1. HARVONI sofosbuvir400mg/ledipasvir 100 mg QD
Premio Galeno
Circolo della Stampa, Corso Venezia 48 Milano
25 novembre 2015
Paolo Fedeli MD

2. ledipasvir/sofosbuvir: A Single Tablet Regimen (STR)
ledipasvir (LDV)
Picomolar potency against HCV GT 1a and 1b1
Effective against NS5B RAV S282T2
Once-daily, oral, 90 mg
sofosbuvir (SOF)
Potent antiviral activity against HCV GT 1–6
Effective against NS5A RAVs3
High barrier to resistance
Once-daily, oral, 400-mg tablet
ledipasvir/sofosbuvir STR
Once-daily, oral fixed-dose (90/400 mg) combination tablet, RBV-free
Limited DDIs, no food effect
>2000 patients treated in clinical trials
LDV NS5A inhibitor
SOF - NS5B nucleotide polymerase inhibitor
Transition:
Here is an overview of the ledipasvir/sofosbuvir single-tablet regimen.
Main Messages:
Ledipasvir is an NS5A inhibitor and sofosbuvir is an NS5B inhibitor.
The single-tablet regimen (STR) of ledipasvir/sofosbuvir has been used to treat over 1400 HCV patients in clinical trials.
It has been filed with the FDA for the treatment of HCV GT 1 patients and has been granted Priority Review and Breakthrough status.
The expected FDA action date (PDUFA date) is October 10, 2014.
SOF - NS5B nucleotide polymerase inhibitor
LDV NS5A inhibitor
FDA Approval 10 October 2014 European Approval 18 November 2014
1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172; 3. SOVALDI® [SmPC]. Gilead Sciences, Inc. EMA, 2014

3. HARVONI First FDC, STR regimen to treat Gt1 HCV chronic infection
First FDC, STR regimen to treat Gt1 HCV chronic infection
Efficacy: high rates of SVR, confirmed in real world data
Tolerability: good safety profile, <1% D/C rate for SAEs
Opportunity to shorten treatment schedule
Used in several subpopulation: confirm results with high efficacy and good safety profile across all population studied
Efficacy and Effectiveness confirmed in all stages of hepatic disease (from F0 up to decompensated cirrhosis)

4. Ledipasvir/Sofosbuvir as the First HCV Single Tablet Regimen (STR)
2014
Background comparison:
Each hard capsule contains 200 mg of boceprevir. The recommended dose of boceprivir is 800 mg administered orally three times daily (TID) with food (a meal or light snack). Maximum daily dose of Victrelis is 2,400 mg.
Regimen: 6 capsules of boceprivir + ribavirin + peg injection 4

5. LDV/SOF Clinical Development Program
ELECTRON
LONESTAR
ION-2
SOLAR-1
SOLAR-2
Nosocomial HCV
ION-4
HCV/HIV
Co-infection
LONESTAR-3
French GT 4,5
Bleeding Disorders
ION-3
Re-treatment
ION-1
ELECTRON-2
Egypt GT 4
Korea/ Taiwan/
China
GT 1
Japan
GT 1
French ANRS HCV/HIV
Co-infection
Russia
GT 1,3
Australia
TAP IVDU
ERADICATE
HCV/HIV Co-infection
SYNERGY
Immediate Post-liver Transplant
Post-renal Transplant
Sickle Cell Anaemia
SIRIUS
Brain Imaging Study
GT 1
GT 1/3
GT 1, incl. PI failures
GT 4/5
GT 4
Special populations
GT 1/4
GT 1/2/3/6

6. LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3)
Wk 0
Wk 8
Wk 12
Wk 24
LDV/SOF + RBV
LDV/SOF
ION-1
ION-2
LDV/SOF + RBV
Transition:
This slide shows the study designs for the ION-1, ION-2, and ION-3 studies
Main Messages:
The ION-1 and ION-2 studies evaluated LDV/SOF ± RBV for 12 or 24 weeks in GT 1 treatment-naïve and treatment-experienced subjects, respectively.
The ION-3 study evaluated LDV/SOF ± RBV for 8 weeks and LDV/SOF for 12 weeks in GT 1 treatment-naïve subjects.
There are nearly 2000 patients enrolled in the ION studies.
LDV/SOF
LDV/SOF + RBV
ION-1: treatment naïve,16% cirrhotic; N = 865
ION-2: treatment experienced, 20% cirrhotic; N = 440
ION-3: treatment naïve, non-cirrhotic; N = 647
N = 1952 total patients (224 cirrhotics)
ION-3
LDV/SOF
Afdhal N, et al. N Engl J Med 2014; 370: ; Afdhal N, et al. N Engl J Med 2014;370: ; Kowdley K, et al. N Engl J Med 2014;370:

7. Primary Endpoint (ITT Analysis)
ION-1 (GT 1, Treatment-Naive, LDV/SOF±RBV x 12 or 24 weeks)
Primary Endpoint (ITT Analysis)
Patients with HCV RNA < LLOQ (%)
Transition
Here are the SVR12 results
Main Message
Virtually all patients became undetectable within 4 weeks (≥ 99%) and remained so until Week 12 of treatment.
The confidence interval overlap in SVR between the 12- and 24-week treatment groups indicate comparable outcomes
3 patients experienced virologic failure
1 patient had virologic breakthrough
63 yo Black male, GT1b received 24 weeks of LDV/SOF, suspected of non-adherence based on undetectable drug plasma levels
2 patients had virologic relapse
56 yo White male, with cirrhosis, GT1a received 12 weeks of LDV/SOF relapsed by post-treatment Week 4
65 yo Black male, with cirrhosis, GT1b received 24 weeks of LDV/SOF relapsed between post-treatment Weeks 4 and 12
Background
SVR12 was achieved by
99% of patients on 12 weeks of LDV/SOF (210 of 213 patients, 95% CI, 96 to 100)
97% of patients on 12 weeks of LDV/SOF + RBV (211 of 217 patients, 95% CI, 94 to 99)
98% of patients on 24 weeks of LDV/SOF (212 of 217 patients, 95% CI, 95 to 99)
99% of patients on 24 weeks of LDV/SOF + RBV (215 of 217 patients, 95% CI, 96 to 100)
In ION-1, 3 to 5% of patients in each arm had <80% adherence to study drug (LDV/SOF) and about 87 to 97% of patients had  >90% adherence to LDV/SOF. 2 patients relapsed and both had 100% adherence per pill count.  In general, both drugs have long half-lives so if a patient missed a dose they would still have drug in their system, however we have not determined how many doses you can miss or the impact of missing doses early vs late on treatment. (Data on file)
210/213*
211/217
212/217
215/217
LDV/SOF
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
12 Weeks
24 Weeks
All four treatment arms met the primary endpoint of superiority over the historical response rate of 60% (P < for all comparisons)
*excluding one subject with genotype 4 infection
Error bars represent 95% confidence intervals.
Afdhal N, et al. N Engl J Med 2014; 370: Data on File, Gilead Sciences, Inc.

8. Primary Endpoint (ITT Analysis)
ION-2 (GT 1, Treatment-Experienced, LDV/SOF±RBV x 12 or 24 weeks)
Primary Endpoint (ITT Analysis)
Patients with HCV RNA < LLOQ (%)
Transition
Here are the SVR12 results
Main Message
Virtually all patients became undetectable within 4 weeks (≥ 99%) and remained so until the end of treatment
The confidence interval overlap in SVR between the 12- and 24-week treatment groups indicate comparable outcomes
Overall, 11 of the 440 patients (3%) had virologic relapse after the end of treatment (7 received 12 weeks of LDV/SOF; 4 received 12 weeks of LDV/SOF + RBV)
10/11 patients relapsed by post-treatment Week 4
No patients in the 24-week treatment arms experienced virologic relapse (1 patient withdrew consent, 1 patient suspected of non-adherence based on undetectable drug plasma levels)
Background
SVR12 was achieved by
94% of patients on 12 weeks of LDV/SOF (102 of 109 patients, 95% CI, 87 to 97)
96% of patients on 12 weeks of LDV/SOF + RBV (107 of 111 patients, 95% CI, 91 to 99)
99% of patients on 24 weeks of LDV/SOF (108 of 109 patients, 95% CI, 95 to 100)
99% of patients on 24 weeks of LDV/SOF + RBV (110 of 111 patients, 95% CI, 95 to 100)
102/109
107/111
108/109
110/111
LDV/SOF
LDV/SOF+RBV
LDV/SOF
LDV/SOF+RBV
12 weeks
24 weeks
SVR 12
All four treatment arms met the primary endpoint of superiority over the historical response rate of 25% (P<0.001 for all comparisons)
*One patient had an HCV RNA level of 42 IU/mL at the Week 12 visit, but had undetectable HCV RNA at post-treatment Weeks 4, 12, and 24
†One patient withdrew consent after the post-treatment Week 4 visit, at which time HCV RNA < 25 IU/mL
‡The patient who did not achieve SVR was non-adherent to study treatment as documented by plasma concentrations below or near the lower level of quantitation of LDV and GS (the predominant circulating metabolite of SOF) and at Weeks 2, 4, and 6
Error bars represent 95% confidence intervals
Afdhal N, EASL, 2014, O109
Afdhal N, et al. N Engl J Med 2014;370:

9. Primary Endpoint (ITT Analysis)
ION-3 (GT 1, Treatment-Naive, Non-Cirrhotic, LDV/SOF±RBV x 8 or 12 weeks)
Primary Endpoint (ITT Analysis)
Patients with HCV RNA < LLOQ (%)
Transition
Here are the SVR12 results
Main Message
Virtually all patients became undetectable within 4 weeks (≥ 99%) and remained so until the end of treatment
The rate of SVR among patients receiving 8 weeks of LDV/SOF was non-inferior to response rates in the other 2 treatment groups
All virologic failures were due to relapse (n = 11, 8 weeks of LDV/SOF; n = 9, 8 weeks of LDV/SOF + RBV; n = 3, 12 weeks of LDV/SOF)
Background
SVR12 was achieved by
94% of patients on 8 weeks of LDV/SOF (202 of 215 patients, 95% CI, 90 to 97)
93% of patients on 8 weeks of LDV/SOF + RBV (201 of 216 patients, 95% CI, 89 to 96)
96% of patients on 12 weeks of LDV/SOF (208 of 216 patients, 95% CI, 92 to 98) (based on emerging data)
The patient with BMI of 56 achieved SVR12. (Data on file)
202/215
201/216
208/216
LDV/SOF
LDV/SOF + RBV
LDV/SOF
8 weeks
12 weeks
SVR 12
All three treatment arms met the primary endpoint of superiority over the historical response rate of 60% (P<0.001 for all comparisons)
8 weeks of LDV/SOF was non-inferior to 8 weeks of LDV/SOF + RBV and 12 weeks LDV/SOF
Error bars represent 95% confidence intervals
Kowdley K, et al. N Engl J Med 2014;370:
Data on File, Gilead Sciences, Inc. Data on File, Gilead Sciences, Inc.

10. SVR12 Results with LDV/SOF±RBV for 8, 12, and 24 Weeks
HCV-TARGET Real-World Cohort
SVR12 Results with LDV/SOF±RBV for 8, 12, and 24 Weeks
Virologic Response
LDV/SOF
LDV/SOF+RBV
SVR12, %
Transition:
Here we show the efficacy and safety results from HCV Target.
Main Message:
Real-World Data consistent with clinical trials.
323 subjects qualified for 8 week therapy, but only 41% received an 8 week duration. Response rate was 97% for 8 week and 12 week duration in subjects that qualified for 8 week therapy.
Background:
Baseline predictors of SVR among patients treated with LDV/SOF include: albumin ≥ 3.5 g/dL, PLT (1000/ul), total bilirubin ≤ 1.2 mg/dL, no cirrhosis, compensated cirrhosis vs. decompensated cirrhosis, and no PPI at baseline.
SVR12 by use of PPI at baseline with LDV/SOF:
8 week duration: no PPI at baseline, SVR12 98% (n=124) vs. PPI at baseline, SVR12 93% (n=30).
12 week duration: no PPI at baseline, SVR12 98% (n=464) vs. PPI at baseline, SVR12 93% (n=163).
Most common AE’s included fatigue (24%), headache (22%), nausea (8%), diarrhea (7%), and insomnia (7%).
There were 11 deaths: 10 had cirrhosis, 6 had decompensated cirrhosis.
LDV/SOF alone: acute respiratory failure, breast cancer metastatic, CAD, Death NOS (2), intraventricular hemorrhage, MOF, road traffic accident, septic shock, narcotic overdose.
LDV/SOF + RBV: road traffic accident.
150/ 154
607/ 627
153/ 161
86/ 89
12/ 13
LDV/SOF
LDV/SOF+RBV
Terrault, AASLD, 2015, 94

11. SVR12 with LDV/SOF by Subgroups
HCV-TARGET Real-World Cohort: Treatment Outcomes with LDV/SOF for 8, 12, and 24 Weeks
SVR12 with LDV/SOF by Subgroups
*P<0.05 * *
Transition:
This figure shows the SVR12 rates for LDV/SOF x 8, 12, or 24 weeks by subgroup.
Main Message:
High SVR rates seen across all subgroups
Data with regard to dosing specific agents and concomitant use and timing of administration is not available
Authors’ recommendations are to consider modification of PPI use * * *
Terrault, AASLD, 2015, 94

12. Safety in Real-life setting
HCV-TARGET Real-World Cohort: Treatment Outcomes with LDV/SOF for 8, 12, and 24 Weeks
Safety in Real-life setting
LDV/SOF N=1435
LDV/SOF + RBV N=213
Any AE, n (%)
900 (63)
178 (84)
Fatigue
320 (22)
75 (35)
Headache
307 (21)
50 (24)
Anemia
8 (1)
53 (25)
Nausea
109 (8)
25 (12)
Diarrhea
86 (6)
22 (10)
Rash
30 (2)
21 (10)
Pruritus
27 (2)
Insomnia
89 (6)
19 (9)
Influenza like illness
65 (5)
15 (7)
Dyspnea
44 (3)
20 (9)
Decreased appetite
26 (2)
18 (8)
Dizziness
46 (3)
Cough
37 (3)
13 (6)
Irritability
17 (1)
Dyspnea exertional
5 (0.4)
Transition:
Here we show the efficacy and safety results from HCV Target.
Main Message:
Real-World Data consistent with clinical trials.
323 subjects qualified for 8 week therapy, but only 41% received an 8 week duration. Response rate was 97% for 8 week and 12 week duration in subjects that qualified for 8 week therapy.
Background:
Baseline predictors of SVR among patients treated with LDV/SOF include: albumin ≥ 3.5 g/dL, PLT (1000/ul), total bilirubin ≤ 1.2 mg/dL, no cirrhosis, compensated cirrhosis vs. decompensated cirrhosis, and no PPI at baseline.
SVR12 by use of PPI at baseline with LDV/SOF:
8 week duration: no PPI at baseline, SVR12 98% (n=124) vs. PPI at baseline, SVR12 93% (n=30).
12 week duration: no PPI at baseline, SVR12 98% (n=464) vs. PPI at baseline, SVR12 93% (n=163).
Most common AE’s included fatigue (24%), headache (22%), nausea (8%), diarrhea (7%), and insomnia (7%).
There were 11 deaths: 10 had cirrhosis, 6 had decompensated cirrhosis.
LDV/SOF alone: acute respiratory failure, breast cancer metastatic, CAD, Death NOS (2), intraventicular hemorrhage, MOF, road traffic accident, septic shock, narcotic overdose.
LDV/SOF + RBV: road traffic accident.
Terrault, AASLD, 2015, 94

13. Real-World Cohorts at AASLD Support Clinical Trial Data‡
Real-World Cohorts at AASLD Support Clinical Trial Data
GT 1: LDV/SOF 8 weeks
100%
97%
97%
99%
95%
SVR12 (%)
119
123
251
263
150
154 43 44
103 69 70
Transition:
This graph summarizes SVR12 rates for LDV/SOF x 8 weeks across Gilead’s phase 3 studies and several real world cohorts
Main Message:
Consistently high SVR12 rates for LDV/SOF x 8 weeks were seen across studies
Phase 3 Studies
TRIO Cohort
HCV-TARGET
IFI
GECCO
172
202
Kowdley KV, et al. N Engl J Med 2014;370: ; Curry M, et al AASLD 2015;
Terrault N, et al AASLD 2015; Buggisch P, et al. AASLD 2015; Christensen, et al. AASLD 2015;

14. HARVONI First FDC, STR regimen to treat Gt1 HCV chronic infection
First FDC, STR regimen to treat Gt1 HCV chronic infection
Efficacy: high rates of SVR, confirmed in real world data
Tolerability: good safety profile, <1% D/C rate for SAEs
Opportunity to shorten treatment schedule
Used in several subpopulation: confirm results with high efficacy and good safety profile across all population studied
Efficacy and Effectiveness confirmed in all stages of hepatic disease (from F0 up to decompensated cirrhosis)