1. IRCCS “CSS” San Giovanni Rotondo
Malattia HCV correlata: l’inizio
di una nuova era
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
Daclatasvir
ABT-267
Ledipasvir
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. News from EASL Is SVR durable? GT1: is the future 12 weeks for all?
FDC, SIM-SOF, 3D ABBVIE
GT1: is RBV required?
GT3: gray zone at the present? Future solutions
Data on re-treatment

5. 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

6. 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

7. GT1 8 wks or 12?

8. 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

9. 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
Kowdley KV et al EASL

10. 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 10
Error bars represent 95% confidence intervals.

11. 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

12. 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. 12

13. 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

14. 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.

15. SVR12: by albumin and PLT levels 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

16. Results: Safety Summary GT 1 Treatment-Naïve (ION-3)
Patients, n (%)
LDV/SOF
8 Weeks n=215
LDV/SOF + RBV
8 Weeks
n=216
12 Weeks
Overall safety
AEs
145 (67)
165 (76)
149 (69)
Grade 3‒4 AEs
2 (<1)
8 (4)
7 (3)
Serious AEs
4 (2)
1 (<1)
5 (2)
Treatment discontinuation due to AEs
Death
Grade 3‒4 laboratory abnormality
18 (8)
16 (7)
Hemoglobin <10 g/dL
11 (5)
Hemoglobin <8.5 g/dL

17. Previous treated

18. 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

19. 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

20. 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.

21. 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.

22. ION-2: summary Significant number of PI failure No need of RBV
Limited number of cirrhotics in 12/24 arms
24 wks may be better than 12 wks in cirrhotics

23. Results: Overall Safety Summary GT 1 Treatment-Experienced (ION-2)
12 Weeks
24 Weeks
Patients, n (%)
LDV/SOF
n=109
LDV/SOF+RBV
n=111
Overall safety
AEs
73 (67)
96 (86)
88 (81)
100 (90)
Grade 3‒4 AEs
2 (2)
3 (3)
10 (9)
8 (7)
Serious AEs
6 (6)
Treatment D/C due to AEs
Death
Grade 3‒4 laboratory abnormality
5 (5)
15 (14)
9 (8)
27 (24)
Hemoglobin <10 g/dL
Hemoglobin <8.5 g/dL

24. Results: Adverse Events (≥10% in Any Arm) GT 1 Treatment-Experienced (ION-2)
Preferred term, n (%)
12 Weeks
24 Weeks
LDV/SOF
n=109
LDV/SOF+RBV
n=111
Overall
73 (67)
96 (87)
88 (81)
100 (90)
Fatigue
23 (21)
45 (41)
26 (24)
50 (45)
Headache
28 (26)
26 (23)
25 (23)
35 (32)
Nausea
13 (12)
20 (18)
7 (6)
Insomnia
10 (9)
18 (16)
4 (4)
19 (17)
Arthralgia
17 (15)
Cough
5 (5)
16 (14)
Diarrhea
9 (8)
Rash
2 (2)
11 (10)
6 (6)
Irritability
12 (11)
Dizziness
3 (3)
8 (7)
Dyspnea
Upper respiratory tract infection
6 (5)
Muscle spasms
1 (<1)
Anemia
Dry skin
Most AEs mild or moderate in severity

25. GT2 and 3

26. Early Viral Kinetics Do Not Predict Treatment Outcome With Sofosbuvir + Ribavirin for 12 or 24 Weeks in HCV Genotype 2/3 Patients in the VALENCE Trial
SOF+RBV treatment for 12 wk in pts with HCV GT 2 and for 24 wk in GT 3
was highly efficacious
The majority of pts achieved HCV RNA <LLOQ TND at Week 4
On-treatment viral kinetics were not significantly predictive of response
Patients with HCV GT 3 who became HCV RNA <LLOQ or <LLOQ TND
earlier generally had higher SVR rates; however, the NPVs were insufficient to
support a change in treatment, particularly given the tolerability of the regimen
Zeuzem S et al EASL 2014

27. 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

28. ELECTRON-2 Results: Patients With HCV GT 3, Treatment Naïve
Slide Template
2/25/2019
ELECTRON-2 Results: Patients With HCV GT 3, Treatment Naïve
n=8 relapsers
n=1 discontinued (AE)
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 28

29. ELECTRON-2 Results: Patients With HCV GT 3, Treatment Naïve
Slide Template
2/25/2019
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 29

30. Successful Retreatment With Sofosbuvir-containing Regimens for HCV GT 2 or 3 Pts who Failed Prior Sofosbuvir/RBV
Baseline
characteristics
12 weeks SOF + PEG/RBV
n=34
24 weeks SOF + RBV
n=73
Mean age, y (range)
53 (31–70)
53 (38-63)
Male, n (%)
26 (77)
63 (86)
Black, n (%)
1 (1%)
Mean BMI, kg/m2 (range)
29 (22–39)
28 (20-41)
Cirrhosis* n (%)
14 (41)
25 (34)
IL28B CC, n (%)
11 (32)
27 (37)
Mean ALT, U/L (range)
96 (14-325)
89 (18-310)
Genotype, n (%) 2
6 (18)
5 (7) 3
28 (82)
68 (93)
Mean baseline HCV RNA, log10 IU/mL (range)
6.3 ( )
6.6 (4.4–7.6)
Large number of cirrhotics
Mostly GT3 based upon efficacy of SOF/RBV in GT2
*Cirrhosis status determined in parent protocol.
Esteban R et al EASL 2014

31. Results: SVR12 by HCV Genotype
GT2 failure had cirrhosis
12 week PEG-containing arm with high SVR
24 week arm was lower – but still a good option for IFN-intolerant
4/4
1/2
20/22
24/38

32. Conclusions IFN free regimens associated with durable SVR
GT1 naive: 12 weeks suitable for all in the FUTURE
GT1: RBV not required in combination regimen based on SOF/FDC
GT 3: PRESENT successfull SOF/RBV re-treatment of pts who fail SOF combination
FUTURE: FDC+ RBV promising in GT3