CADTH 2015 Symposium

1. CADTH SYMPOSIUM : HCV:
NATURAL HISTORY AND THERAPEUTICS
Alnoor Ramji
Gastroenterology & Hepatology
Clinical Associate Professor
Division of Gastroenterology
University Of British Columbia
St. Paul’s Hospital Site
ramji_a@hotmail.com

2. Company Name Relationship
Abbvie Investigator, consultant
BI Investigator, Consultant
BMS Investigator, Consultant, Speaker
Gilead Sci. Inc Investigator, Consultant, Speaker
Hoffman LaRoche Investigator, Consultant, Speaker
Nursing Support
Janssen (J. & J.) Investigator, Consultant, Speaker
Novartis Investigator
Merck & Co. Investigator, Consultant, Speaker
Nursing Support
Vertex Pharmaceuticals Investigator, Consultant, Speaker
Disclosures

3. Objectives
• Review the natural history of hepatitis C and
its complications.
• Understand Treatment options for hepatitis C
– Pegylated-interferon + ribavirin +/- Direct acting
anti-virals (DAA’s).
– Combination DAA’s

4. 1a, 1b
2a, 2b,
3a
1a, 1b
2a, 2b,
2c, 3a
4
5a
1b
1b,
6
1b,
3a
1b,
3a
3b
4
Fang et al. Clin Liver Dis. 1997.
HCV Infection:
Worldwide Genotype Distribution
1a, 1b,
2b, 3a
2a

5. 5
HCC: hepatocellular carcinoma.
1. Alter and Seeff. Semin Liver Dis. 2000;20:17-35;
2. Pinette et al. Public Health Agency of Canada. Available from: http://www.phac-aspc.gc.ca/hepc/pubs/pdf/hepc_guide eng.pdf;
3.Myers et al. Can Gastroenterol. 2012;26:359-75.
Projection of Lifetime Outcomes1
100 patients with acute HCV infections100 patients with acute HCV infections
24 patients
chronic, nonprogressive
24 patients
chronic, nonprogressive
24 patients
severe progressive hepatitis
24 patients
severe progressive hepatitis
32 patients
variable progression
32 patients
variable progression
20 patients recover20 patients recover
80 patients
persistent infection
80 patients
persistent infection
All patients should seek antiviral therapy2,3All patients should seek antiviral therapy2,3
End-stage disease, HCC,
liver transplantation, death
End-stage disease, HCC,
liver transplantation, death
Treatment failureTreatment failure Sustained response/cureSustained response/cure
Outcomes:Outcomes:

6. Disease Progression and Morbidities
6
Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie
1. O’Leary 2008; 2. Perz 2006; 3. White 2008
Disease progression in patients with chronic HCV
Morbidities associated with chronic HCV infection1,2
•Cirrhosis
•Decompensated cirrhosis: Ascites, varices,
Encephalopathy
•Hepatocellular carcinoma (HCC)

7. • 312 patients with initially compensated cirrhosis of viral aetiology
Cirrhotic patients at risk of serious
morbidity
Benvegnù L, et al. Gut 2013; 53: 744 9‒
Patients at risk
HCC 312 311 310 303 297 268 226 189 153 129 94 65 45 27 11 5
Variceal bleeding 312 312 312 309 301 269 237 190 163 131 97 71 44 29 13 7
Ascites 312 311 312 305 296 259 223 181 152 125 93 60 48 30 15 9
Encephalopathy 312 312 312 309 300 270 235 192 161 127 95 65 43 30 13 7
Cumulativerisk(%)
Years of follow-up
HCC
Variceal bleeding
Ascites
Portal-systemic encephalopathy
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

8. Variceal Hemorhage

9. Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
SVR(%)
IFN
6 mos
PegIFN/ RBV
12 mos
IFN
12 mos
IFN/RBV
12 mos
PegIFN
12 mos
2001
1998
2011
Standard
IFN
RBV
PegIFN
1991
DAAs
PegIFN/
RBV/
DAA
IFN/RBV
6 mos
6
16
34
42
39
55
70+
0
20
40
60
80
100
The Advancing Present
2014/5
90-98
PegIFN/
RBV/
DAA
Or DAA+RBV

10. Viral Eradication Improves All-Cause
Mortality
10
References: 1. Ravazi 2012; 2. Burra 2009; 3. Guillouche 2011; 4. Van der Meer 2012
• Cure = SVR = reduced risk of
— All-cause mortality; Liver-related mortality; HCV-related complications:-
Progression to HCC or liver failure4
Patientsurvivaloutcomes
withandwithoutSVR
Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie

11. HCV Lifecycle and DAA Targets
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor binding
and endocytosis
Fusion
and
uncoating
Transport
and release
(+) RNA
Translation and
polyprotein
processing
RNA replication
Virion
assembly
Membranous
web
ER lumen
LD
LD
ER lumen
LD
NS3/4
protease
inhibitors
NS5B polymerase
inhibitors
*Role in HCV lifecycle not well defined
NS5A* inhibitors

12. 0
20
40
60
80
100
SVR(%)
PegIFN/RBV
BOC or TVR +
PegIFN/RBV
38-44
67-81
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
2012 – 2014: SVR Rates: Boceprevir or Telaprevir with
PEG-INF + Ribavirin in Genotype 1 Treatment-Naive
Patients: upto 48 Weeks
F0-2 F3-4
52-62

13. Boceprevir Triple therapy Safety Profile
48 PR
n=363
BOC RGT
n=368
BOC/PR48
n=366
Median treatment duration, days 203 197 335
Deaths N=4 N=1 N=1
Serious AEs 9% 11% 12%
Discontinued due to AEs 16% 12% 16%
Dose modification due to AEs 26% 40% 35%
Hematologic parameters
Neutrophil count
(<750 to 500/mm3
/ <500/mm3
)
14% / 4% 24% / 6% 25% / 8%
Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL)
Discontinuation due to anemia
Dose reductions due to anemia
Erythropoietin use
Mean (median) days of use
26% / 4%
1%
13%
24%
121 (109)
45% / 5%
2%
20%
43%
94 (85)
41% / 9%
2%
21%
43%
156 (149)

14. Adverse Event Arm 1 (PR48); n=363 (%) Arm 2 (RGT); n=368 (%) Arm 3 (BOC/PR48); n=366 (%)
Fatigue 59 52 57
Headache 42 45 43
Nausea 40 46 42
Anemia 29 49 49
Dysgeusia 18 37 43
Chills 28 36 33
Pyrexia 32 33 30
Insomnia 32 31 32
Alopecia 27 20 28
Decreased Appetite 25 26 24
Pruritis 26 23 25
Neutropenia 21 25 25
Influenza Like Illness 25 23 22
Myalgia 26 21 24
Rash 22 24 23
Irritability 24 22 22
Depression 21 23 19
Diarrhea 19 19 23
Dry Skin 18 18 22
Dyspnea 16 18 22
Dizziness 15 21 17
Boceprevir Triple: Common Treatment-Related Adverse Events*
*Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

15. 0
20
40
60
80
100
SVR(%)
Simeprevir
85%
90%
2014 /2015 :Virologic Response to PEG-INF + RBV +
Simeprevir or Sofosbuvir in Genotype 1
Treatment-Naive Patients
80%
CirrhosisNo
Cirrhosis
60%
Sofosbuvir
CirrhosisNo Cirrhosis
Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission.
Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.

16. 0
20
40
60
80
100
SVR(%)
SOF/ LDV +/-
RBV x 8-12 wks
97-100% 93-100%
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12
Poordad F, et al. EASL 2014. Abstract O163
2015 /2016 :Virologic Response to Non-interferon
based therapy: Genotype 1 :Treatment-Naive Patients:
Non-cirrhotic and cirrhotic sub-groups
ABT 450/rtv + ombitasvir
+ dasabuvir+RBV
X 12 wks

17. 0
20
40
60
80
100
SVR(%)
SOF/ LDV +/-
RBV 12-24 wks
82-100% 93-100%
2015 /2016 :SVR to Non-interferon based therapy:
Geno. 1 :Treatment Experienced Patients:
Non-cirrhotic and cirrhotic sub-groups
ABT 450/rtv + ombitasvir
+ dasabuvir+RBV
X 12 -24 wks
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

18. AEs
SAPPHIRE I SAPPHIRE II
3 DAA + RBV
(n = 473)
Placebo
(n = 158)
3 DAA + RBV
(n = 297)
Placebo
(n = 97)
Any AE, n (%) 414 (87.5) 116 (73.4) 271 (91.2) 80 (82.5)
AE leading to D/C, n (%) 3 (0.6) 1 (0.6) 3 (1.0) 0
Any serious AE, n (%) 10 (2.1) 0 6 (2.0) 1 (1.0)
Grade 3/4 lab events, n/N (%)
 ALT 4/469 (0.9) 7/158 (4.4) 5/296 (1.7) 3/96 (3.1)
 AST 3/469 (0.6) 3/158 (1.9) 3/296 (1.0) 1/96 (1.0)
 Alkaline phosphatase 0 0 0 0
 Creatinine – – 2/297 (0.7) 0
 Total bilirubin 13/469 (2.8) 0 7/296 (2.4) 0
 Hemoglobin < 8 g/dL 0 0 1/296 (0.3) 0
Hemoglobin < 10 to 8 g/dL, % 5.8 0 4.7 0
Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.
ABT 450/rtv + ombitasvir + dasabuvir+RBV
(Holkira) with RBV in Non-cirrhotic GT1 Pts: Tolerance compared to
placebo

19. Younossi ZM, AASLD, 2014, Poster #1445
Treatment with LDV/SOF (Harvoni) Improves PROs in CHC
Patients with Early as well as Advanced Hepatic Fibrosis

20. 0
20
40
60
80
100
SVR(%)
PegIFN/RBV
X 24 wks
70-80%
97%
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
2014 /2015 :Virologic Response to PEG-INF + RBV
vs. Sofosbuvir + RBV (all-oral) in Genotype 2 and 3
Treatment-Naive Patients
Geno 2
SOF+RBV
X 12 wks
92-94%
Geno 3
SOF+RBV
X 24 wks
Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

21. LDV/SOF (Harvoni) + RBV for HCV Patients with
Decompensated Cirrhosis: SVR-12
SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis
CTP B CTP C
SVR12(%)
26/30 19/22 18/2024/27
Error bars represent 90% confidence intervals.
LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks
SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV
Flamm, AASLD, 2014, Oral #239

22. Ascites Hepatic Encephalopathy
Patients, n
SOF + RBV
n=25
Observation
n=25
SOF + RBV
n=25
Observation
n=25
Baseline 6 9 5 2
Week 12 5 8 3 3
Week 24 0 7 0 4
Cirrhosis and Portal Hypertension Study (SOF+RBV)
Platelets (103
/µL) Albumin (g/dL)
SOF+RBV Observation 24 weeks
ALT (U/L)
CTP A CTP B
Afdhal N, EASL, 2014, O68
p=0.003
p=NS
p=0.001 p=0.001
‡
SOF+RBV for Treatment of Chronic HCV with Cirrhosis
and Portal HTN ± Decompensation: Week 24 Interim Results

23. Hepatitis C: Summary
• HCV has a slowly progressive course to cirrhosis,
with complications of decompensated disease.
• Newer regimen: all-oral, efficacious, well tolerated
• Viral eradication / cure in 70-98%
• Viral eradication has a mortality benefit

24. CADTH SYMPOSIUM : HCV:
NATURAL HISTORY AND THERAPEUTICS
Alnoor Ramji
Gastroenterology & Hepatology
Clinical Associate Professor
Division of Gastroenterology
University Of British Columbia
St. Paul’s Hospital Site
ramji_a@hotmail.com