IRCCS “CSS” San Giovanni Rotondo Malattia HCV correlata: l’inizio di una nuova era Alessandra Mangia IRCCS “CSS” San Giovanni Rotondo

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

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-791325 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]

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

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

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

GT1 8 wks or 12?

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

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

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.

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

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

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 94.6-100 89.9-99.6 94.9-100 other 4/4 1/1 3/3

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.

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

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

Previous treated

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

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

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.

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.

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

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

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

GT2 and 3

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

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

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

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

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 (4.8-7.8) 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

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

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