Update on the HCV Antiviral Pipeline

Todd S. Wills, MDSPNS HCV Treatment Expansion Initiative

Evaluation and Technical Assistance CenterInfectious Disease Specialist

HCV Response Rates in HIV+ and HIV- Patients Treated With PegIFN/RBV

APRICOTHIV Positive

Overall SVR: 40%

PRESCOHIV Positive

Overall SVR: 50%

176 95 191 152 298 140

Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel AIDS. 2007;21:1073-1089.

Pat

ient

s W

ith S

VR

(%)

29

62

36

72

46

76

FRIEDHIV NegativeOverall SVR: 56%

GT1/4 GT2/3GT1/4 GT2/3GT1/4 GT2/3

48 Wks of Therapy,600 mg RBV

24, 48, or 72 Wks of Therapy,

Weight-Based RBV

48 Wks of Therapy,Weight-Based RBV

0

20

40

60

80

100

n =

Potential HCV antiviral targets

NS4AC E1 E2/NS1 NS2 NS3 NS5A NS5BNS4B5’ 3’

RNAbindingsite

Envelopeglyco-proteins

Signalpeptide

Serine protease/helicase

RNA dependentRNA polymerase

Internalribosomalentry site

telaprevir, boceprevir

Response TerminologyTerm Time Point HCV RNA LevelRapid virologic response (RVR)

Wk 4 of therapy Undetectable

Early virologic response (EVR)

Wk 12 of therapy ≥ 2 log10 IU decrease from baseline

Complete early virologic response (cEVR)

Wk 12 of therapy Undetectable

Slow to respond Wk 24 of therapy Undetectable (but with detectable HCV RNA at Wk 12)

End of treatment response (EOT or ETR)

End of therapy Undetectable

Sustained virologic response (SVR)

6 mos posttherapy Undetectable

Adherence• Triple therapy presents

challenges with already busy schedules[143]

– TID dosing– Food requirements

• Data show pegIFN/RBV adherence decreases over time[5]

– Addition of PIs may exacerbate this trend

1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

6:00 AM

7:00 AM

8:00 AM

9:00 AM

10:00 AM

11:00 AM

12:00 PM

1:00 PM

2:00 PMTVR/BOC

(with food)TVR/BOC

(with food)TVR/BOC (with

food)

3:00 PM

4:00 PM

5:00 PM

6:00 PM Dinner RBV RBV RBV

7:00 PM

8:00 PM

9:00 PM

10:00 PM

Dinner

Dentist Appt

Travel to and Meet With

Clients

Patient Appointments

Study Group

Chemistry Lab

Biology

English Composition

Lunch

TVR/BOC (with food) + RBVMonday

Work

MondayTVR/BOC (with food) + RBV

Lunch

TVR/BOC (with food)

Daily Team Conference Call

Typical Student Busy Sales Professional Mother With Small Children and Full-time Nurse

MondayTVR/BOC (with food) + RBV

Wake, feed, and dress children for school

School and daycare drop-off, commute to work

Patient Appointments

Lunch

TVR/BOC (with food)

Travel to and Meet With Client

Calls to Clients

Running Club

Researching Trade Articles

Dinner

TVR/BOC (with food)

Dinner cleanup, make lunches for next day

Pick up kids, commute home

Get children ready for and in to bed

from Clinical Care Options

Sulkowski M, et al. CROI 2011. Abstract 146LB.

Study 110: High Rates of Early Response With TVR + PR in Coinfected Patients

• Similar efficacy results observed with or without concurrent ART• Nausea, pruritus, dizziness, fever more common with TVR vs placebo• Pharmacokinetic interactions with ATV or EFV not clinically significant

Undetectable HCV RNA, Week 4 (ITT)

100

80

60

40

20

0

Und

etec

tabl

e H

CV

RN

A (%

)

Telaprevir + PR PR

012

50

71 7564 70

n/N = 5/7 12/16 9/14 26/37 0/6 1/8 0/8 1/22

No ARTEFV-based ART

ATV/RTV-based ARTTotal

Undetectable HCV RNA, Week 12 (ITT)

100

80

60

40

20

0

Telaprevir + PR PR

17 12 1412

71 75

5768

n/N = 5/7 12/16 8/14 25/37 1/6 1/8 1/8 3/22U

ndet

ecta

ble

HC

V R

NA

(%)

Study 110 – SVR 12 DataTelaprevir Group N=38 Placebo Group

SVR12 28/38 (74) 10/22 (45)

On Treatment Virologic Failure

3/38 (8) 8/22 (36)

Not Suppressed at End of Treatment

5/37 (14) 9/22 (41)

Relapse 1/32 (3) 2/13 (15)

Dieterich D, et al. CROI 2012 Abstract 46

Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects

Adverse Effect TVR+PR PR

Pruritis or Itching 39% 9%

Headache 37% 27%

Nausea 34% 23%

Skin Rash* 34% 23%

Fever 21% 9%

Anemia 13% 18%

Depression 21% 9%

Insomnia 13% 23%

*no cases of severe rash

Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8

Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs

Sulkowski, M. CROI 2012 Abstract 47

Investigational Agents

PSI-7977 – Phase II Trial Data HCV uridine nucleotide analogue

12 WEEK Treatment PSI-7977/P/Rn=47

PSI 7977/P/Rn=54

PSI 7977/Rn=10

PSI-7977n=10

EOT 43 54 10 10

Week 1-4 Relapse 1 0 0 4

SVR 4 42 54 10 6

> Wk 4 relapse 0 0 0 0

SVR 12 42 54 10 pending

SVR 24 42 41 (11 pend) 4 (6 pend) pending

Genotype 1

Genotype 2/3

Lawritz, E. et al. J of Hepatology 54 (s1) 2012

TMC-435 – Phase IIb trial data• HCV NS3/4A Protease Inhibitor (Once-Daily)

• Prior Treatment FailuresTMC12/PR48 n=66

TMC24/PR48N=65

TMC48/PR48N=66

TMC12/PR48n-=66

TMC24/PR48N=68

TMC48/PR48N=65

Pbo48/PR48N=66

RVR Total 44/66 (67)

38/65 (59)

35/66 (53)

41/66 (62)

46/68 (68)

43/65 (66)

1/66 (2)

SVR Total 46/66 (70)

43/65 (66)

40/66 (61)

44/66 (67)

49/68 (72)

52/65 (80)

15/66 (23)

SVR Null 6/16 (38)

9/16 (56)

8/18 (44)

9/17 (53)

7/17 (41) 10/17 (59)

3/16 (19)

SVR Partial 16/23 (70)

11/23 (48)

12/22 (55)

15/23 (65)

18/24 (75)

19/22 (86)

2/23 (9)

SVR Relapse

24/27 (89)

23/26 (89)

20/26 (77)

20/26 (77)

24/37 (89)

23/26 (89)

10/27 (37)

100 mg

150 mg

P<0.001 vs placebo

Zeuzem S., et al. J of Hepatology 54 (s1) 2012

Interferon Sparing Strategies• ABT 450/r – ritonovir boosted HCV PI +• ABT 072 – HCV polymerase inhibitor +

• Weight-based ribavirin

• Open label 12 week treatment trial 11 patients• Interferon sparing

• 91% SVR24• One patient relapsed 8 weeks post Rx

• All patients were IL28B CC

Lawitz, E. et al. Of Hepatology 56(s1) 2012

Interferon AND Ribavirin Sparing Strategies• Daclatasvir (NS5A replication complex inhibitor) +• Asunaprevir (HCV NS3 PI)• Open label trial of both drugs in 43 prior null responders or

with IFN/R intolerance

Null Responders N=21

IFN/R Ineligible or Intolerant N=22

IL28B CC 3/21 (14.3) 16/22 (72.7)

RVR 11/21 (52.4) 19/22 (86.4)

cEVR 19/21 (90.5) 20/22 (90.9)

EOT 18/21 (85.7) 16/22 (72.7)

SVR 12 19/21 (90.5) 14/22 (63.6)

Suzuki, F. et al. J of Hepatology 56 (s1) 2012