# Presentation: 039668

## Pharmaceutic Development Issuesfor 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 offset********costs & 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 Years58 LAM100 Patients (Asian Multicenter Study) 

**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

***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**

## Slide 14

## Child Pugh Scores70 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%)**

**	****                                                  ****	****	**

**Notes:**
Over the course of the study,  with an average treatment period of more than 12 months, the patients’ average (mean) Child-Pugh scores improved by 2 points.  Also, only 3 of 70 patients showed significant disease progression during the study, contrary to the historical observation of progressive clinical decompensation disease in most patients (Weissberg 1984, de Jongh 1992, and other studies).

## Biochemical Changes in Lamivudine Treated Patients27 Non-Transplanted Patients (Perrillo et al., Hepatology 2001) 

**n= 27****	**** n=22****	****     n=17**

**Baseline****	****week 52****	****   week 104**

**Median**
**Albumin**
**(g/dL)**

**Median**
**Bilirubin**
**(mg/dL)**

**4**

**3.5**

**3**

**2.5**

**1.5**

**2**

**2**

**1**

**Notes:**
This is an analogous plot of the median albumin and bilirubin values in these patients with a similar trend toward improvement  being evident on therapy.

## 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;  1****o**** 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

**Notes:**
8/28/98 db must have pulled this slide in, as xyz and yyy look like variables, put sad face and pinked them for notice
9/2/98 added 2nd bullet and dose-ranging on 1st bullet
9/3/98 added last bullet, deleted parentheses, moved to Marc2