1. Pharmaceutic Development Issues for Hepatitis B Nathaniel A. Brown, M.D. Sr. Vice President, Hepatitis Clinical Research Idenix Pharmaceuticals Cambridge, MA, USA

2. Topics for Discussion   HBV versus HIV infection:   Disease differences & implications for treatment studies   Experience with efficacy endpoints in HBV trials   Compensated liver disease   Decompensated liver disease   Pending sources of new types of clinical data   Key issues for discussion – an Industry consensus

3. HBV and HIV Infection: Disease Differences and Implications for Treatment Studies Ÿ Ÿ2 forms of endstage HBV: decompensated cirrhosis & HCC. Both associated with HBV replication, but distinct pathogeneses Antiviral therapy may not affect both Ÿ ŸChronic HBV infection can revert to low-replicative states (HBeAg and HBsAg seroconversion), spontaneously or with therapy, with minimal risk of disease progression Treatment can be stopped in some hepatitis B patients: lifelong care, but not lifelong treatment Ÿ ŸChronic HBV infection generally slower than HIV to cause irreversible damage (10-50 years for HBV vs. 5-20 years for HIV), in untreated patients and after treatment-related breakthrough

4. HBV and HIV Infection: Disease Differences and Implications for Treatment Studies Ÿ ŸDifferences in target cells and replication templates: - 1° target cells more regenerable for HBV than for HIV - hepatocytes turn over; HIV infects long-term cell types - HBV templates not maintained by cellular polymerases - HBV polymerase fidelity 10-fold better than HIV RT Treatment of chronic HBV infection potentially associated with clearance of replication templates over time HBV less likely to be associated with early resistance (e.g. 3TC), and chance for loss of drug-resistant HBV templates – over time, or with switch to new antiviral Rx

5. Hepatitis B vs. HIV Infection: Goals for combination therapy in HBV infection ŸImprove efficacy – increase frequency of durable responses ŸOR: Improve outcomes in refractory or high-risk subgroups  Decompensated cirrhotics  Transplant recipients  Co-infected patients  Possibly HBeAg-negative (pre-core mutant) disease ŸImproved efficacy must offset  costs & potential additional toxicities of combination regimens

6. Efficacy Endpoints in Hepatitis B Compensated Liver Disease   Serologic:   HBeAg loss, seroconversion (gain of anti-HBe)   HBsAg loss, seroconversion (gain of anti-HBs)   ALT normalization   Serum HBV DNA levels – unamplified assays and PCR assays   Composite serologic responses: “Virologic Response”, etc   Histologic:   Necroinflammatory scoring – Knodell, Ishak, ranking   Fibrosis/cirrhosis scoring – Knodell, Ishak, ranking

7. HBeAg Seroconversion (HBeAg-, HBeAb+) Over 4 Years 58 LAM100 Patients (Asian Multicenter Study)  Minimal seroconversion in patients with normal ALT  HBeAg seroconversion proportionally greatest in first year

8. Baseline Factors and HBeAg Seroconversion Multivariate Analysis of Integrated Phase III Lamivudine Data (Perrillo et al., Hepatology, July 2002) A multivariate analysis used stepwise logistic regression to investigate the influence of baseline factors on HBeAg seroconversion + loss of detectable HBV DNA (hybridization assay) at week 52. The most important pre-treatment factors, in order, were: ŸTreatment (p  0.001) ŸBaseline ALT (p  0.001) ŸHAI score (p  0.001) ŸHBV DNA values (p = 0.11)

9. Post-Treatment Durability of HBeAg Responses Integrated Phase III Data: LAM100 Patients, 52 Weeks of Therapy 77 76 74 77 0 10 20 30 40 50 60 70 80 90 HBeAg Loss HBeAb Present HBV DNA n.d.* HBeAg Loss HBeAb Present HBV DNA n.d.* on 2 occasions n=45/58 n=31/40 n=26/32n=18/23 Percent of Patients with Response Maintained 3-4 Months Post-Rx HBeAg Response Status at End of Therapy (Week 52) HBeAg Loss HBV DNA n.d.* *n.d. = HBV DNA not detectable by solution hybridization

10. Histology as an Efficacy Endpoint in HBV Trials: Important Findings   Suppression of HBV replication (  HBV DNA) is associated with decreased necroinflammatory activity in liver   IFN and LAM trials: 3-4 point HAI reductions occurred in non- seroconverters with non-detectable HBV DNA (by hybridization)   LAM and ADV trials – some histologic worsening (including fibrosis) in placebo recipients after 1 year   Fibrosis/cirrhosis improves with antiviral Rx in some patients   Histologic stage of disease (cirrhosis vs. no cirrhosis) does not appreciably influence responses to nucleosides   Antiviral Rx associated with decreased stellate cell activation   cccDNA in liver decreases with long-term antiviral Rx

11. Histology as an Efficacy Endpoint: Problems   Liver bx – picture of disease, but “only a snapshot in time & space”   Waxing/waning disease, and biopsy sampling error, reduce prognostic value of liver biopsy in chronic HBV infection   Histologic scoring has wide inter- and intra-observer variation   Accounting for missing biopsy data (10-40% of total) in placebo- controlled vs. active-controlled studies   Implications for efficacy: non-inferiority, superiority   Sample size calculations problematic due to unpredictable extent of missing data and scoring imprecision   Liver biopsies uncommonly used in practice: sometimes for disease staging, but almost never to monitor response to Rx   Many investigators cannot participate in global HBV trials that require biopsies (especially in China and elsewhere in Asia)

12. Relationships Among Efficacy Responses in Trials   Broad relationship of efficacy endpoints evident in results of placebo- controlled lamivudine and adefovir trials   Clinical improvements (histology, ALT, etc) occurred disproportionately in patients on active antiviral treatment   Precise correlations between efficacy parameters difficult to assess   Addressed by others today   Integrated phase III lamivudine data: Serologic markers (ALT, HBV DNA) adequately predicted lack of histologic worsening at Week 52   ALT normalized or improved by 50%: HAI “worse” at W52 in only 5%   HBV DNA non-detectable or  by 50%: HAI “worse” at W52 in only 9%

13. Efficacy Endpoints in Hepatitis B Decompensated Liver Disease   Survival   Improvement in Child-Pugh score   Improvement in bilirubin, albumin, PT, etc

14. 88% actuarial survival Non-survivors Survivors Overall Early mortality:  bili,  albumin  creatinine Detectable HBV DNA 0 20 40 60 80 100 061218243036 Months Percent of Patients Surviving Survival in 133 Lamivudine-Treated Patients with Decompensated Chronic Hepatitis B Fontana et al., AASLD2000; and Gastroenterology, in press Survival better than historic reports – more data needed

15. Child Pugh Scores 70 Lamivudine-treated patients, 50 with data >6 months (Hann et al., DDW2000) Mean/median baseline CP score9.3/9.0 Mean/median last visit CP score 7.6/7.0 Improved by  2 points 21 (42%) Unchanged ( Changed by < 2 points )26 (52%) Worsened by  2 points3 (6%)

16. Biochemical Changes in Lamivudine Treated Patients 27 Non-Transplanted Patients (Perrillo et al., Hepatology 2001) n= 27 n=22 n=17 Baselineweek 52 week 104 Median Albumin (g/dL) Median Bilirubin (mg/dL) 4 3.5 3 2.5 1.5 2 2 1

17. Efficacy Endpoints in HBV Trials: Conclusions    ALT & histologic responses related to HBV DNA suppression   HBV DNA suppression also associated with  HBeAg responses   But immune response (  ALT pre-treatment) also required   Serologic monitoring (ALT & HBV DNA) predicts lack of histologic worsening   Clinical and biochemical signs of disease progression are rare during 1 ‑ 2 year trials in compensated patients   Some histologic deterioration seen in placebo recipients   Improvements in hepatic function seen in patients with decompensated disease – more data needed   Improved or stabilized CP scores,  bilirubin,  albumin   Possible survival benefit in decompensated patients

18. Pending Sources of New Types of Clinical Data Current nucleoside/tide comboRx trials in treatment-naïve patients:   Glaxo-Gilead collaborative trials, LAM + ADV   Idenix Phase IIb trial, LdT + LAM Large clinical endpoints trial (Glaxo NUCB4006)   >600 Asian patients with documented HBV cirrhosis   LAM vs Placebo, sequential analysis   Stopped by DSMB for efficacy on clinical disease progression Perinatal HBV Transmission Study (Glaxo NUC30914)   25% failure rate (to vaccine + HBIg) in high-viremic mothers   3-arm randomized trial (2:2:1): vacc + HBIg + PLA vs. vacc + HBIg + LAM vs. vacc + LAM   LAM given to mothers from gestation week 32 to postnatal week 4   410 patients; 1º endpoint is HBsAg status of infant at 1 year of age

19. An Industry Perspective: Scientific Issues and Issues for Discussion Today CONTRIBUTORS Achillion Lisa Dunkle Bristol Myers Squibb Deborah DeHertogh, Bruce Kreter, Michael Brady, Katherine Takaki Eli Lilly James McGill, Margaret Wasilewski GlaxoSmithKline Stephen Gardner, Fraser Gray, Lynn Condreay Idenix Nat Brown, Maureen Myers, Dave Standring, George Chao Roche Nigel Pluck, S. Chris Pappas Schering Plough Janice Albrecht Triangle Pharmaceuticals Franck Rousseau, Elsa Mondou Tulane University Shobha Joshi

20. An Industry Perspective: Endpoint and Trial Design Issues Are Critical! Rated “critically important” by ALL respondents:   Histology as an efficacy endpoint   Active vs. placebo controls in future trials Rated “critically” to “very” important for discussion today:   HBV DNA suppression (alone) vs. short-term clinical endpoints (HBeAg, histology, ALT)   Endpoints in HBeAg-negative (pre-core mutant) hepatitis B   Correlation between serologic and histologic endpoints   Criteria for non-inferiority vs. superiority in Phase III trials   How to deal with non-standardized HBV DNA assays

21. An Industry Perspective: Discussion Framework for the Issues What are therapy goals in chronic hepatitis B?   Therapeutic response endpoints   Treatment discontinuation endpoints Choices for 1  efficacy endpoint in:   HBeAg+ patients (histology, HBeAg/Ab, ALT, HBV DNA)   HBeAg- patients (histology, ALT, HBV DNA) Active vs. placebo controls in future trials   What 1  endpoint best discriminates between 2 active Rx’s?

22. An Industry Perspective: Important Scientific Issues Virology knowledge gaps:   cccDNA formation & persistence   Antiviral targets other than polymerase? Immunology knowledge gaps:   Immune factors in HBV persistence vs clearance   Viral suppression vs. immune effects for durable responses (implications for antiviral Rx vs. antiviral + immunomodulator) Clinical knowledge gaps:   Undefined correlation between HBV DNA suppression and clinical efficacy endpoints   No established early determinants of long-term outcomes

23. A Personal Perspective: Facilitating Progress in HBV Therapeutics   DAVDP & Committee guidance: endpoint and design issues   Future HBV registration trials:   Global (to ICH/FDA standards)   Most patients from Asia, some from N.America/EU/elsewhere   Most trials with active control designs (monoRx and comboRx) Need 1° serologic endpoints for efficiency and precision   ‘Clinical’ endpoints linked with HBV DNA suppression?   Desirable for trials in patients with compensated liver disease   After assay standardization, HBV DNA as 1° endpoint in some circumstances?   Conditional approvals, decomp, co-infected patients? Goal: Optimize progress against severe morbidity/mortality

24. Q & A