1. Therapeutic Background & Study Rationale
GS-US (RESCUE)
Therapeutic Background & Study Rationale
Lorenzo Rossaro
Medical Monitor
08 December 2015
Adjust to GSI template
GS-US Confidential & Proprietary

2. STUDY RATIONALE
GS-US Confidential & Proprietary

3. Study Drug Background Ledipasvir
Picomolar potency against HCV GT 1a and 1b1
Effective against NS5B RAV S282T2
Once-daily, oral, 90 mg
Sofosbuvir
Potent antiviral activity against HCV GT 1–6
High barrier to resistance
Once-daily, oral, 400-mg tablet
Ledipasvir/Sofosbuvir FDC
Once-daily, oral fixed-dose (400/90 mg) combination tablet
No food effect
Apx 3000 patients in initial filing
LDV NS5A inhibitor
SOF nucleotide polymerase inhibitor
SOF nucleotide polymerase inhibitor
LDV NS5A inhibitor
1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172.

4. Background
Several thousand HCV patients have been treated with sofosbuvir (SOF)-based therapy, including in combination with simeprevir (SMV) ± RBV or with RBV ± PegIFN, since SOF was approved by regulatory authorities
SVR rates ranged from 68% to 100% in Phase 2 and 3 studies, evaluating SOF in combination with other antivirals. SVR rates reported in real world cohorts are similar to rates observed in phase 2 and 3 studies.
In SOF phase 3 studies, virologic failure was not associated with S282T RAV
In the phase 2 COSMOS study, virologic failure was associated with NS3/4A RAVs but not with S282T
Ledipasvir/sofosbuvir (LDV/SOF) is an all-oral NS5A/NS5B inhibitor STR, indicated for treatment of HCV GT 1 in treatment-naïve and experienced patients with or without cirrhosis
Effective against prior PI+PegIFN+RBV failure
SOF and LDV are fully active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors
Effective for treatment of GT 4 in 19 of 20 patients enrolled in SYNERGY
Limited data indicates that patients who fail to achieve SVR with sofosbuvir therapy may be successfully cured with 12 or 24 weeks of retreatment with LDV/SOF

5. Retreatment of Relapsers to SOF+RBV with LDV/SOF STR
SYNERGY Trial (NIAID, LDV/SOF)
Retreatment of Relapsers to SOF+RBV with LDV/SOF STR
SOF+RBV relapsers from NIAID SPARE study treated with a single-tablet regimen of LDV/SOF for 12 weeks
Study Weeks 8 12 24
N = 14
SOF+RBV relapsers
LDV/SOF 90/400 mg
SVR 12
LDV/SOF STR
N=14
Median age (range)
59.5 (48–70)
Male, n (%)
13 (93)
African American, n (%)
IL28B non-CC, n (%)
12 (86)
Median BMI (range)
28.5 (20–41)
Genotype 1a, n (%)
8 (57)
Median HCV RNA log10 IU/mL (range)
6.45 (5.5–6.8)
HAI Stage 3–4 Fibrosis, n (%) *
7 (50)
Transition:  
This is an arm of the NIAID SYNERGY study that looked at retreating SOF+RBV relapsers from the SPARE study with the single tablet regimen (STR) of LDV/SOF (90mg/400mg) once daily for 12 weeks
Main Message: 
SOF+RBV relapsers from the NIAID SPARE study were treated with an STR of LDV/SOF for 12 weeks with the primary endpoint being SVR12.
The 14 subjects enrolled were primarily male, African American, and IL28B CC. The majority of patients had HCV GT 1 a and 50% of patients had HAI stage 3-4 fibrosis
Background: 
Subjects enrolled: mean age of 59 years, 93% male, 93% African-American, 86% IL28B CT/TT, 57% GT-1a, 50% advanced liver disease with a mean baseline HCV RNA of 6.29 log10 IU/ml. Fibrosis was determined by liver biopsy
One patient demonstrated S282T mutation post SOF/RBV therapy at post-treatment week 4 that resolved prior to LDV/SOF initiation at post-treatment week 12. The presence of NS5B mutations was assessed by population sequencing (Sanger methodology) with a sensitivity of 20-25%
All adverse events-headache-1, myalgia-2, congestion-1, constipation-1, diarrhea-1 and rash-1
The patient with the elevated serum creatinine (SrCr) started with a SrCr of 1.55 and was on ACE inhibitor and went back to grade 2 after discontinuation of study drug. This was felt to possibly be related to study drug, but there no changes in SrCr or eGFR between groups over time
Very little anemia in the LDV/SOF group as compared the original SOF + RBV group (Mean hemoglobin drop from baseline at 12 weeks with LDV/SOF was 0.3g/dL vs. 1.2 g/dL with SOF + RBV)
The mean time between stopping SOF+RBV therapy in the SPARE Trial and initiating LDV/SOF therapy in the SYNERGY Trial was 54 weeks (range: weeks)
14/14
*Fibrosis staging prior to enrollment in NIAID SPARE study
Osinusi A, EASL, 2014, O11

6. LDV/SOF ± RBV in Difficult-to-Treat HCV Populations
ELECTRON-2 (LDV/SOF±RBV)
LDV/SOF ± RBV in Difficult-to-Treat HCV Populations
Phase 2, open-label study of LDV/SOF + RBV for 12 weeks in HCV GT 1 prior SOF relapsers without cirrhosis
Prior treatment history of SOF relapsers included SOF + RBV ± DAA
Wk 0
Wk 12
Wk 24
SVR12
LDV/SOF + RBV
GT 1; n=19 Prior SOF exposure
LDV/SOF + RBV n=19
Mean age, y (range)
55 (39–65)
Male, n (%)
13 (68)
White, n (%)
18 (95)
Mean BMI, kg/m2 (range)
27 (19–38)
Cirrhosis, n (%)
IL28B CC, n (%)
4 (21)
GT 1a
17 (89)
Mean HCV RNA, log10 IU/mL (range)
6.3 (4.8–7.0)
Transition:
This slide shows 4 of the arms from the ELECTRON -2 study of ledipasvir/sofosbuvir (LDV/SOF) +/- ribavirin in more difficult to treat populations, including patients with prior failure to SOF containing DAA regimens, those with advanced liver disease (including decompensated cirrhosis), and genotype 3.
Main messages:
90 patients were treated with LDV/SOF±RBV for 12 weeks.
19 patients who had relapsed having previously received SOF+RBV (naïve and PR non-responders), LDV/SOF+RBV for 6 weeks, or SOF+GS-9669+RBV were assigned to receive LDV/SOF+RBV for 12 weeks.
20 patients with Child-Turcotte-Pugh Class B were assigned to receive LDV/SOF for 12 weeks. 50% had evidence of hepatic encephalopathy. RBV not included due to potential safety concerns.
51 treatment-naïve patients with HCV genotype 3, including those with compensated cirrhosis, were randomized to receive LDV/SOF±RBV for 12 weeks.
Background:
Patients retreated following failure of the following SOF based regimens: 6x SOF/RBV (previous nulls), 4x SOF/RBV (previous treatment naïve), 1x SOF/GS9669 and 8x LDV/SOF + RBV
16% of GT3 patients were cirrhotic at baseline
Among CTP B cirrhotic patients, 4 (20%) had ascites and 6 (30%) had hepatic encephalopathy.
SVR12 (%)
19/19
Gane E, EASL, 2014, O6

7. LDV/SOF Single Tablet Regimen in Treatment-Experienced GT 1 HCV
Retreatment of patients who failed in prior SOF studies with LDV/SOF + RBV for 12 weeks
Wk 0
Wk 12
Wk 24
SOF failures (N=51)
LDV/SOF + RBV
SVR12
Demographics
Mean age, y (range)
54 (27‒68)
Men, n (%)
31 (61)
Black/African American, n (%)
8 (16)
Mean BMI, kg/m2 (range)
30.4 (21.1‒47.9)
IL28B CC, n (%)
4 (8)
GT 1a, n (%)
30 (59)
Mean HCV RNA, log10 IU/mL (range)
6.2 (4.4‒7.3)
HCV RNA ≥800,000 IU/mL, n (%)
38 (75)
Prior HCV treatment, n (%)
SOF+PegIFN+RBV
25 (49)
SOF±RBV
21 (41)
Without SOF
5 (10)
Cirrhosis, n (%)
15 (29) *
Transition
This is a study in which was evaluated whether LDV/SOF + RBV for 12 weeks is effective in HCV GT 1 treatment-experienced patients who have failed prior SOF-based therapy
Main Messages
51 patients chronically infected with HCV GT1, with prior failure to SOF-based regimens, were retreated with LDV/SOF + RBV, for 12 weeks
The primary endpoint assessed was SVR12
Background
This study included 2 other treatment arms:
LDV/SOF failures, retreated with LDV/SOF for 24 weeks
SOF failures, with advanced liver disease, retreated with LDV/SOF + RBV for 24 weeks
Mean BMI was 30.4, 92% non-CC IL28B genotype, 59% GT1a, 29% cirrhotics, prior treatment: 49% SOF + PR, 41% SOF + R, 10% SOF + placebo
SVR12 (%)
50/51
*One patient who relapsed had GT 3a infection
LDV/SOF+RBV for 12 weeks resulted in 100% SVR in GT 1 patients who failed a prior SOF-containing regimen .
Wyles, AASLD, 2014, Oral #235

8. LDV/SOF ± RBV for SOF Re-treatment
LDV/SOF ± RBV in Treatment-Experienced GT 1 HCV: SOF Study Retreatment, ELECTRON-2, & SYNERGY *
HCV RNA <LLOQ, %
Transition
This slide shows the efficacy results of LDV/SOF +/- RBV in treatment-experienced GT 1 patients from the SOF retreatment study, ELECTRON-2, and SYNERGY
Main Message
LDV/SOF ± RBV for 12 weeks achieved 100% SVR in GT 1 patients who failed prior SOF-based therapy
50/51
19/19
14/14
SOF Retreatment Study
ELECTRON-2
SYNERGY
Wyles D., et al. Hepatology Published Online April 2015; Wyles, AASLD, 2014, Oral #235; Gane, EASL, 2014, Oral #6; Osinusi, et al. Ann Intern Med. 2014;161:
LDV/SOF ± RBV for 12 weeks achieved 100% SVR in GT 1 subjects who failed prior SOF-based therapy
*One subject who relapsed had GT 3a infection
Error bars represent 95% CIs.

9. LDV/SOF in TE Cirrhotic Subjects: SVR12
SIRIUS: Retreatment of Cirrhotic Subjects Who Failed Both PegIFN+RBV and PI+PegIFN+RBV
LDV/SOF in TE Cirrhotic Subjects: SVR12
Transition:
- The SIRIUS study produced high SVR regardless of regimen or duration.
Main Message:
SVR12 was 96% in the 12 week treatment arm (74/77) and 97% in the 24 week treatment arm (75/77)
22/24 patients with baseline RAVS achieved SVR (92%)
All 5 patients who failed treatment were due to relapse [5/154 (3%)], 4/5 relapsers were prior non-responders, 3 were GT1b and 2 were GT1a
The study started with 155 patients but the final analysis was only done on 154 patients because 1 patient dropped out in the placebo phase because of sepsis
Background:
Regarding number of prior null responders, this terminology doesn’t apply to PI + PegIFN + RBV failures unlike for PegIFN + RBV failures
1 patient randomized to receive placebo 12 wk→LDV/SOF+RBV 12 wk received LDV/SOF for 24 wk
SVR12 in Prior Null Responders in SIRIUS:
LDV/SOF x 24 weeks SVR12 = 40/41 ( 97.6%)  
LDV/SOF+RBV x 12 weeks SVR12 = 33/34 ( 97.1%)
(Data on file)
74/77
75/77
LDV/SOF+RBV 12 Weeks
LDV/SOF 24 Weeks
TE cirrhotics had a similar response to LDV/SOF+RBV for 12 weeks and LDV/SOF for 24 weeks
Error bars represent 95% confidence intervals.
Bourliere M., et al. Lancet Infect Dis. Published Online March 13, 2015.; Bourliere, AASLD, 2014, Oral #LB-6

10. Rationale for Duration of Therapy in RESCUE Study Design
The optimal regimen of LDV/SOF (±RBV) and duration of treatment in these SOF-based failures remains unknown
We conduct a prospective randomized study to evaluate the need for RBV as part of a 12 week LDV/SOF regimen for treatment of HCV in SOF-based treatment-experienced patients with or without cirrhosis
In patients with cirrhosis, we compare efficacy of LDV/SOF for 12 weeks ± RBV to 24 weeks of LDV/SOF

11. Rationale for Conducting RESCUE
Beside the scientific reasons, additional unmet needs:
Currently, SOF + SMV ± RBV and SOF + RBV ± PEG failure patients may not have access to additional therapy, either with commercial Harvoni or in the form of a clinical trial, based on geography
Some patients may not have insurance or have lost coverage
SOF/VEL/GS-9857 may not be available until 2017 in NA and some patients will require treatment sooner, particularly cirrhotics 
Local approvals (globally) of SOF/VEL/GS-9857 will take even longer
LDV/SOF may be a good alternative due to the well-established safety profile, few DDIs, experience in real-world, and will be available globally in advance of SOF/VEL/GS-9857

12. Study schema
A Phase 3b, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of Ledipasvir/Sofosbuvir, With or Without Ribavirin, in HCV Infected Subjects Who Have Failed Prior Treatment With Sofosbuvir-based Therapies 12 24
Study Weeks
Group 1, n = 90
SVR12
LDV/SOF
Cohort 2: Cirrhotic
Cohort 1: Non-cirrhotic
LDV/SOF + RBV
Group 3, n = 125
*Randomization stratified by GT 1 or 4, prior therapy with SOF+SMV or SOF + RBV ± PegIFN
N = 430
SOF TE GT 1 or 4 36
Group 2, n = 90
1:1*
SVR12
Group 4, n = 125
LDV/SOF
SVR24