# Presentation: 664571

## Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B

**Adefovir Dipivoxil 10 mg ****for the ****Treatment of Chronic Hepatitis B**

- NDA 21-449
- August 6, 2002
- Gilead Sciences, Inc.

**Notes:**
Good morning.
My name is Alan Taylor from Gilead Sciences.
We are here to review the New Drug Application for ADV, which was submitted to the FDA on March 21, 2002.
Efficacy and safety in compensated liver disease (HBeAg+, HBeAg-)
Treatment-naïve 
Treatment-experienced
Efficacy and safety in lamivudine-resistant HBV
No adefovir-associated resistance up to 136 weeks

## Proposed Indication

- Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease

## Consultants

- Jules L. Dienstag, MDProfessor of Medicine, Harvard Medical SchoolMassachusetts General Hospital (Gastrointestinal Unit)
- Zachary D Goodman,  MD, PhDChief, Division of Hepatic PathologyArmed Forces Institute of Pathology
- Paul Klotman, MDChief, Division of Nephrology and Chairman, Department of Medicine      Mt. Sinai School of Medicine
- Eugene Schiff, MDProfessor of Medicine and  Chief, Division of HepatologyDirector,Center For Liver Diseases University of Miami School of Medicine
- Teresa Wright, MDProfessor of Medicine
- 	University of California, San Francisco

## Agenda

**Agenda**

**Introduction ****	****	****	****      Alan Taylor, PhD**
- Chronic Hepatitis B		       Vice President
- Pre-clinical			       Regulatory Affairs
- Clinical Pharmacokinetics
**Clinical Efficacy & Safety****	****      Carol Brosgart, MD**
- Pivotal studies			       Vice President
- Supportive studies 		       Clinical Research
- Further studies

**Notes:**
In today’s presentation I will review the TDF preclinical data and the clinical development program.

Dr. Jay Toole will present the efficacy and virology data from our clinical studies and I will end our presentation with concluding remarks.

Despite the number of antiretrovirals available today, there is still a tremendous unmet medical need.  People with AIDS and their caregivers face daunting challenges with resistance, compliance, drug interactions, tolerability and durability of treatment effect.

Tenofovir disoproxil fumarate is a novel antiretroviral which address of these challenges.

## Chronic Hepatitis BA Global Healthcare Issue

- 1Lok AS, Gastroenterology 2001
- 2Lee W, NEJM 1997

**Chronic Hepatitis B****A Global Healthcare Issue**

- 400 million with chronic hepatitis B worldwide1
- HBeAg+
- HBeAg–
- 25-33% develop progressive disease
- Cirrhosis or hepatocellular carcinoma
- 1 million deaths per year
- 1.25 million with chronic hepatitis B in US2
- 17,000 hospitalizations and 5,000 deaths per year
- 6th leading indication for adult liver transplantation

- 400 million with chronic hepatitis B worldwide1
- HBeAg+
- HBeAg–
- 25-33% develop progressive disease
- Cirrhosis or hepatocellular carcinoma
- 1 million deaths per year
- 1.25 million with chronic hepatitis B in US2
- 17,000 hospitalizations and 5,000 deaths per year
- 6th leading indication for adult liver transplantation

**Notes:**

2 billion  people infected, HBV is a major world wide problem, prevalence varies in Asian countries in 75% .
Adefovir has the potential to address the limitations of current therapies - most notably the development of resistance with lamivudine therapy.

##  Current Therapies for Chronic Hepatitis B

- Limited treatment options
- Interferon alpha
- Cytokine immunomodulator
- Parentally administered
- Safety and tolerability issues
- Contraindicated for decompensated liver disease
- Lamivudine
- Nucleoside analog
- Orally administered
- Resistance

## Goals for New Antiviral Therapies for Chronic Hepatitis B

- Safe and well-tolerated for long term use
- Effective in all patient populations
- HBeAg+ and HBeAg–
- HBV genotypes (A-G)
- Compensated and decompensated liver disease
- Post-liver transplantation
- Drug resistant virus
- High threshold for the development of resistance

## Adefovir Dipivoxil

**Adefovir Dipivoxil**

- Oral prodrug of adefovir
- Nucleotide analog of adenosine monophosphate
- Potent *in vitro* activity against hepadnaviruses, retroviruses, and herpes viruses
- Competitive inhibitor of HBV DNA polymerase
- Ki = 0.1 M
- Long intracellular half-life (12-36 hours)
- Adefovir-associated resistance mutation sites identified in HIV RT not present in HBV DNA polymerase
*In vitro* activity against wild-type andlamivudine-resistant HBV

**Notes:**
As Adefovir-associated resistance mutation
 sites identified in HIV RT not conserved in 
HBV DNA polymerase we do not know what 
mutations in HBV DNA polymerase 
would confer reduced susceptibility to adefovir   
Alan for 2nd to last bullet

##  In Vitro Activity of AdefovirWild-type and Lamivudine-resistant HBV

** *****In Vitro *****Activity of Adefovir****Wild-type and Lamivudine-resistant HBV**

- Xiong et al. Hepatology, 1998, 28:1669-1673

**Notes:**
Source:  438 CSR dated 4-APR-02.  Table 9-1, Page 26
Created by:
Created on: 4-Mar-02

Modified by:
Modified on:

## Preclinical Pharmacology and Toxicology

- Antiviral activity and safety in DHBV, WHV, and transgenic mice expressing HBV
- Reduced serum viremia in all models
- In DHBV model, reduced cccDNA in liver and  DHBV DNA/viral antigen in bile duct epithelial cells
- No adverse effects in woodchucks
- Dose proportional PK of adefovir following oral administration of adefovir dipivoxil
- Eliminated as unchanged adefovir in urine
- Kidney principal target organ

**Notes:**
  Studies in animal models were undertaken to characterize the pharmacology and toxicology of adefovir administered IV and adefovir dipivoxil administered orally. Renal tubules were the clinically relevant target organ identified in all species and monitoring for nephrotoxicity was a key component of the clinical safety evaluation.   In the evaluation for effects on reproduction, adefovir dipivoxil had minimal adverse effects.  IV adefovir administered at exposures 38 times the human AUC was teratogenic and embryotoxic associated with significant maternal toxicity.  No adverse effects were observed at systemic adefovir exposures 12 times humans.  Adefovir dipivoxil was not genotoxic in vivo and was not carcinogenic in lifetime rodent bioassays.

## Adefovir Dipivoxil 10 mgClinical Pharmacokinetics

- Oral bioavailability 59%, T1/2  7 hours
- Pharmacokinetics not affected by food, chronic hepatitis B disease, demographic characteristics
- No clinically relevant drug-drug interactions
- Not substrate or inhibitor of CYP450
- Lamivudine, acetaminophen, ibuprofen, trimethoprim/sulfamethoxazole
- Change in dosing interval required in patients with moderate to severe renal impairment
- Increased exposure with CLcr < 50 mL/min
- No dose alteration for hepatic impairment

**Notes:**
 Oral bioavailabiliy of adefovir dipivoxil 10 mg is 59% in humans. Pharmacokinetics of adefovir were similar in the fasted and fed state and not significantly influenced by patient demographics including presence of chronic hepatitis B disease, age, gender, ethnicity or bodyweight.
No clinically relevant drug-drug interactions were observed with four representative drugs commonly administered to patients with chronic hepatits B. Adefovir is eliminated by urinary excretion.  In a study of patients with renal impairment, increases in adefovir concentrations were observed in patients with creatinine clearance less than 50 mL/min.  Adjustments of the dosing interval are required in patients with moderate to severe renal impairment.  Our recommendations for dosing according to renal function are provided in you background package.  No alterations in dosing frequency are recommended for patients with hepatic impairment.

## Adefovir Dipivoxil in Chronic Hepatitis B Dose Selection

- Doses of 5-125 mg evaluated in chronic hepatitis B
- 3 - 4 log10 copies/mL reduction in HBV DNA at all 	doses > 5 mg at 4-12 weeks
- Adefovir dipivoxil 60 and 120 mg in HIV
- 10 and 30 mg selected for evaluation in HBV
- Sustained HBV DNA reduction and increased ALT normalization up to 136 weeks
- No adefovir-associated resistance mutations identified (n=27)
- Renal laboratory abnormalities at 30 mg
- 10 mg target dose for registration

## Chronic Hepatitis BExposure to Adefovir Dipivoxil

- Total
**2084**

- ADV 10 mg
**1647**

- Other ADV doses
**437**

- Phase 2, Supportive Studies, Early Access
**831**** **

-  Pivotal studies and
- transplantation
**816**

-  48 Weeks
-  **578**

-  72 Weeks
**420**** **

-  96 Weeks
**256**

- As of NDA Safety update

## Clinical Efficacy and Safety

**Clinical Efficacy and Safety**

- Carol Brosgart, MD
- Vice President, Clinical Research
- Gilead Sciences

**Notes:**
Good Morning CB here to present data for an extensive clinical Development program in Chronic Hepatitis B in HBe Ag + and HBe Ag- both treatment experienced and treatment naïve and a also including patients with lam-resistant including comps, decomps tranplantation and co-infecn with HIV

## Adefovir Dipivoxil Pivotal Studies

- 96

- 48

- Liver Histology

**Study 438**
**HBeAg–**

- Week

- 0

- Liver Histology

**ADV 10 mg   (n=171)**

**Study 437**
**HBeAg+**

**ADV 30 mg   (n=173)**

**Placebo        (n=167)**

**Placebo        (n=142)**

**ADV 10 mg   (n=138)**

**ADV 10 mg   (n=123)**

**ADV 10 mg    (n=79)**

**Placebo         (n=40)**

**Placebo         (n=71)**

**ADV 10 mg    (n=85)**

**Placebo         (n=61)**

**ADV 10 mg    (n=60)**

**Notes:**
After 48 weeks, patients re-randomized to
ADV 10 mg  ADV 10 mg
ADV 10 mg  Placebo
Placebo  ADV 10 mg
After 96 weeks, patients eligible to receive                        open-label ADV 10 mg

## Studies 437 and 438 Key Inclusion Criteria

- Documented HBsAg positive for  6 months
- Compensated liver disease
- Adequate renal function
- HIV, HCV, and HDV seronegative
- Liver biopsy

**    ****HBeAg****–**
-  105 copies/mL
-  1.5–15

**    ****HBeAg+**
-  106 copies/mL
-  1.2–10

**HBV DNA**
**ALT x ULN**

## Studies 437 and 438Baseline Characteristics (ITT)

**Notes:**
 Studies multicenter, multinational studies , enrolled samller numbers of balck patients rather than in the US alone

## Studies 437 and 438Baseline HBV Characteristics (ITT)

## Studies 437 and 438Primary Endpoint

- Improvement in liver histology at week 48, relative to baseline (ADV 10 mg vs. placebo)
- Defined as  2 point reduction in the Knodell necroinflammatory score with no worsening in fibrosis
- Missing/unevaluable week 48 biopsy = no improvement
- Histology assessed
- One histopathologist blinded to treatment assignment and sequence (baseline or week 48)
- Knodell and Ishak scoring systems
- Evaluable paired biopsies
- 86% HBeAg+
- 91% HBeAg–

## Studies 437 and 438 (ITT) 48 WeeksPrimary Endpoint: Improvement in Liver Histology

- Studies 437 and 438 (ITT) 48 Weeks**Primary Endpoint: Improvement in Liver Histology**

**p<0.001****a**

- Patients
- (%)

**PLB**

**ADV **
**10**

**PLB**

**ADV**
**10**

**HBeAg+**

**HBeAg–**

**p<0.001****a**

- Missing/unevaluable week 48 biopsy = no improvement

- aCochran-Mantel-Haenszel Test

## Studies 437 and 438 Integrated 48 Weeks (ITT)Histological Improvement by Demographic Characteristics

**Notes:**
 When integrated PLB 28% vs ADV 57.
In every category treatment benefit demonstrated for ADV over placebo.   
Treatment effect for ADV ranged from 52% to 63%
Treatment effects for placebo 24%to 37%. In men and women the treatment effect seen over placebo The treatment difference  in men appeared greater than in women. Driven by a large placebo response in Women. 

## Studies 437 and 438 Integrated 48 Weeks (ITT)Histological Improvement by Baseline HBV Characteristics

## Studies 437 and 438 Secondary Endpoints

- Ranked assessment of liver histology
- Change in serum HBV DNA
- Roche Amplicor PCR, LLQ = 400 copies/mL
- Change in ALT
- HBeAg loss and seroconversion (Study 437)
- Resistance

## Studies 437 and 438 (ITT) 48 WeeksNecroinflammation – Ranked Assessment

**p<0.001****a**

**p<0.001****a**

**HBeAg+**

**HBeAg–**

- Improved

- Worsened

- Patients
- (%)

**42%**

**80%**

**51%**

**3%**

**ADV**
**10**

**PLB**

**PLB**

**ADV**
**10**

**41%**

**71%**

**34%**

**13%**

**40%**

**20%**

**0%**

**20%**

**40%**

**60%**

**80%**

**60%**

- aCochran-Mantel-Haenszel Test

## Studies 437 and 438 (ITT) 48 WeeksFibrosis – Ranked Assessment

**p<0.001****a**

- Studies 437 and 438 (ITT) 48 Weeks**Fibrosis – Ranked Assessment**

**24%**

**41%**

**26%**

**14%**

**30%**

**20%**

**10%**

**0%**

**10%**

**20%**

**30%**

**40%**

**50%**

**PLB**

**ADV**
**10 **

- Improved

- Worsened

**25%**

**48%**

**38%**

**4%**

**PLB**

**ADV**
**10 **

- Patients
- (%)

**40%**

- aCochran-Mantel-Haenszel Test

**HBeAg+**

**HBeAg–**

## Studies 437 and 438 Median Change from Baseline in HBV DNA 

- aWilcoxon Rank-Sum Test

**p<0.001****a**

**HBeAg-**

**p<0.001****a**

**HBeAg+**

**PLB**

**ADV 10**

- -4

- -3

- -2

- -1

- 0

**PLB**

**ADV 10**

- Weeks

-  0   4   8  12 16  20 24 28 32 36 40 44 48

- -4

- -3

- -2

- -1

- 0

-  0   4   8  12 16  20 24 28 32 36 40 44 48

- log10 copies/mL

## Studies 437 and 438 (ITT) 48 WeeksSerum HBV DNA < 400 copies/mL

**p<0.001****a**

**p<0.001****a**

**PLB**

**ADV**
**10 **

**PLB**

**ADV**
**10 **

**HBeAg+**

**HBeAg–**

**Patients**
**(%)**

- aCochran-Mantel-Haenszel Test

- Missing = Failure

## Studies 437 and 438 (ITT) 48 Weeks ALT Normalization

**PLB**

**ADV**
**10 **

**PLB**

**ADV**
**10 **

**HBeAg+**

**HBeAg–**

**p<0.001****a**

**p<0.001****a**

**Patients**
**(%)**

- aCochran-Mantel-Haenszel Test

- Missing = Failure

## Study 437 (ITT) 48 WeeksHBeAg Loss and Seroconversion

**PLB**

**ADV**
**10 **

**PLB**

**ADV**
**10 **

**p=0.001****a**

**p<0.05****a**

**Patients**
**(%)**

- aCochran-Mantel-Haenszel Test

- Missing = Failure

## Study 437 and 438 Efficacy Beyond 48 Weeks

## Study 437 and 438 All ADV 10 mg (n=492)Efficacy Beyond 48 weeks

- aK-M estimates

**Notes:**
1 patient underwent S seroconversion

## Studies 437 and 438 ADV 10 mgEfficacy Summary

- Statistically significant improvement in
- Liver histology
- HBV DNA
- ALT
- HBeAg loss and seroconversion (Study 437)
- Histological improvement appears similar across all baseline demographics and disease characteristics
- Continued improvement in efficacy beyond 48 weeks

## Studies 437 and 438 Safety of Adefovir Dipivoxil 10 mg

**Notes:**
Baseline Biopsy + Week 48 = 86%

## Studies 437 and 438 0-48 WeeksAdverse Events and Discontinuations

## Studies 437 and 438 Integrated 0-48 WeeksGrade 1-4 Treatment-Related Adverse Eventsa

- 	                                        **PLB                    ADV 10**
**	****	****	****(n=228)****	****  (n=294)**** **
- Asthenia		14%	13%
- Abdominal pain		 11%	  9%
- Headache	 	 10%	  9%
- Nausea	 	  8%	  5%
- Flatulence	 	  4%	  4%
- Diarrhea		  4%	  3%
- Dyspepsia	 	  2%	  3%

- aObserved in  3% of ADV treated patients

## Studies 437 and 438 Integrated 0-48 Weeks Grade 3-4 Laboratory Abnormalitiesa

- 		                **	****   ****PLB            ADV 10**
**	****	****	**** ****(n=228)         (n=294)**
- ALT (> 5 x ULN)	 	 41%		20%
- AST (> 5 x ULN) 	  	23%		  8%
- Hematuria ( 3+)	 	 10%	           11%
- CK (> 4 x ULN) 	    	7%	             7%
- Amylase (> 2 x ULN) 	    	4%	             4%
- Glycosuria ( 3+)	    	3%		  1%

- aObserved in   1% of ADV treated patients

## Studies 437 and 438 Integrated 0-48 Weeks                          Grade 1-4 Renal Laboratory Parameters

## Studies 437 and 438 Integrated 0-48 WeeksRenal Laboratory Abnormalities

- 					 	       **PLB          ADV 10 **
**	****	****	****	****        ****	****	****    ****(n=228)       (n=294)**
- Serum creatinine
- 	Increase  0.5 mg/dLa	        	         0%	      0%
- 	Median change (mg/dL) 		         0.0	      0.0
- Serum phosphorus
- 	<1.5 mg/dLa	                               0%	      0%
- 	Median change (mg/dL)		         0.1	      0.1

- aConfirmed (two consecutive laboratory abnormalities)

**Notes:**
No difference also seen at >= 0.3 mg/dL

## Studies 437 and 438 0-48 Weeks Renal Laboratory Abnormalities

- aConfirmed (two consecutive laboratory abnormalities)

**Notes:**
No difference also seen at >= 0.3 mg/dL

## Studies 437 and 438 Integrated ADV 10 mgRenal Laboratory Abnormalities 0-96 Weeks

- aConfirmed (two consecutive laboratory abnormalities)

**Notes:**
No difference also seen at >= 0.3 mg/dL

## Study 437 and 438 All ADV 10 mgResolution of  0.3 mg/dL Increases in Serum Creatinine 0-96 Weeks (n=29)  

**Resolved on**
**drug**
**n=20**

**Stable on**
**drug**
**n=8**

**Resolved on **
**discontinuation**
**n=1**

## Studies 437 and 438 Integrated 0-48 WeeksALT Elevations > 10 x ULN 

**	****	****	****	****	****	****PLB****	****         ADV 10 **
**	****	****	****	****        ****	****         ****(n=228)          (n=294)**
- ALT > 10 x ULN 		          17%    	           6%
- ALT > 10 x ULN with:
- 	 Bilirubin  2.5 mg/dL and	  2%	           0%
-      	  1mg/dL above baseline
-   	 Albumin < 3 g/dL			  1%	           0%
- 	 PT prolonged  1.5 sec 	<1%	           0%
- 	 above ULN

## Studies 437 and 438 Integrated ADV 10 mgALT Elevations > 10 x ULN 48-96 Weeks

**	****	****	****	****	****    ****ADV********ADV     ADV********PLB **
**	****	****	****	****        ****	****         ****(n=164)          (n=111)**
- ALT > 10 x ULN 		             6%              25%
- ALT > 10 x ULN with:
- 	 Bilirubin  2.5 mg/dL and            <1%	            3%
-      	  1 mg/dL above baseline
-   	 Albumin < 3 g/dL			  0%	            0%
- 	 PT prolonged  1.5 sec 	  0%	            0%
- 	 above ULN

**Notes:**
Need to know profile about each of the patients that flare.

Onset within 4-12 weeks
Associated with increases in serum HBV DNA
Generally self-limited or resolved on re-initiation of  treatment

## Studies 437 and 438 Integrated 0-96 WeeksAdefovir Dipivoxil 10 mg Safety Summary

- Safety and tolerability of ADV 10 mg similar to placebo through 48 weeks
- Increases in ALT and AST more frequent on placebo
- Safety appears similar with extended dosing
- Incidence of increases in serum creatinine is low
- One patient discontinued
- No hypophosphatemia
- Increases in serum ALT after stopping treatment
- Liver function should be closely monitored for at least 12 weeks after discontinuation of therapy

## Adefovir Dipivoxil 30 mgEfficacy and Safety

## Study 437 (ITT)Efficacy Results 48 Weeks

## Study 437Renal Laboratory Abnormalities 48 Weeks 

- aConfirmed (two consecutive laboratory abnormalities)

**Notes:**

Source Table F12 D

## Study 437 Assessment of Adefovir Dipivoxil 30 mg

- Efficacy demonstrated with ADV 10 and 30 mg
- Renal laboratory abnormalities with ADV 30 mg
- Safety profile of ADV 10 mg similar to placebo           and favorable for long-term dosing

## Resistance Surveillance

**Notes:**
Baseline Biopsy + Week 48 = 86%

## Studies 437 and 438Resistance Surveillance

- Prospective, blinded analysis
- Methods
- Sequenced RT domain of HBV DNA polymerase (344 amino acids)
- Compared baseline and week 48
- Assessed phenotypic resistance *in vitro* for all emerging substitutions at conserved sites
- 498 of 695 patients with paired samples had detectable HBV DNA > 400 copies/mL at baseline and week 48

**Notes:**
Source:  
Created by:
Created on:
Modified by:
Modified on:

## Studies 437 and 438Resistance Surveillance Results

- 10 patients with substitutions at conserved sites
- 6 in placebo
- 4 in ADV
- 2 ADV 10 mg, 2 ADV 30 mg
- S467A, H481L, V562A, H582Q
- All had ~4 log10 copies/mL HBV DNA reductions at week 48 and no rebound viremia
- All susceptible to adefovir *in vitro*
- No adefovir-associated resistance mutations identified up to 48 weeks

##  Supportive Studies 

## Lamivudine Resistance

- Incidence of mutations (YMDD)1-3
- 24% at 1 year
- 69% at 5 years
- Resistance associated with
- Loss of HBV DNA suppression
- Increased ALT
- Loss of histological and clinical benefit

- 1 Lai et al. Gastroenterol Hepatol, 2000
- 2 Leung MWY et al. J Hepatology, 1999
- 3 Guan et al. APDW, 2002

## Study 435 Compassionate Access

- Adefovir Dipivoxil 10 mg for the Treatment                        of Patients Pre- and Post-Liver Transplantation                with Lamivudine-Resistant HBV

## Study 435 Mortality Rates in Advanced Liver Disease

- One year survival rates prior to the availability of therapies for chronic hepatitis B
- Post-liver transplantation:   73%1
- Decompensated cirrhosis:  65%2
- Survival improved with therapies for hepatitis B
- Lamivudine resistance is associated with significant morbidity and mortality in                  high-risk patients

- 1 Weissberg et al. Ann Intern Med.,1984
- 2 Perillo et al. Hepatology 2001

## Study 435Baseline Characteristics

- aMedian

## Study 435Baseline HBV Disease Characteristics

**Notes:**
121 patients
- 10 patients in cohort 2
Safety data includes all 131 patients

HBV DNA < 400  29% A   23% B

## Study 435Median Change from Baseline in HBV DNA

**169**

**Post-**
**transplant**

**161**

**156**

** ****149**

**116**

** ****88**

** ****57**

** ****43**

** ****27**

** ****24**

** ****15**

**103**

**Pre-**
**transplant**

** ****98**

** ****91**

** ****84**

** ****52**

** ****28**

** ****13**

**  ****2**

**  ****2**

**  ****2**

**  ****0**

- -5.0

- -4.0

- -3.0

- -2.0

- -1.0

- 0.0

- 0

- 4

- 8

- 12

- 24

- 36

- 48

- 60

- 72

- 84

- 96

- 4

- 8

- 12

- 24

- 36

- 48

- 60

- 72

- 84

- 96

**Pre-transplant**

**Post-transplant**

- log10 copies/mL

**Notes:**
Source verified 435 ICSR, table 11-2  NDA section 15,  Table F3  
Source: Table 15 in TFLs 
Cohort 1    
 n = 68 at Baseline               61 at week 12                        46 at week 24   
       29 at week 36              18 at week 48  

Cohort 3      
n = 35 at baseline              27 at week 12                           22 at week 24  
      15 at week 36               10 at week 48

## Study 435 Week 48Secondary Efficacy Endpoints 

- Study 435 Week 48**Secondary Efficacy Endpoints **

- Through NDA Safety Update

## Study 435Survival

**Post-**
**transplant**

**185**

**170**

**155**

**135**

**127**

**117**

- 0.0

- 0.2

- 0.4

- 0.6

- 0.8

- 1.0

- 0

- 8

- 16

- 24

- 32

- 40

- 48

- 56

- 64

- 72

- 80

- 88

- 96

- Week

**109**

** ****94**

** ****84**

** ****69**

** ****55**

** ****42**

** ****28**

**Pre-**
**transplant**

** ****96**

** ****69**

** ****50**

** ****37**

** ****24**

** ****11**

**  ****5**

**  ****3**

**  ****2**

**  **

**  **

**  **

**  **

- Study 435**Survival**

**Post-transplant**

**Pre-transplant**

**Notes:**
Source verified 435 ICSR, table 11-2  NDA section 15,  Table F3  
Source: Table 15 in TFLs 
Cohort 1    
 n = 68 at Baseline               61 at week 12                        46 at week 24   
       29 at week 36              18 at week 48  

Cohort 3      
n = 35 at baseline              27 at week 12                           22 at week 24  
      15 at week 36               10 at week 48

## Study 435Patient Disposition 

- Study 435**Patient Disposition **

- Through NDA Safety Update

## Study 435Renal Laboratory Abnormalities by Week 96

- 			                              **Post-                Pre-**
**	****	****	****	****               ****transplant****       transplant**b
**	****	****	****	****                 ****(n=196)            (n=128)       **
- Serum creatinine
- 	Increase  0.5 mg/dLa                26                     15 Median change (mg/dL) 	           0.1                    0.2
- Serum phosphorus
- 	<1.5 mg/dLa	                         1   	                 0
- 	Median change (mg/dL)	           0.0                    0.3

- aConfirmed (two consecutive laboratory abnormalities)
- b Week 72

**Notes:**
Safety update version 2 TFLs  Table 15 

## Study 435 Post-Transplantation Patients with Confirmed Increases in                                  Serum Creatinine  0.5 mg/dL from Baseline (n=26)

- Concomitant cyclosporine or tacrolimus (n=26)
- Pre-existing medical condition placing patient at risk for renal dysfunction (n=11)
- Pre-existing renal impairment (CLcr< 50 mL/min) (n=8)
- Decompensated cirrhosis at baseline (n=4) or disease progression during treatment (n=6)
- Acute intercurrent medical event prior to onset of serum creatinine increase (n=13)
- Other concomitant nephrotoxic agents administered just prior to event (n=2)

- Through NDA Safety Update

## Study 435 Pre-Transplantation Patients with Confirmed Increases in                                  Serum Creatinine  0.5 mg/dL from Baseline (n=15)

- Serum creatinine increase post liver transplantation (n=11)
- Decompensated cirrhosis (n=3)
- Disease progression or addition of gentamicin
- Non-treatment emergent (n=1)
- 3 months following last dose of ADV

- Through NDA Safety Update

## Establish creatinine clearance at baseline to select appropriate initial dose interval
Monitor throughout therapy and adjust dose interval if required

- Monitor throughout therapy and adjust dose interval if required

- Adefovir Dipivoxil 10 mg ** **** ****Dosing Recommendations in Patients with ****or at risk of Renal Impairment**

## Study 435Summary

- Efficacy
- Change in HBV DNA and ALT similar to pivotal studies
- Normalization of albumin, bilirubin, and prothrombin time
- Stabilization or improvement in CPT Score
- No adefovir-associated resistance mutations identified through 48 weeks (n=55)
- Safety
- Safety profile consistent with advanced liver disease and co-morbidities
- Renal function should be monitored closely before and during therapy

## Lamivudine-Resistant HBVOther Supportive Studies

##  Study 461 Median Change from Baseline in HBV DNAa 

*a*Data through primary endpoint Week 16 reported in NDA

**p<0.001 compared**
**to LAM**

**ADV+LAM**
**(n=19)**

**ADV (n= 19)**

**LAM (n=19)**

-  Study 461 **Median Change from Baseline in HBV DNA****a**** **

- Weeks

- 0

- 8

- 16

- 24

- 32

- 40

- 48

- log10 copies/mL

## Study 461ALT Normalization Week 48

- ADV + LAM

- ADV

- LAM

- Patients
- (%)

- (n=19)

- (n=19)

- (n=19)

## Further Studies

## Further Studies

- Long term safety and efficacy up to 5 years
- Durability of seroconversion up to 5 years
- ADV dosing guidelines in chronic hepatitis B   patients with renal impairment
- Safety and efficacy in pediatrics, pregnancy, and other populations
- Drug-drug interaction studies
- Co-infection (Studies ACTG 5127, 5149)
- Combination therapy in treatment-naïve patients
- Resistance surveillance

## Adefovir Dipivoxil for the Treatment of Chronic Hepatitis B

- Efficacy and safety in HBeAg+ and HBeAg- compensated liver disease
- Efficacy and safety in patients with lamivudine-resistant HBV
- No adefovir-associated resistance mutations identified up to 48 weeks

## Proposed Indication

- Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease