Future therapies

Massimo LevreroDepartment of Internal Medicine - DMISM

LEA INSERM U785 Life-Nanoscience Laboratory for Functional Genomics

Sapienza University - Rome

Inhibitors of polyprotein processing

Inhibitors of replication

Potential Antiviral Targets and Approaches

IFN

IFN lambdaIFN alfa

Immuno-modulators

Direct-acting antivirals

(DAAs)Therapeutic

vaccinesHost-targeting

antivirals (HTAs)

Replication, polyprotein processing and/or assembly

Entry

NS5Bpolymerase inhibitors

NS3protease inhibitors

NS5Areplication

complex inhibitors

Popescu C-L & Dubuisson J. Biol Cell 2009;102:63-74.

Preclinical

Phase I

Phase II

Phase III

Filed

BoceprevirBoceprevir(MSD)(MSD)

TelaprevirTelaprevir(Vertex/JJ)(Vertex/JJ)

TMC-435TMC-435(Tibotec/JJ)(Tibotec/JJ)

MK7009MK7009(MSD)(MSD)

ITMN191/R7227 ITMN191/R7227 (Roche/Intermune)(Roche/Intermune)

BI201335BI201335(BI)(BI)

BMS650032BMS650032(BMS)(BMS)

GS9256GS9256(Gilead)(Gilead)MK5172MK5172

(MSD)(MSD)

ABT450ABT450(ABT)(ABT)

ACH2684ACH2684(Achillion)(Achillion)

BMS 790052(BMS)

AZD-7295(AZN)

BMS 824393(BMS)PPI-1301

EDP-239(Enanta)

GSK

Vertex

Idenix719MSD

Taribavirin(Valeant)

IFN λ(Zymogen/Novartis)

Debio025/ NIM811

(Novartis)

Nitazoxamide(Romark)

Silibinine

Vitamine D

BMS

BI

ROCHE

Gilead

R7128(Roche /pharmasset)

PSI 7977pharmasset)

BIJapon Tonbacco

R0622 (Roche)Medivir (Tibotec)

GLS9393 (GSK)PSI 938

(Pharmasset)

BiocrystINX 189 (Inhibitrex)

BMS791325 (BMS)Filibuvir

(PFE)GS9190 (Gilead)

ANA598 (Anadys)BI201127

(BI)

Vx222 (Vertex)

ABT333ABT072 (ABT)

IDX 375 (Idenix)

IDX 184 (Idenix)

SCY-835

PPI-461

VBY-376VBY-376

VX-985VX-985(Vertex)(Vertex)

VX-813VX-813(Vertex)(Vertex)

GS9451GS9451(Gilead)(Gilead)

RG7348(Roche)

TMC 647055 (Tibotec)

A837093(Abbott)

VX-916VX-759

CelgosivirBavituximab

AVL-181AVL-181(Avila)(Avila)

AVL-192AVL-192(Avila)(Avila)

PSI-661 (Pharmasset)

ACH-2928(Acillion)

GS-5885

Vertex

Abbott

Pharmasset

Nucleoside NS5B

Polymerase Inhibitors (8)

Nucleotide NS5B Polymerase Inhibitors (4)

Non Nuc NS5BPolymerase inhibitors (12)

NS3/4A Protease inhibitors (19)

NS5A inhibitors (13)

DAA combinations (17)

Others (6)

Cyclophilin. I (2)

IDX 077 (Idenix)

IDX 079 (Idenix)

ABT267ABT267(ABT)(ABT)

HCV pipeline by mechanism of action

Preclinical

Phase I

Phase II

Phase III

Filed

BoceprevirBoceprevir(MSD)(MSD)

TelaprevirTelaprevir(Vertex/JJ)(Vertex/JJ)

TMC-435TMC-435(Tibotec/JJ)(Tibotec/JJ)

MK7009MK7009(MSD)(MSD)

ITMN191/R7227 ITMN191/R7227 (Roche/Intermune)(Roche/Intermune)

BI201335BI201335(BI)(BI)

BMS650032BMS650032(BMS)(BMS)

GS9256GS9256(Gilead)(Gilead)MK5172MK5172

(MSD)(MSD)

ABT450ABT450(ABT)(ABT)

ACH2684ACH2684(Achillion)(Achillion)

VBY-376VBY-376

VX-985VX-985(Vertex)(Vertex)

VX-813VX-813(Vertex)(Vertex)

GS9451GS9451(Gilead)(Gilead)

AVL-181AVL-181(Avila)(Avila)

AVL-192AVL-192(Avila)(Avila)

NS3/4A Protease inhibitors (19)

IDX 077 (Idenix)

IDX 079 (Idenix)

A second wave and a second generation of NS3 / NS4A protease inhibitors

Viral genotype “still” determines the approach to HCV Therapy

• Genotypes 2 and 3– Therapy today and in the near future will be pegIFN/RBV

• Genotype 1– Additional option of an HCV protease inhibitor combined

with pegIFN/RBV– Boceprevir and telaprevir approved in Europe in July-

September 2011• Both indicated for untreated and previously treated HCV• Different regimen formats• Different criteria for shortening therapy

Phase III virological efficacy Boceprevir ( Victrelis®) or Telaprevir ( Incivo®)

BoceprevirSVR increases from 38% to

63/66%

Naive patients Increased SVR compared to Peg-IFN/RBV

TelaprevirSVR increases from 44% to

72/75%

Poordad F et al. N Engl J Med 2011: 364: 1195-1206Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.

BoceprevirRelapsers

SVR increases from 29% to 75%

Partial-Responders SVR increases from 7% to 52%

Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV

TelaprevirRelapsers

SVR increases from 24% to 83/88%

Partial-responders SVR increases from 15% to 54-59%

Null-respondersSVR increases from 5% to 29/33%

Phase III virological efficacy Boceprevir ( Victrelis®) and Telaprevir (Incivo ®)

Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3

PROVE-2[1]

SV

R (

%)

0

20

40

60

80

100

BPR 48 Wk(No Lead-in)

(n = 16)

BP + Low-Dose

R (48 Wk)(n = 59)

SPRINT-1[2]

36

50

36

60

Both PegIFN and RBV Required in Protease Inhibitor Combination Regimens

1. Hezode C, et al. N Engl J Med. 2009;360:1839-1850. 2. Kwo PY, et al. Lancet. 2010;376:705-716.

Dosages not consistent between above studies.

TPR 12 (n = 82)

TP 12 (n = 78)

SV

R (

%)

0

20

40

60

80

100

Patient groups with the greatest need for improved therapies: TVR and BOC SVR by Patient Type

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

5. Zeuzem S, et al. EASL 2011. Abstract 5. 6. Vierling JM, et al. AASLD 2011. Abstract 931.

0

20

40

60

80

100

SVR

(%)

Relapser Naive White/Nonblack

Null Responder

Naive Black Partial Responder

Cirrhotic Null

Responder

68-75[3,4]

53-62[3-4]

*Pooled TVR arms of REALIZE trial.

75-83[1,2]

52-59[1,2]

29-38[1,6]

14[5]*

Probability of Resistance during Triple Therapy

Patients with virologic treatment failure during triple therapy (break-through, stopping rules)

Jacobson et al., NEJM 2011; Zeuzem et al., NEJM 2011

0

10

20

30

40

50

60

naiv REL P-NR NULL

On-

trea

tmen

t viro

logi

c fa

ilure

8%(13% with

8 weeksTVR)

Telaprevir

1%

19%

52%

Bacon et al., NEJM 2011; Poordad et al., NEJM 2011

0

10

20

30

40

50

60

naiv REL P-NR NULL

9%

n.a.

Boceprevir

35%

Switch TVR ↔ BOC in case of break-through?

Sarrazin et al., J Hepatol 2011 in press

V36A/M

T54S/A

V55A Q80R/K

R155K/T/Q

A156S A156T/V D168A/E/G/H/T/Y

V170A/T

Telaprevir*(linear)

Boceprevir*(linear)

SCH900518*(linear)

BILN-2061 **(macrocyclic)

Danoprevir*(macrocyclic)

MK-7009*(macrocyclic)

TMC435*(macrocyclic)

BI-201335*(macrocyclic?)

BMS-650032*(macrocyclic)

GS-9451*(macrocyclic)

ABT450*(macrocyclic)

IDX320**(macrocyclic)

ACH1625**(macrocyclic)

MK-5172***(macrocyclic)

* mutations associated with resistance in patients ** mutations associated with resistance in vitro*** no viral break-through during 7 days monotherapy

Sarrazin et al., J Hepatol 2011 in press* mutations associated with resistance in patients ** mutations associated with resistance in vitro*** no viral break-through during 7 days monotherapy

Challenges of Using 1st generation Protease Inhibitors in Clinical Practice

• Increase in adverse effects[TVR: anemia, rash] [BOC: anemia, dysgeusia]

• Regimen complexity, TID dosing, Pill burden• Adherence• Concerns over resistance• Improved SVR rate but still room for improvement• Use restricted to genotipe 1

1st wave DAAs

EfficacyGenotype

dependencyBarrier to resistance

NS3/4A(protease inhibitors)

+++ + + –

NS5A +++ + – + –

NS5B (nucleosides)

+ – +++ +++

NS5B (non-nucleosides)

+ – + +

EfficacyGenotype

dependencyBarrier to resistance

NS3/4A (protease inhibitors)

+++ +++2 ++2

NS5A +++ +++3 ++3

NS5B (nucleosides) +++1 +++ +++

NS5B (non-nucleosides)

++ + +

New DAAs

1e.g. PSI-7977, PSI-938; 2e.g. MK-5172, ACH-1625; 3e.g. PPI-461

Protease Inhibitors in Clinical Development

Drug Current Clinical Phase

Doses per Day Active Against HCV Genotype

Side Effects

TMC-435 III 1 1,2,4,5,6 Bilirubinemia

BI 201335 III 1 1,2 ? Jaundice, Rash, Gastrointestinal

Danoprevir II 3 1,2 ? Gastrointestinal, neutropenia, ALT increase

Vaniprevir II 2 1,2 ? Vomiting

MK-5172 I 1 1,2,3,4,5,6 Na

Ciesek S et al, Clin Liver Dis 2011;15:597-609

New Agents Generally Maintain or Improve Upon Efficacy in GT1 Treatment-Naive

Phase II Studies, Drug + PegIFN/RBV

0

20

40

60

80

100

SVR

(%)

71-83 68-85 65-85 75-86 61-84BI 2

01335[

3]

Danopre

vir[4

]Nar

lapre

vir[5

]

TMC435[

6]

Vanipre

vir[7

]

BOC or TVR [1,2]

63-75

38-50

Filibuvir

[8]

56

Tego

buvir[9

]

42-83

Daclat

asvir

[10]

53-76

Alisporiv

ir[1

1]

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79.

5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088.

9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.

Not head-to-head comparisons

New Pis Improve Responses in Difficult-to-Treat Patients

Efficacy in Null RespondersAgent Trial, Phase Pts Meeting Efficacy Measure, %

Telaprevir and Boceprevir[1,2]

BOC or TVR + PR REALIZE/PROVIDE, III SVR: 29-38

Investigational Protease inhibitors BI 201335 + PR[3] SILEN-C2, IIb SVR: 21-35 TMC435 + PR* ASPIRE, IIb SVR: 41-59 Vaniprevir + PR[4] IIb SVR: 40-80

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Vierling JM, et al. AASLD 2011. Abstract 931. 3. Sulkowski M, et al. EASL 2011. Abstract 66. 4. Lawitz E, et al. AASLD 2011. Abstract LB-13.

Quad Therapy: Do We Have an Ideal DAA Combination?

Genotype Dependency Antiviral Efficacy Barrier to Resistance

NS3A (PI) + +++ +/++

NS5A +/++ +++ +/++

NS5B (NUC) +++ +/++ +++

NS5B (non-NUC) + +/++ +

Combine potent antiviral efficacy with high genetic barrier

Welzel T et al, Clin Liver Dis 2011;15:657-664

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks

Combination Therapy for Null Responders

1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.

100

80

60

40

20

0

36

Daclatasvir + Asunaprevir

Daclatasvir + Asunaprevir + PR

SVR2

4 (%

)

90 90*

N/A

US Study[1] Japan Study[2]

*all genotype 1b patients.

Additional announced IFN-free study designs in treatment-experienced patients

Combination Therapy for Null Responders

Drug 1 Drug 2 Overall Regimen

TMC435 QD PSI-7977 QD ± RBV12 or 24 wks

ABT-450/RTV QD

ABT-333 BID + RBV

Danoprevir/ RTV BID

Mericitabine BID

+ RBV24 wks

Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor

Combination Regimens in GT1 Treatment-Naive Patients

Strategy: protease inhibitor (telaprevir) + nonnucleoside polymerase inhibitor (VX-222)[1]

– ± pegIFN/RBV for 12 wks, then RGT

Strategy: protease inhibitor (ABT-450/r) + nonnucleoside polymerase inhibitor (ABT-333 or ABT-072)*

– + RBV for 12 wks– All 44 patients achieved cEVR– Of 10 patients tested thus far,

9 achieved SVR24100

80

60

40

20

0

Patie

nts

(%)

9382 87 83

VX-222 400 mg BID + TVR + PRVX-222 100 mg BID + TVR + PR

SVR24; 12 total wks of therapy

SVR12; 24 total wks of therapy

1. Nelson DR, et al. AASLD 2011. Abstract LB-14.

INFORM-1: An all Oral IFN Free Regimen of RG7128 + RG7227

RG7128 1000 mg BID + RG7227 900 mg BID

Days1 3 5 7 9 11 13

Limit of DetectionMed

ian

Log 10

HCV

RN

A (IU

/mL)

1

2

3

4

5

6

7

TF - Nulls

Naïves

LLOD: Lower limit of detection LLOQ: Lower limit of quantification

Gane EJ, et al. Lancet 2010; 376(9751):1467-75.

50

25

0

10

20

30

40

50

60

70

80

90

100

<LLOQ<LLOD

88

63

Nul

ls Nul

ls

Naï

ves

Naï

ves

EOT

HCV

RN

A <

LLO

Q o

r LLO

D (%

)

SOUND-C1: BI 201335 (PI) plus BI 207127 (non-NUC) plus RBV in Naive HCV-1 Patients

Proportion of patients with HCV RNA <25 IU/mL during treatment

n/N (%) Day 8 Day 15 Day 22 Day 29

400 mg tid BI 207127 + BI 201335 + RBV 4/15 (27) 7/15 (47) 10/15 (67) 11/15 (73)

G1a 2/10 5/10 6/10 6/10

G1b 2/5 2/5 4/5 5/5

600 mg tid BI 207127 + BI 201335 + RBV 3/17 (18) 14/17 (82) 17/17 (100) 17/17 (100)

G1a 2/8 8/8 8/8 8/8

G1b 1/8 5/8 8/8 8/8

G6e 0/1 1/1 1/1 1/1

Zeuzem S, et al. Gastroenterology in press

The SOUND-C2 study: up to 59 % of SVR-12

Ongoing Research Evaluates Potential for All-Oral Therapy

Several all-oral regimens under investigation

Drug 1 Drug 2 Drug 3 RBV

BI 201335 BI 207127 N/A ±

PSI-7977 PSI-938 N/A ±

ABT-450/ RTV ABT-333or ABT-072

N/A +

PSI-7977 Daclatasvir N/A ±

GS-9256 Tegobuvir N/A ±

GS-9451 GS-5885 ± Tegobuvir ±

Asunaprevir Daclatasvir BMS-791325 N/A

Protease inhibitorNucleos(t)ide analogue polymerase inhibitorNonnucleoside polymerase inhibitor

NS5A inhibitor

All-oral regimens of single drug + RBV also under investigation.

IFN-free regimens shown to be highly effective in GT2/3[1]

Nucleotide analogue PSI-7977 + RBV for 12 wks– PegIFN included for 0, 4, 8, or 12 wks

100

80

60

40

20

0

SVR

(%)

100 100 100 100

PSI-7977 + 0 wks PegIFN

(IFN-free)

PSI-7977 + 4 wksPegIFN

PSI-7977 + 8 wksPegIFN

PSI-7977 + 12 wksPegIFN

1. Gane EJ, et al. AASLD 2011. Abstract 34.

Planned or ongoing Phase III Trials

TVR BID + PR

TVR BID + PR PR

Telaprevir in GT1 IL28B CC patients

PSI-7977 + RPSI-7977 across genotypes

TMC435 + PR

TMC435 + PR PR

PRTMC435 in GT1 patients

BI 201335 + PR

BI 201335 + PRPR

PR

BI 201335 in GT1 patients

BI 201335 + PRPR

Daclatasvir + PRPR

Daclatasvir in GT1/4 patients

Daclatasvir + PR

QUADTelaprevir + VX-222 + PR in GT1

Can We Make Regimens Simpler?Can We Improve Adherence?

Several Drugs in Development Are Dosed Once or Twice Daily

*With RTV boosting.

QD

ABT-072ABT-267ABT 450*ACH-1625BI 201335Daclatasvir

GS 5885GS9451IDX 184INX-189

MK-5172Narlaprevir*

PSI-7977PSI-938TMC435

BID

ABT-333AsunaprevirBI 201335BI 207127

BMS 791325Danoprevir*

FilibuvirGS9256

MericitabineSetrobuvirTegobuvirVaniprevir

VX-222

TID

BI 207127Danoprevir

Fewer AEs With Some Investigational Agents (Preliminary Data)

Agent AEs More Frequent in Experimental Arm vs PegIFN/RBV

Discontinuations due to AEs, % (Wk)

Boceprevir/Telaprevir[1,2] Anemia, dysgeusia, neutropenia, rash, anorectal symptoms 13-14 (48)

ABT-072[3] (N = 27) Headache 0 (12)

ABT-333[3] (N = 18) None 0 (12)

ABT-450/r[4] (N = 30) None 0 (12)

Alisporivir[5] (N = 215) Transient hyperbilirubinemia 5 (48)

Asunaprevir[7] (N = 36) Fatigue 11 (12)

BI 201335[6] (N = 355) GI events, jaundice, and rash 8 (48)

Daclatasvir[8] (N = 36) None 8 (12)

Danoprevir[9] (N = 194) ALT elevation, neutropenia, nausea, diarrhea 4 (12)

Mericitabine[10] (N = 81) None 6 (36)

PSI-7977[11] (N = 95) None 3 (12)

Setrobuvir[12] (N = 63) Rash 2 (12)

TMC435[13] (N = 309) Mild bilirubin increases 7 (24)

Vaniprevir[14] (N = 169) GI events 6 (48)

Studies displayed include those with data through at least 12 wks and with discontinuation rates lower than BOC/TVR.

1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Gaultier, et al. APASL 2011. 4. Lawitz E, et al. EASL 2011. Abstract 1220. 5. Flisiak R, et al. EASL 2011. Abstract 4. 6. Bronowicki JP, et al. EASL 2011. Abstract 1195.

7. Sulkowski M, et al. EASL 2011. Abstract 60. 8. Pol S, et al. EASL 2010. Abstract 1189. 9. Terrault N, et al. AASLD 2010. Abstract 32. 10. Pockros P, et al. EASL 2011. Abstract 1359. 11. Nelson D, et al. EASL 2011. Abstract 1372. 12. Lawitz E, et al. AASLD 2010. Abstract 31.

13. Fried M, et al. AASLD 2010. Abstract LB-5. 14. Lawitz E, et al. AASLD 2011. Abstract LB-13.

Can We Make Regimens Simpler?Can We Improve Adherence?

Evolution of HCV Therapy

2001 2011 Future

PegIFN/RBVProtease inhibitorNucleos(t)ide polymerase inhibitorNonnucleoside polymerase inhibitorNS5A inhibitorHost targeting agent

Next

?

Majority of protease inhibitors have targeted genotypic coverage but

MK-5172, TMC435 have broad coverage[1,2]

Most nucleos(t)ide analogue polymerase inhibitors are pan-genotypic

1. Brainard DM, et al. AASLD 2010. Abstract 807. 2. Fried M, et al. AASLD 2010. Abstract LB-5 .

?

Conclusions

• The next generation of protease inhibitors are in development (expected to be available in 2015 or even earlier)

• Different DAA combination therapies are being evaluated in early phase trials– Whether Peg-IFN and/or RBV will be needed in all patientsis unclear

Final aim for a DAA combination regimen – All oral– QD– Safe and well tolerable – Pan-genotypic– IL28-independent– Limited resistance