Response Guided Vs.Response Unguided Therapy

K.Rajender Reddy M.DProfessor of Medicine

University of PennsylvaniaPhiladelphia, USA

Factors in Complexity of HCV Therapy

Lead In

No Lead In

Age/Gender

IL28B

Relapser

Partial Responder

Null Responder

Treatment Naïve

ObesityObesity

Race/ethnicity

Viral load/Genotype

Protease Inhibitor Based HCV Therapy:Easy to Treat and Difficult to Treat Genotype 1

Patient Populations

Easy to Treat

• Low viral load• Women• Younger age• Absence of fibrosis• IL 28 B CC• Interferon sensitive• Relapsers

Difficult to Treat

• High viral load• Obesity/Metabolic syndrome• Blacks• IL 28 B-C/T, T/T• Cirrhosis• Older population• Interferon insensitive• Partial and Null Responders

Response Guided Therapy

Response Unguided Therapy

Protease Inhibitor Trials: Summary

• Treatment Naïve– Telaprevir (TPV)

• ADVANCE

-- RGT• ILLUMINATE

– RGT and RUGT

– Boceprevir (BOC)• SPRINT-2

– RGT + RUGT

• Treatment Experienced– Telaprevir (TPV)

• REALIZE– RUGT

– Boceprevir (BOC)• RESPOND-2

– RGT + RUGT

Limitations and Unique Aspects of the Trials

• In both TPV and BOC studies, small number of • Patients with cirrhosis• Older population• High BMI patients

( Post-Hoc Analyses)

• IL-28B– Boceprevir – limited data

– Telaprevir – limited data

• Blacks– Boceprevir

• Prospective study

– Telaprevir• Post-hoc analysis

• Prior Treatment Experienced– Boceprevir – RGT + RUGT

– Telaprevir – RUGT

ADVANCE: Overall SVR and Relapse Rates According to Treatment Arm

Jacobson IM et al. N Engl J Med 2011;364:2405-2416.

6%

75%

7%

69%

27%

44%

0

20

40

60

80

100

SVR Relapse

% ofPatients

T12PR

T8PR

PR

271/363 250/364 168/361 17/264 18/247 51/189

ADVANCE: SVR for T12PR in Selected Subgroups

Jacobson IM et al. N Engl J Med 2011;364:2405-2416.

SVR(%)

112/149

244/325

159/214

16/26

Male 45 yrs White

Female >45 to 65 yrs Black

118/142

150/214

ADVANCE: SVR for T12PR in Selected Subgroups

Jacobson IM et al. N Engl J Med 2011;364:2405-2416.

245/328

64/82

26/35

207/281

Hispanic HCV Subtype 1a HCV RNA <800,000

Non-Hispanic HCV Subtype 1b HCV RNA 800,000

152/213

118/149

SVR(%)

ADVANCE: SVR for T12PR in Selected Subgroups

Jacobson IM et al. N Engl J Med 2011;364:2405-2416.

SVR%

117/156

55/77

109/134

87/129

No/Minimal Fibrosis BMI <25 (Normal)

Portal Fibrosis BMI 25 to <30 (Overweight)

Bridging fibrosis BMI 30 (Obese)

Cirrhosis

32/52

129/155

13/21

Cirrhosis

ILLUMINATE(TPV): SVR in Cirrhosis and Blacks in those with eRVR ( T12/PR24 Vs.T12/PR48)

SVR%

T12|PR24(RGT T12|PR24

T12|PR48(RUGT) T12|PR48

RUGT

12/18 11/12 15/17 16/17

FDA analysis and Sherman KE, et al. N Engl J Med 2011;365:1014-24 10

SPRINT-2: SVR and Relapse Rate by Fibrosis Score

SPRINT-2 and RESPOND-2: BOC + PegIFN/RBV in HCV GT 1 with Advanced Fibrosis/Cirrhosis

N=328 N=319 N=24 N=34 N=42 N=158 N=233 N=231 N=12 N=17 N=25N=313

Bruno S, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 7.

RESPOND-2: SVR by Cirrhotics (F4) vs. Non-Cirrhotics (F0/1/2/3) According to Treatment

Arm

24%

0%

64%

35%

66%

77%

0

20

40

60

80

100

Cirrhosis No Cirrhosis

% ofPatients

PR 48 RGT BOC/PR48

0/10 6/17 17/22 16/66 85/132 85/128

RUGT

Bacon BR et al. N Engl J Med 2011;364:1207-1217.

Treatment Naïve-Blacks

SPRINT-2: SVR in Primary Patient Cohorts According to Treatment Arm

Poordad F et al. N Engl J Med 2011:364:1195-1206.

23%

40%38%42%

67%63%

53%

68%66%

0

20

40

60

80

100

PR48 RGT BOC/PR48

p<0.001

p<0.001

p<0.001

p<0.001

p=0.004

p=0.04

All Patients(Both Cohorts)

Nonblack Cohort Black Cohort

137/363

233/368

242/366

137/363

125/311

211/316

213/311

12/52

22/52

29/53

SVR(%)

RUGT

Prior Treatment Experienced

RESPOND-2: SVR and Relapse Rates for All Subjects According to Treatment Arm

28%23%

14%

59%

12%

66%

0

20

40

60

80

100

SVR Relapse

% ofPatients

PR48

RGT

BOC/PR48

n=80 n=162 n=161 n=25 n=111 n=121

Bacon BR et al. N Engl J Med 2011;364:1207-1217.

RESPOND-2: SVR by Response to Previous Peg-IFN/RBV Therapy According to Treatment

Arm*

31%

7%

70%

40%

75%

52%

0

20

40

60

80

100

Previous Partial Responder Previous Relapser

PR 48 RGT BOC/PR48

2/29 23/57 30/58 16/51 73/105 77/103

SVR(%)

RUGT

Bacon BR et al. N Engl J Med 2011;364:1207-1217.

RESPOND-2: SVR According to Viral Load

Bacon BR et al. N Engl J Med 2011;364:1207-1217.

17%

40%

56%

80%

65%

80%

0

20

40

60

80

100

Low ( 800,000 IU/mL) High (>800,000 Iu/mL)

PR48 RGT BOC/PR48

12/15 11/65 83/147 91/14116/206/15

SVR(%)

RGT vs RUGT

Interferon Response

SPRINT-2 and RESPOND-2: Evaluation of Predictive Value of PegIFN/RBV 4-week

Lead-in Therapy

Vierling JM, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011: Abst. 481.

Relationships Between Week 4 Lead-in and SVR

Poorly responsive to interferon <1.0 log10 viral load decline at treatment

Week 4

Responsive to interferon ≥1.0 log10 viral load decline at treatment

Week 4

133/ 203/ 200/3/83 27/97 36/95 0/12 15/46 15/44 260 252 254 17/67 80/110 90/114

IL 28 B

SPRINT-2 ( Treatment Naïve): SVR by IL28B Polymorphism

% S

VR

5064

6377

4455

33116

67103

82115

1037

2342

2644

* ~90% eligible for short duration therapy

*

Poordad F, et al. EASL 2011, Abst..

RGT vs RUGT

RESPOND-2( Treatment Experienced): SVR by IL28B Polymorphism

613

2228

1722

529

3862

4866

510

611

1318

* ~80% eligible for short duration therapy

Poordad F, et al. EASL 2011, Abst..

% S

VR

*

RUGT

HCV Therapy:Candidates for Response Unguided Therapy

Easy to Treat

• Absence of fibrosis • Low viral load• Younger age• Women• IL 28 B CC• Interferon sensitive• Relapsers

Difficult to Treat

• High viral load• Obesity/Metabolic syndrome• Blacks• IL 28 B-C/T, T/T-Treatment

Experienced• Cirrhosis• Older population• Interferon insensitive• Null and Partial Responders

Response Unguided Therapy