Simeprevir, Faldaprevir and Sofosbuvir

2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.

Paris Hepatitis Conference

Pr Tarik Asselah

14 janvier 2014

MD, PhD Service d’Hépatologie & INSERM U773 University Paris Diderot Hôpital Beaujon, Clichy [email protected]

2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.

• Introduction • New IFN-based triple therapy for HCV genotype 1 Protease inhibitors - Simeprevir (Quest-2, Promise) - Faldaprevir (StartVerso 1, StartVerso 3) - Other PI : MK5172, Asunaprevir, etc…. Polymerase inhibitor - Sofosbuvir (Neutrino) • Summary and Conclusion Direct-acting antivirals

5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase

C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B

Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors

Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir ACH-3102 IDX-20963 BMS- ABT-450 PPI-668 791325 MK-5172 GSK-2336805 ACH-3422 PPI-383 Sovaprevir Samatasvir GS-9669 ACH-2684 MK-8742 TMC-647055 Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014 Investigational HCV Regimens in Phase III Trials in 2014

Triple Therapy: 1 DAA + PegIFN alfa/RBV IFN-Free Regimens

. Simeprevir (PI) . Sofosbuvir + RBV . Faldaprevir (PI) . Sofosbuvir + GS-5885 (FDC) ± RBV . Sofosbuvir (NI) . Daclatasvir + asunaprevir . Daclatasvir (NS5A) . ABT-450/RTV + ABT-267 ± ABT-333 ± RBV . MK 5172 (PI) . Faldaprevir + BI207127 + RBV . Danoprevir (PI) . MK 5172 + MK 8742 . Alisporivir (CYP)

Asselah and Marcellin P,. Liver International 2014 General Characteristics of Direct-Acting Antivirals

NS5A NS5A NS5B NS5B Non PI, 1st PI, 2nd Inhibitors, 1st Inhibitors, 2nd Nucleoside Nucleoside Generation Generation Generation Generation Inhibitors Inhibitors

Efficacy

Resistance Profile Pangenotypic Efficacy Adverse events Drug-drug interactions

Good profile Average profile Least favorable profile

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 Priorities for Direct-Acting Antivirals

Potency Genotype Coverage Highest Importance Resistance Barrier Safety/Tolerability

Treatment Duration Half life & Pills burden

Drug-drug Interaction Secondary Priorities

Cost

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.

Response-guided treatment QUEST-1, naïve

n=264 PR SMV 150mg + PR Follow-up PR Follow-up n=130 Placebo + PR PR Placebo + PR Follow-up

0 12 24 48 72 QUEST-2, naïve

SMV 150mg + PR N=257 PR Follow-up PR Follow-up

N=134 Placebo + PR PR PR Follow-up

Week 0 12 24 48 72

PROMISE, relapsers

SMV 150 mg PR N=260 PR Follow-up + PR Follow-up

N=133 PBO + PR PR PR Follow-up

Week 0 12 24 48 72 9 Simeprevir (SMV) Simeprevir SVR12 (%)

Proportion of patients, % *Based on the Cochran-Mantel-Haensze test controlling for type of PegIFN/ribavirin and stratification factors stratification and PegIFN/ribavirin of type for controlling test Cochran-Mantel-Haensze the on *Based Placebo/PR 67/134 50 (PI): G1 naïve, phase III (QUEST-2) III phase naïve, G1 (PI): P <0.001* Manns etManns al. EASL 2013, Abstract 1413. 209/257 SMV/PR 81,3 QUEST-2: Response-guided Treatment (RGT) allows shortened treatment duration with high SVR12

SVR12 in SMV/PR 100 86 80 s 91.4% (235/257) t n e

of patients met ti a 60 p

RGT criteria and f o

were eligible for o ti

r 40 24 weeks of o p o treatment r P 20

202/235 0 202/235 • 8.6% (22/257) of patients did not meet RGT criteria – among them, 31.8% (7/22) achieved SVR12

RGT, response-guided therapy; RGT criteria: HCV RNA < 25 IU/mL detectable or undetectable at Week 4 and <25 IU/mL undetectable at Week 12

10 Quest-2: Changes in haemoglobin

Hemoglobin

Entire treatment phase – hemoglobin, µmol/L

200 Placebo 180

E SMV S ±

, 160 s e u l

a 140 v

n a

e 120 M

100

0 2 4 8 12 16 20 24 36 48 Weeks

Manns et al. EASL 2013, Abstract05.03.2013 1413. 11 Simeprevir (SMV) (PI): G1 relapsers (Promise)

SMV/PR Placebo/PR SVR12 (%)

100 84 85 75 80

58 52 53 60 47 43

20 62/131 191/254 23/44 49/84 36/83 138/165 70/133 228/267 0 G1a G1a G1a G1b with Q80K without Q80K

Lawitz et al. DDW 2013, Abstract 869b. Simeprevir: adverse events (phase III trials)

QUEST-1 QUEST-2 PROMISE

Placebo + PR, Placebo + PR, SMV + PR, % Placebo + PR, % SMV + PR, % SMV + PR, % % % (N = 264) (N = 134) (N = 257) (N = 264) (N = 130) (N = 130) Serious AEs 4 3 2 2 4 3 Discontinuation 3 3 1 2 3 3 due to AEs Fatigue 38 40 39 35 Pruritus 11 21 15 19 28 28 Rash (any type) 25 27 11 24 23 23 Anaemia 11 16 14 16 20 17

Jacobson et al. DDW 2013, Abstract 1674582. Manns et al. EASL 2013, Abstract 1413. Lawitz et al. DDW 2013, Abstract 869b. Simeprevir (PI): 12 weeks phase III trial (G1 naïve)

Ongoing trial Response-guided therapy of 12 or 24 weeks guided by HCV-RNA measurements at treatment weeks 2, 4, and 8.

Baseline Week 4 Week 12 Week 24 Week 36 Week 48

Follow up N=150 patients. Single arm, open-label Triple Therapy SMV + PR Continue PR to Wk 24 Follow up

PR: PegIFNα-2a 180 ug/wk + RBV 1000-1200mg/day

Clinicaltrials.gov: NCT01846832 Faldaprevir (FDV) (PI): phase III trial, G1 naïve (StartVerso1)

Arm 1 Placebo + PR PR Follow-up (n=133)

ETS Placebo + PR Follow-up Arm 2 FDV 120 mg + (n=261) PR No ETS FDV 120 mg + PR PR Follow-up

ETS Follow-up Arm 3 FDV 240 mg + Placebo + PR (n=262) PR No ETS PR Follow-up

Day 1 Week 12 Week 24 Week 48 Week 72

Ferenci et al. EASL 2013, abstract LB 1416. Faldaprevir (FDV) (PI): G1 naïve, results (StartVerso1)

(∆ = 26.7; 95% CI, 17.1–36.3; p<0.0001)

(∆ = 28.6; 95% CI, 19.0–38.2; p<0.0001) ) % (

2 1 R V S

69/132 204/259 210/261

SVR12 rates adjusted for race and genotype ITT, intention-to treat Faldaprevir (FDV): Early treatment success (ETS) allows shortened treatment duration with high SVR12 ) % (

s t n e i t a p

f o

n o i t r o p o r P

226/259 194/226 FDV 120 mg FDV 120 mg ETS ETS + SVR12a

ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4 and <25 IU/mL (undetected) at Week 8. aDenominator = patients with ETS Changes in haemoglobin

Placebo + PR 18 FDV 120 mg + PR

FDV 240 mg + PR

n 16 i b o ) l L g d o

/ 14 g m (

e a D h

S 12

n ± a e

M 10

8 0 4 8 12 16 20 24 Weeks Faldaprevir: adverse events (phase III trial results)

Placebo + PR FDV 120 mg + PR FDV 240 mg + PR N=264 N=521 N=524 AEs leading to discontinuation of all 10 (4) 27 (5) 40 (8) medication, n (%) AEs leading to discontinuation of FDV 1 (<1) 6 (1) 14 (3) or placebo only, n (%) Serious AEs, n (%) 16 (6) 39 (7) 43 (8)

AEs of at least moderate intensity 156 (59) 302 (58) 332 (63) (any)a, n (%) Rash 11 (4) 39 (7) 50 (10) Photosensitivity 0 (0) 0 (0) 3 (1) GI 19 (7) 58 (11) 96 (18) Anemia 38 (14) 73 (14) 70 (13) Bilirubin associated 2 (1) 18 (3) 47 (9)

One patient with cirrhosis at baseline developed acute-on-chronic liver failure after 16 days of FDV (24 0mg) and PR, discontinued all treatment and died 12 days later. The event was considered not related to FDV but to pegylated interferon by investigator. aDAIDS Grade 2 to 4; protocol-defined AEs of special interest. DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events; DC, discontinuation; GI, gastrointestinal. Faldaprevir (PI): phase III trial design, G1 experienced (StartVerso3)

Prior relapse Relapser: Rebound from HCV Arm 1 (n=49) Placebo + PR PR RNA undetectable at end of 48 week treatmenta but Arm 2 (n=99) FDV 240 mg + PR Placebo + PR PR (RGT a) detectable within 24 weeks of follow-up Arm 3 (n=102) FDV 240 mg + PR PR (RGT a)

Prior partial response Partial responder: HCV RNA Placebo + PR PR drop by ≥2 log10 from baseline Arm 1 (n=29) to week 12, but never FDV 240 mg undetectable Arm 2 (n=57) + PR Placebo + PR PR Breakthrough: HCV RNA undetectable during treatment, Arm 3 (n=55) FDV 240 mg + PR PR but rebound to detected during ongoing treatment

Prior null response Arm 1 (n=146)b FDV 240 mg + PR Placebo + PR PR Null responder: Absence of HCV RNA drop by ≥2 log10 Arm 2 (n=141) FDV 240 mg + PR from baseline to week 12 PR

Day 1 Week 12 Week 24 Week 48

aStopping rule for RGT criteria: all relapsers, who did not achieve ETS (HCV RNA <25 IU/mL (detected or undetected) at week 4 and <25 IU/mL (undetected) at week 8, had extended PR treatment to week 48; bN=146 patients randomized, but N=145 patients treated. PR, pegylated interferon α-2a/ribavirin; QD, once daily; RGT, response-guided therapy.

Jacobson et al. AASLD 2013, abstract 1100. Faldaprevir (FDV) (PI): SVR12, G1 experienced (StartVerso3)

100 Prior relapse Prior partial response

80 70 70

60 58 Prior null response 47

40 33 33

20 14 3 7/49 69/99 71/102 1/29 33/57 26/5526/55 48/145 46/14146/141 0 FDV FDV FDV FDV FDV FDV Placebo Placebo 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 24 weeks MK-5172 (PI) plus PEG-IFN/RBV: G1 naïve non-cirrhotic

SVR24 and HCV-RNA TND at Last Visit*

99 % 96 % 98 % 92 % (67/68) (64/67) (64/65) 100 (61/66) ) % (

t 67 % i s

i 75 (44/66) v

t s a l

a 50

D 86 % 92 % 91 % 87 % N

T (55/64) (61/66) (58/64) (52/60)

r o 25 54 % 4

2 (31/57) R V S 0 BOC + PR MK-5172 MK-5172 MK-5172 MK-5172 100 mg + PR 200 mg + PR 400 mg + PR 800 mg + PR

SVR24 HCV RNA TND at last visit

Manns et al. EASL 2013, Abs. 66 Asunaprevir (PI) plus PEG-IFN/RBV: G1 naive

101/159 24/54 55/94 45/63 16/18 3/7

G1a G1b

Bronowicki et al. EASL 2013, Abs. 1420 Sofosbuvir (NI): phase III trial design; G1 naïve (Neutrino)

Post-therapy follow-up N = 327 Sofosbuvir + PR

Final Weeks analysis 12 SVR12

Lawitz et al. N Engl J Med. 2013; 368(20):1878-87 Sofosbuvir (NI): SVR12, G1 naïve, phase III trial (Neutrino)

No cirrhosis

Cirrhosis

92 % 100 90 % 89 % 80 %

80 )

% 60 (

2 1 R V

S 40

295/327 261/292 252/273 43/54 0 Total Genotype 1 SVR12 Population

Lawitz et al. N Engl J Med. 2013; 368(20):1878-87 Sofosbuvir : side effects (Neutrino)

Sofosbuvir + PR, % (N = 327)

SAEs 1

Discontinuations due to AEs 2

Fatigue 59

Anaemia 21

Rash (any) 18

Pruritus 17

Neutropenia 17

Lawitz et al. N Engl J Med. 2013; 368(20):1878-87 2nd wave IFN-based triple therapy for HCV genotype 1: Simeprevir, Faldaprevir and Sofosbuvir.

DAA + PEG-IFN + RBV N SVR12 DAA+PR vs. PR

Simeprevir QUEST-21 391 81% vs. 50% (7% F4)

Faldaprevir StartVerso12 652 79-80% vs. 52% (120 vs. 240 mg) (17% ≥ F3)

Sofosbuvir3 292 89 % vs no control arm (17% F4)

1Manns MP et al. Late breaker p1413 EASL 2013 2Ferenci P et al. Late breaker p. 1416, EASL 2013 3Lawitz E, et al. N Engl J Med 2013;368:1878-87. Summary:DAAs in IFN-containing 2nd wave regimens IFN-based : results, triple therapy for HCV G1 summary • The available data on second-generation IFN-based regimens is very promising due to:

● Higher proportion of patients candidates for short treatment duration

● Better safety profile when compared with first-generation PIs

● Less pill burden • However, a proportion of patients remain difficult to cure and more studies are needed in these populations. These include

● Cirrhotic patients

● Previous null responders

● Failure to triple therapy

● Patients infected with genotype 4 • Finally we need to explore cost effectiveness of DAA treatment strategies HCVHCV worldwide:worldwide: LimitedLimited accessaccess toto newnew treatmenttreatment optionsoptions inin countriescountries withwith thethe highesthighest HCVHCV prevalenceprevalence

FAR EAST USA & EUROPE EASTERN 9 M /ASIA Canada MEDITERRANEAN 21.3M 60 M 4 M Japan 2M SOUTH EAST ASIA AFRICA 32.3 M 32 M SOUTH AMERICA 10 M AUSTRALIA 0.2 M

MajorityMajority ofof thethe WorldWorld 170 Millions worldwide NoNo treatmenttreatment oror DualDual┃┃PegIFN/RBVPegIFN/RBV WHO, 1999 Conclusion & Perspectives

DAA + PR IFN free

Boceprevir Sofosbuvir/ ledipasvir FDC ± RBV

Telaprevir ABT-450r/ABT-267 FDC + ABT-333 ± RBV

Simeprevir Faldaprevir + Deleobuvir + RBV G1b Faldaprevir Daclastavir + asunaprevir G1b Sofosbuvir Other IFN-free combinations Daclatasvir

Other DAA + PR Off-label combinations

2014-2015 2015-2016

Asselah and Marcellin P,. Liver International 2014 Perspectives 1 (G1 naïves) SVR12 (%) 100 100 100 100 100 96 100 100 95 95 95 89 92 92 87

80 68

40/4242/42 118/135 24/25 24/27 13/13 25/25 21/21 17/25 19/20 21/21 18/19 71/77 77/84 13/13 12/12 0 G1b G1b G1 G1 G1b G1 G1 G1 G1 G1 G1 G1 G1 G1a G1 ABT450/r DCV MK-5172 MK-5172 MK-5172 SOF SOF SOF SOF SOF SOF DCV DCV FDV SMV ABT 267 ASV MK-8742 MK-8742 MK-8742 LDV LDV LDV LDV LDV LDV ASV ASV DBV SOF 20 mg 50 mg 50 mg RBV RBV RBV RBV BMS-791325 PPI-668 RBV RBV RBV 12 W 8 W 6 W 8 W 8 W 12 W 75 mg 150 mg ± RBV SVR4 SVR4

Pearl-1, ABT450/r + ABT 267; Lawitz et al. AASLD 2013, A75. Lonestar : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Lawitz et al. AASLD 2013, A215/1844. Daclatasvir (DCV) + asunaprevir (ASV); Chayama et al. AASLD 2013, A211. Daclatasvir (DCV) + asunaprevir (ASV) + BMS-791325; Everson et al. AASLD 2013, ALB1.

C-Worthy , MK-5172/MK-8742 + RBV; Lawitz et al. AASLD 2013, A76. Faldaprevir (FDV), deleobuvir (DBV) +PPI-668; Lalezari et al. AASLD 2013 ALB20.

Electron, SOF/ledipasvir (LDV) + RBV; Gane et al. AASLD 2013, A73 Cosmos : sofosbuvir (SOF)/simeprevir (SMV) + RBV; Jacobson et al. AASLD 2013, ALB3. Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 Perspectives 2 (G1 experienced)

SVR12 (%) 100 100 100 100 100 96.3 95 90 92.9 93.3

80 79.3 70

36/4042/42 25/25 26/26 7/10 9/9 18/19 21/21 13/14 14/15 26/27 19/24 0 G1b NR G1 G1 G1 G1 G1 IP G1 IP G1 G1 G1 G1 ABT450/r SOF SOF SOF SOF SOF SOF SMV SMV SMV SMV ABT 267 LDV LDV LDV LDV LDV LDV SOF SOF SOF SOF RBV GS-9669 RBV RBV RBV 12 W 12 W 12 W 12 W 12 W 12 W 12 W 24 W 12 W 24 W F3/F4 F3/F4 F4 F4 F0-F2 F0-F2 F0-F2 F0-F2 Pearl-1, ABT450/r + ABT 267; Lawitz et al. AASLD 2013, A75. Electron : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Gane et al. AASLD 2013, A73 Lonestar : sofosbuvir (SOF)/ledipasvir (LDV) + RBV; Lawitz et al. AASLD 2013, A215/1844. Cosmos : sofosbuvir (SOF)/simeprevir (SMV) + RBV; Jacobson et al. AASLD 2013, ALB3. Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013 And the Winner The Patient. is…………………….

APV SOF DCV SMV FDV ABT MK