1. Obiettivi e strategie di un
futuro IFN free
Alessandra Mangia
IRCCS “CSS”
San Giovanni Rotondo

2. Publications in the NEW ENGLAND JOURNAL of MEDICINE on HCV April – May 2014

3. DAAs approved or in current phase III trials against HCV GT1
Anti-NS3/4A ‘…previrs’
A serine protease, essential for post-translational processing of HCV polyproteins1
Telaprevir
Boceprevir
Asunaprevir
Simeprevir
Faldaprevir
ABT-450/r
Anti-NS5B
‘…buvirs’
An HCV-specific, RNA-dependent RNA polymerase1
Nucleos(t)ide analogue
Non-nucleoside analogue
Sofosbuvir
ABT-333
BMS
Anti-NS5A
‘…asvirs’
Multifunctional membrane-associated phosphoprotein, essential component of the HCV-RNA replication complex2,3
Ledipasvir
Daclatasvir
ABT-267
1. Pawlotsky JM, et al. Gastroenterology 2007; 2. Tellinghuisen TL, et al. Nature 2005; 3. Gish RG & Meanwell NA. Clin Liver Dis. 2011;
All drugs listed on clinicaltrials.gov. [Accessed March 2014]

4. HCV treatment: the EU skyline
SOF
approved January 2014
SIM
approved March 2014
Expected approvals
DAC
August/September 2014
LDV/SOF
November 2014
3D ABBVIE
December 2014

5. News from EASL
Is SVR durable?
GT1: is the future 12 weeks for all?
FDC, SIM-SOF, 3D ABBVIE
GT1: is RBV required?
GT2 and GT3: gray zone at the present? Future solutions
Data on re-treatment

6. Is SVR durable?
To assess the durability of SVR24 in patients from the SOF Phase 3 studies
To evaluate the persistence of resistance-associated variants in the viral population of patients who did not achieve SVR24 in the SOF Phase 3 studies
Cheng W et al EASL 2014

7. SVR24 was durable in 100% of patients
Long term Follow-up of pts treated with SOF in the Phase 3 studies FISSION, POSITRON, FUSION, NEUTRINO
Of 480 patients with SVR24 from the Phase 3 trials,435 (91%) and 90 (19%) had available Week 24 and 48 data, respectively
SVR24 was durable in 100% of patients

8. Individualized duration? 8 wks 12 wks 24 wks

9. The ION studies:ION3/ION1 (naive)
LDV/SOF
LDV/SOF + RBV
Wk 0
Wk 8
Wk 12
Wk 24
Wk 20
SVR12
Wk 0
Wk 12
Wk 36
Wk 24
LDV/SOF
SVR12
LDV/SOF + RBV

10. GT 1 Treatment-Naïve (ION-3) Results: Demographics
8 Weeks
12 Weeks
LDV/SOF
n=215
LDV/SOF + RBV
n=216
Mean age, y (range)
53 (22–75)
51 (21–71)
53 (20–71)
Male, n (%)
130 (61)
117 (54)
128 (59)
Black, n (%)
45 (21)
36 (17)
42 (19)
Hispanic, n (%)
13 (6)
12 (6)
14 (7)
Mean BMI, kg/m2 (range)
28 (18–43)
28 (18–56)
28 (19–45)
IL28B CC, n (%)
56 (26)
60 (28)
GT 1a, n (%)
171 (80)
172 (80)
Mean baseline HCV RNA, log10 IU/mL (range)
6.5 (1.4–7.8)
6.4 (3.9–7.7)
6.4 (2.3–7.8)
Baseline HCV RNA ≥800,000 IU/mL
181 (84)
171 (79)
Arms were balanced with respect to demographics and baseline characteristics

11. Results: Non-Inferiority Comparison GT 1 Treatment-Naïve (ION-3)
Relapsers = 5% vs 4% vs 1%
SVR12 (%)
202/215
201/216
206/216
206/216
LDV/SOF
LDV/SOF + RBV
LDV/SOF
8 Weeks
12 Weeks 11
Error bars represent 95% confidence intervals.

12. ION-1 Baseline characteristics
SOF/LDV
12 Weeks
(N=214)
SOF/LDV+RBV
(N=217)
24 Weeks
Baseline Characteristics
Age, mean (SD)
52 (11)
52 (12)
53 (10)
Male, n (%)
127 (59)
128 (59)
139 (64)
119 (55)
Black, n (%)
24 (11)
26 (12)
32 (15)
HCV Gentoype 1a
144 (67)
148 (68)
146 (67)
143 (66)
Presence of Cirrhosis, n (%)
34 (16)
33 (15)
36 (17)
IL28B Non-CC Alleles, n (%)
159 (74)
141 (65)
165 (76)
144 (66)
Log10 HCV RNA (IU/ML), mean (SD)
6.4 (0.7)
6.4 (0.6)
6.3 (0.7)
Interferon Ineligible, n (%)
14 (7)
20 (9)
19 (9)
Virologic Response (ITT)
SVR12, n/N (%)
211/214 (99)
211/217 (97)
212/217 (98)
215/217 (99)
On-Treatment Failure, n/N (%)
0/214
1/217
0/217
Relapse, n/N (%)
1/213 (0.5)
Lost (no SVR12 visit), n/N (%)
4/214 (2)
6/217 (3)
3/217
2/17
Mangia A et al EASL 2014

13. Results: SVR12 GT 1 Treatment-Naïve (ION-1) SVR12 (%) LDV/SOF
Provide Table 13: HCV RNA <LLOQ by visit
211/214
211/217
212/217
215/217
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals. 13

14. Results: SVR12 by GT1 subtype
SOF/LDV
RBV 1a
141/142
(99)
142/142
(100)
143/143
141/141 1b
66/66
67/67
66/68
(97)
71/71
other
4/4
1/1
3/3
Results: SVR12 by GT1 subtype
GT 1 Treatment-Naïve (ION-1)
SOF/LDV
12 wks
RBV
24 wks 1a
141/142
(99)
142/142
(100)
143/143
141/141 1b
66/66
67/67
66/68
(97)
71/71
other
4/4
1/1
3/3

15. SVR12: Absence of Cirrhosis vs Cirrhosis GT 1 Treatment-Naïve (ION-1)
ADD: Small number of cirrhotic failure: X in FDC 12 week are.
179/180
32/34
178/184
33/33
181/184
31/33
179/181
36/36
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.

16. SVR12: Absence of Cirrhosis vs Cirrhosis GT 1 Treatment-Naïve (ION-1)
SOF/LDV
12 wks
RBV
24 wks
Albumin <3.5
5/6
83.3
6/6
100
11/11
12/12
>3.5
206/208 99
205/211 97
201/206 98
203/205
PLT <90
4/5 80
5/5
4/4
>90
207/209
204/209
211/213

17. Using SOF as a backbone

18. COSMOS (phase 2): Study design
SMV + SOF + RBV
Post-treatment follow-up 4 12 24 36 48
Arm 1
Week
SMV + SOF
Arm 2
Arm 3
Arm 4
N=14
N=24
N=14
N=27
Enrolment ratio 2:1:2:1
Cohort 1: Prior null responders (METAVIR F0-F2)
Final SVR12 for all arms
Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4)
Interim SVR4 for Arms 3 and 4
Lawitz E et al EASL 2014

19. Cosmos cohort 2: baseline characteristics
SMV/SOF
RBV
24 wks
No 14
No 24
12 wks
No 27
TOTAL
Male % 70 44 74 71 67
Race W/B
97/3
81/19
93/7
86/14
91/9
Ethnicity 10 31 19 14 17
Median age 58 57
Median BMI 28 29 27 32
Median HCV RNA
6.3
6,6
6.7
6.6
GT1a 77 75 82 79 78
GT1a with Q80K 48 42 36 30 40
Treatment history 50 56 54
Il28B nonCC 73 88 85
cirrhosis 43 63 41 47

20. COSMOS cohort 2: SVR

21. COSMOS cohort 2: SVR12 by HCV GT1 subtype and baseline
NS3 Q80K polymorphism
SVR (%)
6/6
11/11
11/11
4/4
7/7
4/4
5/5
13/14
7/8
3/3
7/8
3/3
18/18
38/40
25/26
24 weeks
12 weeks
Overall

22. Does RBV matter?

23. The ION2: Treatment-Experienced
Wk 0
Wk 12
Wk 36
Wk 24
LDV/SOF
SVR12
LDV/SOF + RBV
GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor
Broad inclusion criteria
Targeted 20% enrollment of patients with cirrhosis
No upper age or BMI limit
Platelet count ≥50,000/mm3, no neutrophil minimum
440 patients randomized 1:1:1:1 across four arms
Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response
Afdhal N et al EASL 2014

24. Results: Demographics GT 1 Treatment-Experienced (ION-2)
12 Weeks
24 Weeks
LDV/SOF
n=109
LDV/SOF+RBV
n=111
Mean age, y (range)
56 (24–67)
57 (27–75)
56 (25–68)
55 (28–70)
Male, n (%)
74 (68)
71 (64)
68 (61)
Black, n (%)
24 (22)
16 (14)
17 (16)
20 (18)
Hispanic, n (%)
7 (6)
12 (11)
11 (10)
Mean BMI, kg/m2 (range)
29 (19–47)
28 (19–45)
28 (19–41)
28 (19–50)
IL28B CC, n (%)
10 (9)
16 (15)
18 (16)
GT 1a, n (%)
86 (79)
88 (79)
85 (78)
Mean HCV RNA, log10 IU/mL (range)
6.5 (5.0–7.5)
6.4 (4.6–7.3)
6.4 (4.7–7.4)
6.5 (3.1–7.4)
HCV RNA ≥800,000 IU/mL
103 (95)
98 (88)
93 (85)
96 (87)
Prior non-responders, n (%)
49 (45)
46 (41)
51 (46)
Prior protease inhibitor failures, n (%)
66 (61)
64 (58)
50 (46)
Cirrhosis, n (%)
22 (20)
Arms were balanced with respect to demographics and baseline characteristics

25. SVR12: PEG/RBV vs PI + PEG/RBV Failures GT 1 Treatment-Experienced (ION-2)
Failed PEG/RBV
Failed Protease Inhibitor
SVR12 (%)
Table 12.1
40/43
62/66
45/47
62/64
58/58
49/50
58/59
51/51
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.

26. SVR12: Absence of Cirrhosis vs Cirrhosis GT 1 Treatment-Experienced (ION-2)
83/87
19/22
89/89
18/22
86/87
22/22
88/89
22/22
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
12 Weeks
24 Weeks
Error bars represent 95% confidence intervals.

27. ION-2: summary Significant number of PI failure RBV not required
Limited number of cirrhotics in 12/24 arms
24 wks may be better than 12 wks in cirrhotics

29. GT3

30. ELECTRON-2: Ledipasvir/Sofosbuvir FDC Is Safe and Effective in Difficult-to-Treat Populations Including GT 3 Pts, Decompensated GT 1 Pts, and GT 1 Pts With Prior Sofosbuvir Experience
GT 1 Prior SOF
GT 1 CPT Class B
GT 3 Treatment Naïve
Baseline characteristics
LDV/SOF + RBV n=19
LDV/SOF
n=20
n=25
LDV/SOF + RBV
n=26
Mean age, y (range)
55 (39–65)
56 (47–72)
43 (22–63)
48 (28–64)
Male, n (%)
13 (68)
17 (85)
13 (52)
11 (42)
White, n (%)
18 (95)
22 (88)
23 (88)
Mean BMI, kg/m2 (range)
27 (19–38)
31 (20–50)
27 (19–37)
28 (18–42)
Cirrhosis, n (%)
20 (100)
3 (12)
5 (19)
IL28B CC, n (%)
4 (21)
7 (35)
9 (36)
15 (58)
GT, n (%) 1a
17 (89)
18 (90) 1b
2 (11)
2 (10) 3a
25 (100)
26 (100)
Mean HCV RNA, log10 IU/mL (range)
6.3 (4.8–7.0)
6.0 (4.9–6.7)
6.3 (4.0–7.3)
6.3 (4.3–7.6)
Gane EJ et al EASL 2014

31. ELECTRON-2 Results: Patients With HCV GT 3, Treatment Naïve
Slide Template
12/31/2018
ELECTRON-2 Results: Patients With HCV GT 3, Treatment Naïve
100
100 80 64 60
SVR12 (%) 40
EF63-9
Source: Slides submitted by client
New create: 9/17/13 (reformat); 9/20/13 (Cis) 20
16/25
16/25
26/26
26/26
LDV/SOF 12 Weeks
LDV/SOF + RBV 12 Weeks
Error bars represent 95% confidence intervals.
GILEAD 31

33. SOFOSBUVIR APPEARS THE BACKBONE FOR HCV THERAPY
Conclusions
IFN free regimens associated with durable SVR
GT1 naive: 12 wks of SOF/FDC suitable for all in the FUTURE
GT1: RBV not required in future SOF/FDC regimens
GT 3: PRESENT successfull re-treatment of pts who fail SOF combination
FUTURE: SOF/FDC+ RBV promising in GT3 for 12 wks
SOFOSBUVIR APPEARS THE BACKBONE FOR HCV THERAPY

34. GRAZIE