treatment will be offered for post liver transplantation, post kidney transplantation patients and combined HCV/HBV infection regardless the fibrosis stage

• . Other groups like Pediatric age group and kidney disease patients will be kept for discussion after the availability of enough data.

• Patients with documented extra-hepatic manifestations will be prioritized for treatment according to the same guidelines.

• Treatment experienced patients should not start evaluation for new treatment regimens except after 6 months from cessation of interferon therapy.

Gamal Esmat