1) The document discusses the development of the drug Incivek for the treatment of hepatitis C virus (HCV) genotype 1. 2) It describes two phase 3 clinical trials called ADVANCE and ILLUMINATE that evaluated the efficacy and safety of Incivek in combination with pegylated interferon and ribavirin. 3) The trials found high sustained viral response rates, particularly in patients who achieved an early viral response, supporting the approval of Incivek for the treatment of HCV genotype 1.

1. CI-1
An Overview of the Incivex Drug Development Process: The
Road to Finding a Cure for HCV Genotype 1
,
1
©2012 Vertex Pharmaceuticals Incorporated
Abdul J Sankoh, PhD,
Vertex Pharmaceuticals, Biostatistics Department

2. CI-2
OPresentation Outline
• The Hepatitis C Virus• The Hepatitis C Virus
– Global Distribution of Different Genotype and subtypes
– Complications from HCV
• Incivek Development and Regulatory Milestones
• Phase 3 development plan:
– Paradigm Shift in the Treatment of HCVg
– ADVANCE STUDY (adaptive) Design
– ILLUMINATE STUDY (adaptive) Design
2

3. CI-3
C ( C )What is Hepatitis C Virus (HCV)?
Hepatitis C is an infectious disease affectingHepatitis C is an infectious disease affecting
primarily the liver, caused by the hepatitis C virus
(HCV).
– A small (55–65 nm in size), enveloped, positive-sense
single-stranded Ribonucleic acid (RNA) virus of the
f il Fl i i idfamily Flaviviridae::
– HCV is spread primarily by blood-to-blood contact
associated with intravenous drug use, poorly
sterilized medical equipment and transfusion.
3
– Hepatitis C only infects humans and chimpanzees.

4. CI-4
Th H titi C ViThe Hepatitis C Virus

5. CI-5
Global Geographic Distribution of HCV
Genotypes and SubtypesGenotypes and Subtypes
6 major Genotypes
Zein N N Clin. Microbiol. Rev. 2000;13:223-235

6. CI-6
Hepatitis C Is a Global Disease
• ~ 170 million people currently infectedp p y
• 3 to 4 million people newly infected annually
• 75% of cases in US are Genotype 1
World Health Organization (WHO) website: http://www.who.int/vaccine_research/diseases/viral_cancers/en/print.html
Reprinted from Alter MJ, et al. World J Gastroenterol. 2007;13:2436-2441.

7. CI-7
In the US, Prevalence of HCV Higher
Than HIV or HBV
Number of infected individuals vsNumber of infected individuals vs
number aware they are infected (diagnosed)
Undiagnosed
2.7-3.9 million infected
75% undiagnosed
ected
4
3
Undiagnosed
Diagnosed
1.4 million infected
65% undiagnosed
1.1 million infected
21% undiagnosed
umberinfe
millions)
3
2
65% undiagnosed21% undiagnosed
Totalnu
(
1
0
Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: The National
Academic Press; 2010
HCVHBVHIV

8. CI-8
Natural History of HCV Infection
Acute HCVAcute HCV
Resolved
25% 30%
Chronic Hepatitis C
70% 75%
20 yrs
Cirrhosis
10% 20%
20 yrs
Hepatocellular carcinoma
(1% 4%/yr)( /y )
Liver failure
Santantonio T et al, J Hepatology. 2008;49:625-33.
NIH Consensus Conference Statement, June 2002.
John-Baptiste A et al, J Hepatology. 2010;53:245-51.
Seeff LB, Liver International. 2009;29(suppl 1):89-99.

9. CI-9
What Do Patients With HCV
Cirrhosis Face?
bDecreased quality of lifea,b
• Fatigue
• Weight loss
• Depression
Complicationsc
• GI bleeding (varices, gastropathy)
• Ascites
• Bacterial infectionsDepression
• Muscle wasting
• Impaired cognition
Bacterial infections
• Encephalopathy
Overt
Minimal
H ll l i• Hepatocellular carcinoma
Liver Transplantation
• Hepatitis C is most frequent
indicationd Deathindication
• 30% develop cirrhosis 5 7 yrs
post transplante
Death
• ~ 12,000 deaths/yr (based on
death certificate documentation)f
• Likely an under representationg
a Bonkovsky HL, et al. J Hepatol. 2007;46:420-431. b Bonkovsky HL and Woolley JM. Hepatology. 1999;29:264-70. c Planas R, et al. J Hepatol.
2004;40:823-30. d Berg CL, et al. Am J Transplant. 2009;9:907-931. e Berenguer M. Clin Liver Dis. 2007;11:355-376. f Everhart JE, et al.
Gastroenterology. 2009;136:1134-1144. g Wise M, et al. Hepatology. 2008;47:1128-1135.

10. CI-10
Time of HCV Acquisition in Patients with
Different HCV Genotypes.yp
Zein N N Clin. Microbiol. Rev. 2000;13:223-235

11. CI-11Mean Time (years) Between Exposure to HCV
and Diagnosis of HCV-Related Complications
Zein N N Clin. Microbiol. Rev. 2000;13:223-235

12. CI-12
Incivek Key Development & Regulatory Milestonesy p g y
2011
Key development
Priority review
Approval & Launch
2010
Key development
milestonesa
CMC pre-NDA meeting
Clinical pre-NDA meetingNDA rolling
submission
2008
2009
Study 108 (ADVANCE)
Study 111 (ILLUMINATE)
Study C216 (REALIZE) Phase 3
Clinical advice meeting
2007
2008
Study 106 (PROVE-3)
Study 104EU (PROVE-2)
Study 107
Phase 2
Clinical advice meeting
2005
2006
Study 103
Study 102
Phase 1
Study 104 (PROVE-1)
Study 104EU (PROVE 2)
Key regulatory
milestones
2004
2005
a Dates refer to first patient enrolled.
Study 101
Phase 1milestones

13. CI-13
State of HCV Treatment Prior to Incivek
Approval
• Goal = Sustained Viral Response (SVR)p ( )
– Considered virologic cure
• Peg-IFN/RBV standard of care for HCV
– SVR for Genotype 1 naive
• 40% 52% of patients achieve SVRa-f
• Duration of therapy 48 weeksa-fDuration of therapy 48 weeks
• Low success rates with retreatment in
nonresponders and relapsers (10% 25%)g-i
• Peg-IFN/RBV has known toxicitiesa-i
• Rationale for response-guided therapy with
potential to shorten therapypotential to shorten therapy
a Pegasys [package insert]. Nutley, NJ: Hoffmann-La Roche Inc.; 2011. b Copegus [package insert]. Nutley, NJ: Hoffmann-La Roche Inc.; 2010.
c Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355. d Fried MW, et al. NEJM. 2002;347:975-982. e Manns MP, et al. Lancet. 2001;358:958-965.
f McHutchinson JG, et al. NEJM. 2009;361:58-593. g Bacon BR, et al. Hepatology. 2009;49:1838-1846. h Jensen DM, et al. Ann Intern Med.
2009;150:528-540. i Poynard T, et al. Gastroenterology. 2009;136:1618-1628.

14. CI-14
Common Factors That May Lead to
Lower SVR with Peg-IFN/RBV
• Genotype 1Genotype 1
• High HCV RNA levels
• Cirrhosis/bridging fibrosisCirrhosis/bridging fibrosis
• Age 40 years
• Heavy body weight• Heavy body weight
• Insulin resistance
• African American and Latino ethnicity• African American and Latino ethnicity
• Genetic polymorphisms (IL28B)
HIV i f ti• HIV coinfection

15. CI-15
Telaprevir—A Paradigm Shift in the
T t t f HCVTreatment of HCV
Easing Patient Treatment Burden!Easing Patient Treatment Burden!
Abbreviations: AE, adverse event; SVR, sustained virologic response.

16. CI-16
Original Phase 3 Development Program
Proposal
• Given strength of Phase 2 data fromGiven strength of Phase 2 data from
– Prove1 (Naïve)
P 2 (N ï )– Prove 2 (Naïve)
– Prove 3 (Nonresponders)
• Conduct
– 1 Phase 3 Naïve Patient Study (ADVANCE)
– 1 Phase 3 Treatment Experience Study
(REALIZE)

17. CI-17
ADVANCE Study Designy g
Study- Naïve Treatment- Late Phase
Wk Wk Wk Wk WkWk
Follow up
8 12 24 48 72
SVR
eRVR+ Follo p
4
Follow-up
SVR
Follow-up
n = 364 T8/PR Pbo/
PR PR eRVR :
PR to Wk 48
eRVR+: Follow-up
Follow-up
SVR
Follow up
n = 363 T12/PR PR eRVR :
SVR
eRVR+: Follow-up
Follow-up
SVR
eRVR :
PR to Wk 48
Follow-up
SVR
n = 361 Pbo/PR PR
eRVR = extended Rapid Viral Response; PR= Standard of Care

18. CI-18
FDA & Physicians Want to Know
• Clinically whether some subjects mightClinically, whether some subjects might
benefit from additional exposure to SOC
• Statistically, whether 24-week treatment is not
inferior to 48-week treatment
• Basically,Basically,
– A study comparing 24-week to 48-week
treatment (eRVR+)( )
– Thus the ILLUMINATE STUDY

19. CI-19
SVR Rates by eRVR Status
ADVANCE Study 108—Treatment-Naive
T12/PR100 97
ctable
T12/PR
T8/PR
Pbo/PR
70
80
90
92
87
hundetec
RNA,%
50
60
70
60
52
42
tientswith
HCV
20
30
40
42
Pat
24-week regimen
0
10
20
195/212 179/207 90/151 82/157
48-week regimen
28/29 139/332
RVR RVR24-week regimen
eRVR+
48-week regimen
eRVR
eRVR+ eRVR

20. CI-20
ILLUMINATE Study Designy g
Study 111—Treatment-Naive
Wk
Randomized Wk
48
Wk
72
Wk
24
n = 540 T12/PR PR
Wk
12
20 Wk
24
Follow-up for SVR
eRVR+
PR to Wk 48 Follow-up for SVR
n 540 T12/PR PR
D/C
before
Wk 20
eRVR PR to Wk 48 Follow-up for SVR
Follow-up for SVR
Wk 20

21. CI-21
Study Design Rationale and
Key Statistical Objecivesy j
Study 111—Treatment-Naive
• Evaluate differences in SVR rates betweenEvaluate differences in SVR rates between
24- and 48-week telaprevir-based regimens
in patients who achieved eRVR
– Rule out inferiority of 24-week to 48-week
regimen
– Non-inferiority margin of 10.5% (from Ph2
data)

22. CI-22
Study Objective:
T (T12+C24) not inferior to C (T12+C48)T (T12 C24) not inferior to C (T12 C48)
FDA’s review comments on SAP with FixedFDA s review comments on SAP with Fixed
Margin Approach proposal:
A Must also demonstrate sum of differencesMust also demonstrate sum of differencesA. Must also demonstrate sum of differencesMust also demonstrate sum of differences
1: T-C (from ILLUMINATE non-inferiority study)
+
2: C-P (from historical study- PROVE 1)
i.e.,
1 + 2 = (T-C)+(C-P)=T-P> 0 (statistically)
B. Even after inclusion of term for interB. Even after inclusion of term for inter--
trialtrial variability in estimate of variance of abovevariability in estimate of variance of above
22
sumsum..
C= PR= standard of care; T= TVR

23. CI-23
Proposed Synthesis ApproachProposed Synthesis Approach
Question:
Is T>P (test drug effective-assay sensitivity)?
– Answered via cross-trial information
(inference)
• Estimate effect of C relative to P from
hi t i l t di f C d P i thistorical studies of C and P using meta-
analysis (fixed/random effects)
• Show (T-C) +(C-P) > 0 with 95% confidence• Show (T-C) +(C-P) > 0 with 95% confidence
(A) + (B)
Also address retention fraction of C-effect
Connects historical and NI study data for indirect inference: T vs P
23
Connects historical and NI study data for indirect inference: T vs P

24. CI-24
Synthesis Approach for Estimating Test Drugy pp g g
Effect
Using historical data from R, DB, A & WCUsing historical data from R, DB, A & WC
trials (via meta-analyses- fixed or random
effects) to address assay sensitivity (T vs. P)
and constancy of control effect (C vs. P):
Want
T vs. C: Non-inferiority of T to C (Illuminate)
C vs. P:Control effect (C better than P)- Prove 1
T vs. P:T vs. P: Test effect (T better than P)Test effect (T better than P) –– CrossCross--TrialTrial
24

25. CI-25
SVR Rates
Study 111—Treatment-Naive
2 0% difference
100 92
90
2.0% difference
2-sided 95% CI (–4.3%, +8.2%)
60
80
SVR,%
40
60
entswith
20
149/162 144/160
Patie
0
eRVR+
T12/PR24
eRVR+
T12/PR48

26. CI-26
Trial Outcome & Imputing Test Drug effect:Trial Outcome & Imputing Test Drug effect:
(Sum of Differences- Review Comment A)
A. From Active-control trial (ILLUMINATE):
T (ß ) C (ß ) ß =ß ß (T C difference)– T (ßT) C (ßC) ßTC=ßT-ßC (T-C difference)
91.98% 87.50% 4.48%
B From historical trial (Phase 2 Study PROVE 1):B. From historical trial (Phase 2 Study- PROVE 1):
– C0 (ßC) P0 (ßP) ßCP=ßC-ßP(C-P difference)
67.09% 41.33% 25.76%
3. Imputing placebo response in active-control trial & demonstrating
T effect
– That is, estimation of ßTP & 95% CI on ßTP:, TP TP
• A + B = ßTC+ ßCP (T-P difference)
30.23%; (13.64%, 46.82%)
26
; ( , )
LL> 0
• FDA DAID ACM for INCIVEK, April 28, 2011.

27. CI-27Simulation Algorithm to Demonstrate
Superiority of Test Drug (T) to Placebo (C)
Generate random sample from Binomial distributionp
Active-control: B(PT; 162); PT = 0.92; 0.93; 0.87
from this sample, estimate PT
B(PC; 160); PC = 0.88; 0.95; 0.88
From this sample, estimate PC
Historical: B(PC_0; 79); PC_0 = 0.67
From this sample, estimate PC_0
B(P ; 75); P = 0 41B(P0; 75); P0 = 0.41
From this sample, estimate P0
Based on these sample estimates, left side of
27
(PT-PC) + (PC_0 - P0) > 0
• Repeat above steps M times (say M=10,000) to obtain I’s (i=1, 2, … M);
i form a distribution from which (1) can be evaluated.

28. CI-28
Absolute Difference (%) of Test vs. Active
Control- Addressing Variability
Test vs.
Active Control Method
Absolute
Difference (%)
T=92.0%,C=88.0%
T=93.0%,C=95.0%
MC Binomial
MC Beta-Binomial
MC Binomial
3.87
3.98
-1.76,
T=87.0%,C=88.0%
MC Beta-Binomial
MC Binomial
MC Beta Binomial
-2.19
-1.09
1 06MC Beta-Binomial -1.06
-14 -10.5 -6 -2 0 2 6 10 14
28
Beta Binomial to address Variability comment