Pharmaceutic Development Issuesfor Hepatitis B

Nathaniel A. Brown, M.D.Sr. Vice President, Hepatitis Clinical Research

Idenix Pharmaceuticals

Cambridge, MA, USA

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

HBV and HIV Infection:Disease Differences and Implications for Treatment Studies

2 forms of endstage HBV: decompensated cirrhosis & HCC. Both associated with HBV replication, but distinct pathogeneses

Antiviral therapy may not affect both

Chronic 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

Chronic 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

HBV and HIV Infection:Disease Differences and Implications for Treatment Studies

Differences 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

Hepatitis B vs. HIV Infection:Goals for combination therapy in HBV infection

Improve efficacy – increase frequency of durable responses

OR: Improve outcomes in refractory or high-risk subgroups

Decompensated cirrhotics Transplant recipients Co-infected patients Possibly HBeAg-negative (pre-core mutant) disease

Improved efficacy must offsetcosts & potential additional toxicities of combination regimens

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

HBeAg Seroconversion (HBeAg-, HBeAb+) Over 4 Years58 LAM100 Patients (Asian Multicenter Study)

0

10

20

30

40

50

60

70

80

0 52 104 156 208

Weeks of Therapy

% withResponse

All

ALT Norm

ALT >1 xULN

ALT >2 xULN

Minimal seroconversion in patients with normal ALT

HBeAg seroconversion proportionally greatest in first year

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:

Treatment (p 0.001)

Baseline ALT (p 0.001)

HAI score (p 0.001)

HBV DNA values (p = 0.11)

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 HBeAg LossHBeAb PresentHBV DNA n.d.*

HBeAg LossHBeAb PresentHBV DNA n.d.*on 2 occasions

n=45/58 n=31/40 n=26/32 n=18/23

Percent ofPatients with

ResponseMaintained3-4 Months

Post-Rx

HBeAg Response Status at End of Therapy (Week 52)

HBeAg LossHBV DNA n.d.*

*n.d. = HBV DNA not detectable by solution hybridization

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

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)

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%

Efficacy Endpoints in Hepatitis B Decompensated Liver Disease

Survival

Improvement in Child-Pugh score

Improvement in bilirubin, albumin, PT, etc

88% actuarial

survival

Non-survivorsSurvivors

Overall

Early mortality: bili, albumin creatinine• Detectable HBV DNA

0

20

40

60

80

100

0 6 12 18 24 30 36

Months

Percent of Patients

Surviving

Survival in 133 Lamivudine-Treated Patientswith Decompensated Chronic Hepatitis B

Fontana et al., AASLD2000; and Gastroenterology, in press

• Survival better than historic reports – more data needed

Child Pugh Scores70 Lamivudine-treated patients, 50 with data >6 months (Hann et al., DDW2000)

Mean/median baseline CP score 9.3/9.0

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 points 3 (6%)

Biochemical Changes in Lamivudine Treated Patients27 Non-Transplanted Patients (Perrillo et al., Hepatology 2001)

n= 27 n=22 n=17Baseline week 52 week 104

Median

Albumin

(g/dL)

Median

Bilirubin(mg/dL)

4

3.5

3

2.5

1.5

2

2 1

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

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

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

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

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?

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

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

Q & A