Epatite HCV: Luci ed ombre sui nuovi trattamenti antivirali

(1)

3 °°°° Giornate Gastro-Epatologiche Cuneesi

19-20 Febbraio 2010

Epatite HCV:

Luci ed ombre sui nuovi trattamenti antivirali

Alessia Ciancio

Università di Torino

(2)

Goals of Future Therapy

Multiple drugs and mechanisms of action

Effective across a range of genotypes

Enhanced response

Decreased duration

Improved tolerability

Diminished resistance

Applicable to difficult-to-treat populations

(3)

Large and Growing Population of Nonresponders

Based on the assumption that there will be no changes in SOC and 40-50% of treatment naive patients will not

achieve SVR

Year

P a ti e n ts

2009 2012 2015 2018 2021 2024 2027

Nonresponder Pool

Naive Patients Treated

(4)

Selected HCV Drugs in Clinical Development

Type of Drug Drug

Interferons Albinterferon alfa-2b

Controlled-release interferon alfa-2b

Interferon alfa-2bXL

ITCA638

Peginterferon-lambda (PEG-rIL-29)

Ribavirin prodrug Taribavirin Other drugs Nitazoxanide

Silibinin

(5)

Selected HCV Drugs in Clinical Development

HCV Inhibitors Drug

Entry inhibitors PRO206*

NS3/4A protease inhibitors Telaprevir (VX-950)

Boceprevir (SCH 503034)

TMC435

R7227 (ITMN-191)

MK-7009

BI201335

SCH 900518

Nucleos(t)ide analogues R7128

IDX184 Nonnucleoside RdRp inhibitor GS-9190

ANA598

BI207127

VCH-916

Filibuvir (PF-00868554)

NS5A inhibitors BMS-790052

Cyclophilin inhibitors DEBIO-025

SCY-635

NIM811 HCV assembly/release inhibitors Celgosivir

*Development recently halted.

(6)

Hepatitis C Drug Scenario

Imino sugars Histamine HCl

S ta g e S ta g e

Phase II Phase II On Market On Market

Phase III Phase III

Phase I Phase I

Research Research Preclinical Preclinical

Thymosin

IC41 Vaccine IFN & PEG IFN

Many others including immune stimulants

gene therapy

Ribozymes E2 Vaccine RBV

Antisense

Viramidine

Gamma IFN

IL 10 & IL 12 others HCV-796

ANA 245 Telaprevir

Antifibrotics CPG 10101 Omega IFN

Boceprevir

R1626

BILB 1941 Albumin IFN-alfa

BILB 2061 Valopicitabine

BILN 2061 -100 -fold less a ctivit y in g enoty pes 2 /3 Prog ram h alted due to ca rdioto xicity

BILN 2061

BILN 2061 - -100 100 -fold l - ess a ctivit y in g enoty pes 2 /3 fold l ess a ctivit y in g enoty pes 2 /3 Prog ram h alted due to

Prog ram h alted due to cardi otoxi city cardi otoxi city

Dev elop men t of

Dev elop men t of valo pici tabi ne

valo pici tabi ne plac ed o n h old plac ed o n h old

bas ed o n ri sk/b ene fit p rofi le o bse rved bas ed o n ri sk/b ene fit p rofi le o bse rved

Dos ing of HCV -796 hal ted for po ssib le h epa toto xici ty

8% with sig nifi can t AL T el eva tion s

(7)

Alb-Interferon alfa-2b Plus RBV

**SVR* Results, G1 naif**

*SVR = HCV RNA < 10 IU/

*SVR = HCV RNA < 10 IU/mLmL posttreatmentposttreatment

alb-IFN 1200 µg Q2W (n = 442) alb-IFN 900 µg Q2W (n = 440) PEG-IFN 180 µg QW (n = 441)

Zeuzem S, et al. AASLD. 2009.

48.3 48.3 47.3 47.3

51 51

00 2525 5050 7575 100100

Sustained Virological Response Rate (%)Sustained Virological Response Rate (%)

Treatment Groups Treatment Groups

+ Rbv 1000-1200 mg

Primary Efficacy End point:

noninferior sustained

response rate

(8)

Alb-Interferon alfa-2b Plus RBV

**SVR* Results, G2/3 naif**

*SVR = HCV RNA < 10 IU/

*SVR = HCV RNA < 10 IU/mLmL posttreatmentposttreatment

79.8 79.8

80 80 84.8 84.8

00 2525 5050 7575 100100

Sustained Virological Response Rate (%)Sustained Virological Response Rate (%) alb-IFN 1200 µg Q2W (n = 442) alb-IFN 900 µg Q2W (n = 440) PEG-IFN 180 µg QW (n = 441)

Treatment Groups Treatment Groups

+ Rbv 800 mg

Primary Efficacy End point:

noninferior sustained

response rate

(9)

*SVR12 = HCV RNA < 10 IU/

*SVR12 = HCV RNA < 10 IU/mLmL at week 12 at week 12 posttreatmentposttreatment

29 29

13 13

00 1010 2020 3030 4040

Week 12 Antiviral Response Rate (%)Week 12 Antiviral Response Rate (%)

alb-IFN 1200 µg Q2W alb-IFN 900 µg Q2W alb-IFN 1200 µg Q4W

22.6 22.6

Treatment Groups Treatment Groups

Alb-Interferon alfa-2b Plus RBV

**SVR12* Results, G1 NR**

Zeuzem S, et al. EASL. 2007.

(10)

N = 1323

Alb-Interferon alfa-2b Plus RBV

Pts with life-threatening SAE

Discontinued due to AEs Patients with Aes (3/4 grade)

• Alopecia

• Cough

• Weight loss

• Rash (Severe)

11.1%

10.9%

11%

4%

22.6%

41.2%

37.6%

23.6%

13.8%

19.5%

24.5%

25.6%

14.7%

19.7%

AlbIFN (900µg)/RBV PEG IFN/RBV

Interstitial Pulmunary Disease

!

Wh at w ill b e th e ro le o f Al bin terf ero n in the ma rke tpla ce?

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Viral Enzyme Inhibitors: Emerging Therapies

Viral Enzyme Inhibitors Viral Enzyme Inhibitors

Protease

Polymerase STAT-C

Specifically Targeted Antiviral Therapy for

HCV

(12)

HCV Protease Inhibitors

(13)

Phase II PROVE Studies:

Telaprevir + PegIFN Alfa-2a ± ± ± ± RBV

PROVE 1

(N = 250)

TVR + PR PR

PROVE 2

(N = 323)

PR

PROVE 3

(N = 453)

PR

Wk 48 Wk 24

Wk 12 Wk 72

TVR + PR

Treatment-Naive G1

Previous Nonresponders G1

TVR + PR PR

Peginterferon alfa-2a 180 µµµg/wk. Ribavirin 1000 or 1200 mg/day by weight. µ Telaprevir 1250 mg on Day 1 then 750 mg every 8 hrs.

Follow-up Follow-up

TVR + P

Follow-up

TVR + PR PR PR TVR + PR

Wk 36

Follow-up

(14)

0 20 40 60 80 100

S V R R a te , %

41

PR48 (n = 75)

35

T12/PR12 (n = 17)

61

T12/PR24 (n = 79)

P = .020

1. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

2. Hézode C, et al. N Engl J Med. 2009;360:1839-1850.

T12/P12 (n = 78)

36

T12/PR12 (n = 82)

62

T12/PR24 (n = 81)

69 46

PR48 (n = 82)

P = .004

T12/PR48 (n = 79)

P = .002

67 PROVE 1

^[1] ^(n=263)

PROVE 2

^[2]^(n=263)

P = .12 P = .20

PROVE 1/2—Telaprevir + PEG IFN/RBV

SVR, G1 naif

(15)

0 20 40 60 80 100

S V R R a te , %

23

PR48

33

T12/PR12

2

T12/PR24

T12/P12

48

T12/PR12

29

T12/PR24

20 14

PR48 T12/PR48

6 PROVE 1

^[1] ^(n=250)

PROVE 2

^[2]^(n=323)

PROVE 1/2—Telaprevir + PEG IFN/RBV

Relapser rate, G1 naif

P = .02

P = .01 P = .001

P = .08

(16)

PROVE 1 and 2 Pooled Subanalysis:

TVR in Difficult-to-Cure patients

Factors independently predictive of SVR included TVR-based therapy (P < .001), low baseline HCV RNA (P < .001), younger age (P < .04), and white race (P < .001)

Everson GT, et al. AASLD 2009. Abstract 1565.

Age > 50 Yrs

HCV RNA ≥≥≥≥ 800,000 IU/mL

Bridging Fibrosis

12-wk TVR + 24-wk pegIFN/RBV (n = 160)

V ir o lo g ic R e s p o n s e ( % )

0 20 40 60 80 100

59

29

Male Sex 63

39

61

30

69

44

PegIFN/RBV control (n = 157)

P < .001

P < .001 P < .001

P = .045

(17)

TVR12/PEG/RBV24 Arms: B, (n = 115)

PEG IFN/RBV Arm: A (n = 114)

TVR24/PEG IFN Arm: D (n = 111)

14%

51% 53%

24%

0%

20%

40%

60%

80%

100%

H C V R N A n e g a ti v it y ( < 1 0 I U /m L ) [ % ]

TVR24/PEG/RBV48 Arms: C (n = 113)

PEG IFN/RBV TVR12/PEG/RBV 24 weeks of tx

TVR24/PEG/RBV 48 weeks of tx

TVR/PEG 24 weeks of tx

PROVE 3 —Telaprevir + PEG IFN/RBV

SVR, G1 who failed prior SOC

McHutchison JG, et al. AASLD 2009. Abstract 66.

*P < .001 vs control.

* *

(18)

0 20 40 60 80 100

S V R R a te , %

9

PR48

39

T12/PR24

38

T24/PR48

P < .001

69

76 42 20

P < .001

T24/P24

P < .001

11 Non Responder Relapser

P < .001

PROVE 3 —Telaprevir + PEG IFN/RBV

SVR, G1 who failed prior SOC

PR48 T12/PR24 T24/PR48 T24/P24

(19)

N = 80

PROVE 1/2

Undetectable HCV RNA*

Discontinued due to AEs Patients with AEs

• Diarrhea

• Anemia (Grade 1+2)

• Rash (Severe)

88%

^†

52%

18%

4%

80%

34%

57%

7%

75%

21%

38%

0%

PEG IFN/RBV + TVR (Arms B, C, and D) PEG IFN/RBV

(Arm A)

* HCV-RNA W12

No incremental effect on neutrophil or platelet counts in TVR treatment arms

(20)

Randomization

Study Weeks

0 48 72

C H C , G 1 , n a ïv e , n = 5 9 5

PEG-IFN αααα 2b plus RBV

PEG-IFN αααα 2b plus RBV plus boceprevir

4 28

PEG-IFN αααα2b plus

RBV

PEG-IFN αααα 2b plus RBV plus boceprevir

PEG-IFN αααα2b plus RBV plus boceprevir PEG-IFN

αααα2b plus RBV

PEG-IFN αααα 2b plus RBV plus boceprevir

*

Phase II SPRINT-1 : Boceprevir+ PEG IFN/RBV G1 naif

Peginterferon alfa-2b 1.5 µµµµg/kg/wk. Ribavirin 800-1400 mg/day and Boceprevir 800 mg every 8 hrs.

(21)

*1 late relapser after follow-up Wk 24; not included in SVR.

SPRINT-1: 28/48BOC + SOC ± ± ± ± Lead-in vs SOC SVR, G1 naif

Kwo P, et al. EASL 2009. Abstract 4

S V R R a te , %

0 20 40 60 80

38 54 56

67 PR Control 48 Wks

PRB 28 Wks

^*

PR 4 Wks

PRB 24 Wks (n = 103)

PRB 48 Wks (n = 104) (n = 107)

(n = 103) 100

PR 4 Wks

PRB 44 Wks (n = 103)

75 P =.013

P =.005

P <.0001

(22)

SPRINT-1: Boceprevir + PegIFN/RBV

in Null Responders to SOC

Two 4-wk lead-in arms of pegIFN alfa-2b + RBV allowed determination of likely virologic response to

– Definition of a “null” response to pegIFN alfa-2b + RBV: < 1 log

₁₀

decrease at Wk 4

Kwo PY, et al. AASLD 2009. Abstract 62.

< 0.5 log drop at

Wk 4 of pegIFN/RBV lead- in

0.5 to < 1.0 log drop at Wk 4 of pegIFN/RBV lead-in

PegIFN/RBV 4 wks →→→→ PegIFN/RBV/Boceprevir 24 wks

PegIFN/RBV 4 wks →→→→ PegIFN/RBV/Boceprevir 44 wks

2/7 5/21 4/9 8/13

0 20 40 60 80 100

29 24

44

62 S V R ( % )

(23)

HCV SPRINT-1 Study – Discontinuations

Kwo et al, EASL 2008, oral, late-breaker

23 35 5 8 9 18 11

11%

4%

15%

8%

19%

8%

0%

10%

20%

30%

Due to AEs Due to viral breakthrough

D is c o n ti n u a ti o n s

Lead-In (n=206) No Lead-In (n=226)

Low dose RBV (n=59) SOC (n=104)

(24)

SPRINT-1: High Grade of Anemia

During 28 Weeks of Treatment

Epoetin-alfa treatment

– PegIFN/RBV lead-in arm pegIFN/RBV + boceprevir: 48%

– PegIFN/RBV + boceprevir: 45%

– PegIFN/RBV: 25%

Kwo P, et al. EASL 2008. Abstract 995.

Anemia Severity 0

20 40 60 80 100

P a ti e n ts ( % )

Grade 0 23 21

45 Grade 1 Grade 2 Grade 3 Grade 4

50 54 46

27 25

10 0 1 0 0 0 0

PegIFN/RBV lead-in pegIFN/RBV + boceprevir (n = 206) PegIFN/RBV + boceprevir (n = 226)

PegIFN/RBV (n = 104)

(25)

HCV Polymerase Inhibitors

(26)

R1626 – Virological Response over Time

5%

24%

48%

33%

13%

53%

66% 69%

10%

52%

74%

81%

5% 5%

10%

5%

0%

20%

40%

60%

80%

100%

Week 1 Week 2 Week 3 Week 4

H C V R N A n e g a ti v e ( < 1 5 I U /m L )

R1626 1500mg +P R1626 3000mg +P R1626 1500mg +P/R SOC

Pockros et al, AASLD 2007, oral presentation

(27)

10%

52%

81% 84%

0%

20%

40%

60%

80%

100%

Week 1 Week 2 Week 4 Week 48

H C V R N A n e g a ti v e ( < 1 5 I U /m L )

R1626 1500 mg +P/R

Nelson D. et al, EASL 2008, oral

Inc ide nce of gra de 4 n eut rop eni a

Dua l lo w 48%

Dua l hi gh 78%

Trip le lo w 39%

SO C

10%

R1626 – Virological Response over Time

(28)

Viral Breakthrough Rates With STAT-C–Containing Regimens

Telaprevir + PegIFN + RBV

^[1,2]

1% to 7%

Boceprevir + PegIFN

+ RBV

^[3]

2% to 6%

Increased in absence or low dose of

RBV

^[2,3]

1. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 2. Hézode C, et al. N Engl J Med.

2009;360:1839-1850. 3. Kwo P, et al. EASL 2009. Abstract 4.

G1 Treatment-Naive Patients With RVR

(29)

• Less fit than other variants

Subtype May Matter Subtype May Matter with Telaprevir Therapy with Telaprevir Therapy

Implication: subtype distinctions may become more important with STAT-C agents

than with PEG IFN + RBV alone

V36M V36M R155K/T R155K/T

• 1 nucleoside substitution in relevant codons of 1a

• 2 substitutions needed in 1b

• 1 nucleoside substitution in relevant codons of 1a

• 2 substitutions needed in 1b

Genotype 1a (n = 6)‏‏‏‏

A156V/T A156V/T

Genotype 1b (n = 14)‏‏‏‏

Kieffer TL, et al. Hepatology. 2007;46:631.

(30)

WT

₃₆ _WT

155

36 155

36/155 T54

WT

36 155

T54 36/155

WT 1

2 3 4

5 6 7

1 2 3 4

5 6 7

1 2 3 4

5 6 7

EOD 14 days Baseline

Follow-up 7–10 days postdosing

Long-term follow-up 3–7 months

postdosing

WT V36 M/A/L

R155

K/T/S/M T54A 36/155 A156V/T 36/156

IC

₅₀

fold

change 1 4 7 12 46 466 781

Telaprevir Dosing Period Postdosing Long-Term Follow-up

1 2 3 4

5 6 7

Median Log HCV RNA

EOD = end of dosing.

Kieffer T, et al. 41st EASL. April 26-30, 2006. Abstract 12.

Dynamics of Viral Variants

Breakthrough Group

(31)

NS3/4A Protease/Polimerse Inhibitors:

Resistance

Resistance mutations can emerge quickly during suboptimal therapy or monotherapy

– Breakthrough due to resistance uncommon in naive patients on triple therapy

– Potential for class resistance

– Long-term fate and impact of resistance mutations unknown

Differences in genetic barrier to resistance between classes and within polymerase class: nucleosides have high barrier

Resistance can be prevented by combining with pegIFN alfa + RBV

Different signature resistance mutation patterns suggest potential for combinations of polymerase inhibitors

Weisberg IS, et al. Clin Liver Dis. 2009;13:441-452. Berman K, et al. Clin Liver Dis. 2009;13:429-439. Sarrazin C, et al. Gastroenterology.

2007;132:1767-1777. Kieffer TL, et al. Hepatology. 2007;46:631-639. Kuntzen T, et al. Hepatology. 2008;48:1769-1778. Kwo P, et al. EASL 2009. Abstract 4. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.

(32)

Conclusion

The potential efficacy of STAT-C is high

STAT-C monotherapy unlikely

Interferon & Ribavirin—not going away soon

If treatment remains IFN-based, efficacy may be limited by

– Inadequate interferon-stimulated gene response – Contraindications and toxicities related to IFN

Increased efficacy may mean shorter duration

– Shorter duration may mean less toxicity

– Toxicity of STAT-C agents still unknown

(33)

Conclusion

Other limiting factors pertinent to STAT-C

– Intrinsic limitations on drug potency – Differences in genotype sensitivity

– Genomic variability of HCV even within genotypes (“quasispecies”) ‏ – Side effects—there is no “free lunch”

Potential for resistance will require monitoring and formulation of appropriate strategies

HCV resistance may be delayed or prevented by using

combinations of potent antiviral drugs and optimizing patient

adherence to therapy

(34)