Professor Suzanne Norris, ICORN

1. Hepatitis C New Treatment
Options 2014
Professor Suzanne Norris
ICORN

2. 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
DAA
+ RBV
± PegIFN
90+
2014
The Good News

3. First Generation DAAs: a major advance:
GT1 Treatment-Naive Patients
0
20
40
60
80
100SVR(%)
PegIFN/RBV BOC or TVR +
PegIFN/RBV
38-44
63-75
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

4. First Generation DAAs: a major advance:
GT1 Treatment Failures
0
20
40
60
80
100
SVR(%)
Relapsers Partial Responders
69-83
PegIFN/RBV
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Bronowicki JP, et al. EASL 2012. Abstract 11.
Null Responders
BOC or TVR + PegIFN/RBV
24-29
40-59
7-15
29-40
5

5. Treatment Limitations
Treatment is more effective but much more difficult

6. New DAAs: Sites of action
Feeney E.R, Chung R.T. Antiviral treatment of Hepatitis C. BMJ 2014;349:g3308..

7. Not All DAAs are created equal
Characteristic
Protease
Inhibitor*
Protease
Inhibitor**
NS5A
Inhibitor
Nuc
Polymerase
Inhibitor
Non-Nuc
Polymerase
Inhibitor
Resistance
profile
Pangenotypic
efficacy
Antiviral
potency
Adverse
events
Good profile Average profile Least favorable profile
*First generation. **Second generation.
Feld J. Keeping up in HCV: Counting down the final days of interferon.

8. Progress May Not Be Linear
Tolerability/Safety
Efficacy
Peg/RBV
Peg/RBV
+ BOC/TVR
Peg/RBV
+ 2nd-gen DAA
IFN-free
DAA combo
IFN-free
DAA combos
Peg/RBV
+ 2 DAAs
1 pill, QD,
No AEs,
100% SVR
Perfectovir

9. Progress May Not Be Linear
Tolerability/Safety
Efficacy
Peg/RBV
Peg/RBV
+ BOC/TVR
Peg/RBV
+ 2nd-gen DAA
IFN-free
DAA combo
IFN-free
DAA combos
Peg/RBV
+ 2 DAAs
SUCCESSovir
Simple
Safe
Effective
Uniform – all populations

10. Summary of New HCV Agents
Class Drug Dosing
NS3/4A protease inhibitor ABT-450/RTV 150/100 mg
NS3 protease inhibitor Asunaprevir 200 mg BID
NS3/4A protease inhibitor MK-5172 100 mg OD
NS3/4A protease inhibitor Simeprevir 150 mg OD
NS5B non-nucleoside polymerase inhibitor Dasabuvir 400 mg BID
NS5B non-nucleoside polymerase inhibitor BMS-791325 75 mg or 150 mg BID
NS5B nucleotide polymerase inhibitor Sofosbuvir 400 mg OD
NS5A inhibitor Ombitasvir 25 mg OD
NS5A inhibitor Daclatasvir 60 mg OD
NS5A inhibitor Ledipasvir 90 mg OD
NS5A inhibitor MK-8742 20 or 50 mg OD
NS5A inhibitor Samatasvir 25-100 mg OD
Courtesy of M Coghlan, St James’s Hospital 2014

11. Licensing Updates October 2014
• Sofosbuvir: Licensed by EMEA. Expected NCPE decision October 2014.
• Simeprevir: Licensed by EMEA. NCPE review approved for use with
PEGIFN&RBV in G1 + G4.
• Daclatasvir: Licensed by EMEA for mono-infection.
• Abbvie: ABT-450/RTV (PI) ± dasabuvir (NNI) + ombitasvir (NS5A) ± RBV x
12 wks. Expected license submission by year end with decision in early
2015 and subsequent review by NCPE.
• Sofosbuvir/Ledipasvir: CHMP (EMEA) have recommended license be
granted in the EU.

12. New DAA options
• IFN-containing DAA regimens
• IFN-free DAA regimens

13. QUEST-1, QUEST-2, PROMISE: Simeprevir +
Peg/Rib in genotype 1 treatment-naive
and relapsers
100
80
60
40
20
0
SVR12(%)
80
50
210/
264
65/
130
81
209/
257
50
67/
134
QUEST-1 QUEST-2
100
80
60
40
20
0
SVR12(%)
79
37
206/
260
49/
133
PROMISE
Treatment-Naive Patients Prior Relapsers
Jacobson I, et al. EASL 2013. Abstract 1425. Manns M, et al. Lancet 2014, June 4th.
P/R
SMV + P/R

14. QUEST Studies: Subtype 1a versus 1b
Jacobson I, et al. AASLD 2013.
Likely relates to presence of Q80K polymorphism in GT1a
62/
131
191/
254
70/
133
228/
267
SVR12(%)
100
80
60
40
20
0
GT1a GT1b
Simeprevir + P/R (RGT 12 + 12) Placebo + P/R
75
47
85
53

15. QUEST: less benefit of Simeprevir if
Q80K positive
100
80
60
40
20
0
SVR12(%)
85
58
228/
267
49/
84
84
138/
165
GT1b GT1a
no Q80K
GT1a +
Q80K
Q80K present in 34% of GT1a patients
No benefit of simeprevir if Q80K positive
53
70/
133
43
52
36/
83
23/
44
SMV + P/R
P/R
Jacobson I, et al. AASLD 2013.

16. 12 weeks 36 weeks
Simeprevir + Peg/Rib for genotype 1
approved indications
• Simeprevir 150 mg/day with food, administered with P/R (Olysio®)
– Fixed duration (no RGT)
• Treatment-naive patients and relapsers (including cirrhotic patients)
• Previous partial or null responders (including cirrhotic patients)
• Stopping rules
12 weeks 12 weeks
Treatment Wk HCV RNA (IU/mL) Action
4 ≥ 25 Discontinue simeprevir, pegIFN, and RBV
12 ≥ 25 Discontinue pegIFN and RBV (SMV stops at 12 wks)
24 ≥ 25 Discontinue pegIFN and RBV
Simeprevir + P/R P/R
Simeprevir + P/R P/R

17. NEUTRINO: Sofosbuvir + P/R for 12 weeks in
treatment-naive
• Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for
12 weeks in treatment-naive patients with GT1/4/5/6 HCV
– 17% cirrhosis; 89% GT1; 9% GT4; < 1% GT5; 2% GT6
– Caveat: small numbers
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Overall
SVR12(%)
89
96
100
100
80
60
40
20
0
GT1 GT4 GT5,6
261/292 27/28 7/7n/N =
90
295/327
92
80
100
80
60
40
20
0
No
Cirrhosis
Cirrhosis
252/273 43/54

18. Sofosbuvir + Peg/Rib for Genotype 1 :
approved indications in US
• Sofosbuvir 400 mg/day with or without food, administered with P/R
• All GT1 patients receive same regimen, regardless of previous treatment
history or fibrosis level
– Same regimen approved for GT4 HCV
• Additional option for GT1 patients ineligible for IFN therapy
– Sofosbuvir + ribavirin for 24 weeks
• If drugs combined with sofosbuvir must be permanently discontinued,
sofosbuvir should also be discontinued
12 weeks
Sofosbuvir + P/R

19. New DAA options
• IFN-containing DAA regimens
• IFN-free DAA regimens

20. How Many DAAs Do We Need?
Assumptions:
1) Production of new virions = ~1012/day
2) HCV genome length = ~9600 nucleotides
3) Error rate = ~10-5/per nucleotide copied
Therefore, average number of changes/genome = 0.096/replication cycle
# of Nucleotide
Changes
Probability # of
Virions/Day
# of All Possible
Mutants
% of All Possible
Mutants/Day
0 0.91 9.1 x 1011
1 0.087 8.7 x 1010 2.9 x 104 100
2 0.0042 4.2 x 109 4.1 x 108 100
3 0.00013 1.3 x 108 1.0 x 1012 3.4 x 10-5
If the theory is right: should need 3 DAAs
Rong L, et al. Sci Transl Med. 2011;2:30-32.

21. DAA Options
• PI backbone – potent/modest barrier
– PI + another low-barrier DAA (NNI/NS5A) for GT1b
– PI + 2 low-barrier DAAs for GT1a
• Nuc backbone – potent/high barrier
– Nuc + low-barrier DAA for GT1a/b
– Nuc + PI
• Include ribavirin?
– May allow fewer DAAs (2 vs 3)
– May allow shorter therapy

22. SAPPHIRE Phase III Studies:
PI backbone + 2 other DAAs
SAPPHIRE-1: GT1 treatment-naive
noncirrhotic patients:
ABT-450/RTV/ABT-267 FDC
+ ABT-333 + RBV for 12 wks
455/
473
307/
322
148/
151
SAPPHIRE-2: GT1 treatment-experienced
noncirrhotic patients (49% null responders):
ABT-450/RTV/ABT-267 FDC
+ ABT-333 + RBV for 12 wks
100
80
60
40
20
0
SVR12(%)
96 95 98
Overall GT1a GT1b
286/
297
166/
173
119/
123
100
80
60
40
20
0
SVR12(%)
96 96 97
Overall GT1a GT1b

23. 96
COSMOS trial: nuc backbone + PI in
treatment naive and null responders
SVR12(%)
F0-F2 Fibrosis
100
80
60
40
20
0
96 93
26/
27
13/
14
SMV (PI) + SOF (Nuc) + RBV 12 wks SMV (PI) + SOF (Nuc) 12 wks
SVR4(%)
F3/F4 Fibrosis
100
26/
27
14/
14
 78% GT1a
 50% Q80K
 94% non-CC
 All nulls
 78% GT1a
 40% Q80K
 79% non-CC
 47% F4
 54% Null
Jacobson I, et al. AASLD 2013
 Major caveats: small numbers, no plan for phase III trial

24. Another Option: Nuc backbone + NS5A
Sulkowski M, et al. AASLD 2012..
SOF (Nuc) + daclatasvir (NS5A)
± RBV x 24 wks
Major caveats: small numbers, no plan for phase III trial
100
80
60
40
20
0
SVR4or12(%)
100
14/14
100
15/15
DCV
+ SOF
24 wks
SOF (Nuc) + daclatasvir (NS5A)
± RBV x 12 wks
40/41
98
39/41
95
12 wks
DCV + SOF
+ RBV
DCV
+ SOF
DCV + SOF
+ RBV

25. ION studies of sofosbuvir (Nuc) + ledipasvir
(NS5A) ± rib in genotype 1
ION-1*: GT1 treatment-naive pts
(16% cirrhotic): SOF/LDV FDC ±
RBV for 12 wks
ION-3: GT1 treatment-naive pts:
SOF/LDV FDC ± RBV
for 8 or 12 wks
SOF/LDV FDC SOF/LDV FDC + RBV
ION-2: GT1 treatment-experienced pts
(20% cirrhotic): SOF/LDV FDC ± RBV for
12 or 24 wks
8 Wks 12 Wks
202/
215
206/
216
201/
216
12 Wks 24 Wks
102/
109
107/
111
108/
109
110/
111
209/
214
211/
217
SVR12(%)
12 Wks
98 97100
90
60
40
20
0
94 93 95 94 96 99 99

26. Over-
treatment
of some?
Tailored
regimen
for each
population
Priorities
Cost
Fewest
drugs
Shortest
duration
Simplicity
One size
fits all
Primary
care
Different Strategies

27. DAA Options
• What about resistance?
• Duration of SVR with shorter DAA regimen?
• Will IFN still have a role?
• Real world data versus trial data?
• What about cirrhotics?

28. Severity of disease increases need for HCV
therapy but also impairs response
 may not need immediate
treatment
 BUT
• Easier to treat
• High likelihood of
response
cirrhosisMild disease
 greater need for treatment
 BUT
• Response to current IFN-
based therapy may be
impaired

29. Cirrhosis: continuous spectrum of disease
ESLD
Child-Pugh B
Portal hypertension –
high risk
Cirrhosis – treatment candidate
Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score
Courtesy of Prof G Foster

30. CUPIC: high-risk patients less likely
to achieve SVR
• CUPIC enrolled treatment-experienced patients with compensated cirrhosis and
notable risk factors
– Patients achieved high SVR rates with TVR or BOC plus pegIFN/RBV
• Patients with cirrhosis who present with significant risk factors require careful
monitoring when treated with pegIFN/RBV
Factors
Platelet Count
≤ 100,000/mm3
Platelet Count
> 100,000/mm3
Albumin
< 35 g/L
N 37 31
Complications, n (%) 19 (51.4) 5 (16.1)
SVR12, n (%) 10 (27.0) 9 (29.0)
Albumin
≥ 35 g/L
N 74 305
Complications, n (%) 9 (12.2) 19 (6.2)
SVR12, n (%) 27 (36.5) 168 (54.9)
Fontaine H, et al. 2013..

31. CUPIC: risk–benefit of achieving SVR12
versus developing serious complications
Platelet Count
≤ 100,000/mm3
Platelet Count
> 100,000/mm3
Albumin
< 35 g/L
Serious AEs >> SVR SVR > Serious AEs
Albumin
≥ 35 g/L
SVR > Serious AEs SVR >> Serious AEs

32. Factors associated with greater benefit or
greater risk of treatment in cirrhotics
Factors Associated With Greater
Benefit of Therapy
Factors Associated With Greater
Risks of Therapy
 ↓ Child-Pugh score
 ↓ MELD score
 ↑ Platelet count
 ↑ Albumin level
 ↓ Age
 ↑ Child-Pugh score
 ↑ MELD score
 ↓ Platelet count
 ↓ Albumin level
 ↑ Age

33. 100
NEUTRINO: SVR by cirrhosis status
with Sofosbuvir + P/R
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
 Open-label, single-arm,
phase III study
 Sofosbuvir 400 mg QD +
PegIFN/RBV for 12 wks
 Treatment-naive patients
with GT 1/4/5/6 HCV
– 17% cirrhosis; platelets ≥
90,000/mm3
– 89% GT 1, 9% GT 4,
< 1% GT 5, 2% GT 6
SVR12(%)
92
80
252/
273 43/54
80
60
40
20
0
GT 1/4/5/6
CirrhoticNoncirrhotic

34. COSMOS: SVR12 in F3/4 genotype 1
simeprevir + sofosbuvir ± ribavirin
Lawitz E, et al. EASL 2014.
• Open-label, randomized phase IIa study of simeprevir + sofosbuvir with or without RBV
for 12 or 24 wks in cirrhotic and noncirrhotic GT 1 treatment naive or previous null
responders
• Primary endpoint: SVR12
SMV/SOF ±
RBV
SMV/SOF +
RBV
SMV/SOF +
RBV
SMV/SOF SMV/SOF
24 Wks 12 Wks Overall
16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39
F3 fibrosis
F4 fibrosis
SVR12(%)
100
80
60
40
20
0
100 100 100 100 100
94 91
98
86
95
n/N =

35. Promising IFN-Free regimens in
genotype 1 cirrhotic patients
Regimen
SVR12, %
Tx Naive Tx Exp PI Failure
Sofosbuvir + ledipasvir[1,2] --- 70 (N = 10) 91 (N = 11)
Sofosbuvir + ledipasvir + RBV[1,2] --- 100 (N = 25) 100 (N = 11)
Sofosbuvir + ledipasvir + GS-9669[1] --- 100 (N = 26) ---
Daclatasvir + asunaprevir[3]* 90 (N = 203)† 82 (N = 205)† ---
Daclatasvir + asunaprevir + BMS-791325 75 mg[4] 94 (N = 16) --- ---
Daclatasvir + asunaprevir + BMS-791325 150 mg[4] 89 (N = 18) --- ---
ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5] 94 (N = 86) 87-97 (N = 122) ---
ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5]* 95 (N = 74) 95-100 (N = 98) ---
1. Gane EJ, et al. AASLD 2013. Abstract 73. 2. Lawitz. E et al. AASLD 2013, Abstract 215.
3. Manns M, et al. EASL 2014. Abstract 166. 4. Everson GT, et al. Gastroenterol. 2014;146:420-429.
5. Poordad F, et al. N Engl J Med. 2014;[Epub ahead of print].
*Treatment duration: 24 weeks; all others 12 weeks.
†Genotype 1b HCV-infected patients only

36. Summary
• First-generation PIs have now been replaced
– SMV + P/R x 24 weeks – issue with Q80K in GT1a?
– HTA Decision re SOF + P/R x 12 weeks due October
– IFN-free therapy on the horizon
• One size fits all versus individualised regimens?
• Will simplify with time
• Cirrhotic patients are the most in need for HCV treatment
• Child-Pugh A patients should be strongly advised to undergo therapy
• More advanced cirrhosis should be treated with caution on a case-by-
case basis
• IFN-free DAA regimens demonstrate significant potency in cirrhotic
patients (but may require longer duration as real world data accrues)
• The final challenge will be paying for Perfectovir

37. Thank you