# Presentation: 664570

## FDA Presentation

- Rafia Bhore, PhD
-    Statistician
- Tan Nguyen, MD, PhD
-    Medical Reviewer

## Outline of FDA Presentation

- Patient demographics
- Efficacy data assessment
- Summary of efficacy endpoint data
- Treatment effect on fibrosis
- Safety data assessment
- Adverse event profile
- Renal safety data
- Viral resistance
- Questions to the Advisory Committee

## Patient Demographics

- Prevalence of hepatitis B virus infection in the US (1988-1994)*:
- Black: 11.9%; Mexican American: 4.4%; White: 2.6%
- African and Hispanic Americans were not well represented in the drug development program.
- Study 437 US sites enrolled 15 (10%) “Black” patients and 3 (2%) “Other” patients.
- Study 435 US sites enrolled 2 “Black” and 2 “Other” patients (< 4% of patients).

- * McQuillan, et al. Am J Public Health 1999;89:14-8

## Efficacy Data Assessment

## Primary Endpoint: Liver BiopsyStudies 437, 438

- Adefovir treatment resulted in statistically significant improvement in liver histology at week 48.*
- Study 437: 67% in ADV 30 mg and 59% in ADV 10 mg versus 28% in placebo
- Study 438: 69% in ADV 10 mg versus 36% in placebo
- Positive treatment effect on fibrosis was evident.

- *  2-point decrease in Knodell NI score without worsening fibrosis.

## Necroinflammatory ScoreStudy 437

## Necroinflammatory ScoreStudy 438

## Fibrosis ScoreStudy 437

## Fibrosis Scores Study 438

## Secondary Endpoint: HBV DNA*Studies 437, 438

- Adefovir treatment resulted in suppression of HBV replication.
- Study 437: -4.38 in ADV 30 mg and -3.52 in ADV 10 mg versus -0.99 in placebo group at week 48
- Study 438: -3.54 in ADV 10 mg versus -1.23 in placebo group at week 48
- Further decrease of -0.5 with additional 48 weeks of treatment with adefovir 10 mg daily (incomplete data).
- Serum HBV DNA returned to baseline within 4 to 8 weeks following cessation of adefovir treatment.

- * Values shown as mean log10 copies/mL

## Serum HBV DNAStudy 437

## Serum HBV DNAStudy 438

## Secondary Endpoint: ALTStudies 437, 438

- Adefovir treatment resulted in a greater progressive decrease in serum ALT over time compared with placebo.
- The proportion of patient with normalization of ALT at week 48 was higher in the adefovir groups compared with placebo group.
- Serum ALT levels peaked in 2 to 3 months (“flare” of disease) after discontinuation of drug.

## Serum ALTStudy 437

## Serum ALTStudy 438

## Treatment Effect on Fibrosis Study 437

| Study 437 | Treatment Group |  |  |
| --- | --- | --- | --- |
|  | ADV 30 | ADV 10 | Placebo |
| Number of biopsy pairs
Ishak fibrosis score*:
  - Improved  1 point
  - Unchanged
  - Worsened  1 point | 147

61 (41%)
71 (48%)
15 (10%) | 152

52 (34%)
83 (55%)
17 (11%) | 149

28 (19%)
89 (60%)
32 (21%) |

- * Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).

## Treatment Effect on Fibrosis Study 438

| Study 438 | Treatment Group |  |
| --- | --- | --- |
|  | ADV 10 | Placebo |
| Number of biopsy pairs
Ishak fibrosis score*:
  - Improved by  1 point
  - Unchanged
  - Worsened by  1 point | 113

38 (34%)
70 (62%)
5 (4%) | 56

8 (14%)
28 (50%)
20 (36%) |

- * Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).

## Assessment of Treatment Effect on Fibrosis

- Compared with placebo, adefovir treatment was associated with:
- Smaller proportion of patients having progression of fibrosis.
- Greater proportion having regression of fibrosis.
- Consecutive liver biopsies within a year can detect treatment effect on fibrosis (i.e., disease stage).
- Serum HBV DNA and/or serum ALT as endpoints in evaluating drug therapy for chronic hepatitis B will not show treatment effect on fibrosis.

## Comments on Ranked Assessment of Liver Biopsy

- No detailed information on the degree of incremental biopsy changes
- Relatively more subjective than the rigid and structured scoring systems
- Results not completely concordant with the established scoring systems
- For example, 23 paired biopsies in study 438 with no changes in fibrosis by both Knodell and Ishak scores were rated by ranked assessment as “worse” or “better.”

## Safety Data Assessment

## Adverse Event ProfileStudies 437, 438

- Adverse event profiles of adefovir groups, particularly the 10 mg group, were comparable to placebo group.
- Fewer patients had markedly elevated ALT (shift from normal to grade 3 or grade 1 to grade 4) while on adefovir treatment.
- Study 437: 2% in adefovir groups; 4% in placebo group
- Study 438: 0% in adefovir groups; 4% in placebo group

## “Hepatic Flare”Studies 437, 438

- During treatment, 3% in placebo group compared with < 1% in adefovir groups had hepatic flare.
- After switching from adefovir to placebo, 35% in study 437 and 47% in study 438 had grade 3/4 ALT elevations.
- 3% had severe post-treatment hepatic flare.
- A 53-y/o man coinfected with HIV/HBV died of “hepatitis flare” 1 1⁄2 months after discontinuing adefovir (30 mg daily) because of nephrotoxicity.

## Renal Safety Data

- Data on treatment-emergent nephrotoxicity in studies 437, 438, and 435 will be presented.
- Analyses are based on confirmed increased in serum creatinine and/or decrease in serum phosphorus.
- Confirmed change: two consecutive abnormal measurements
- Phosphorus: decrease to < 2.0 mg/dL (grade 2 or more)
- Creatinine:  0.3 mg/dL versus  0.5 mg/dL increase from baseline

## Estimated Creatinine Clearance: 0.3 versus 0.5 mg/dL Cutoff

| Study | Baseline
Creatinine† | Reduction in Creatinine Clearance* |  |
| --- | --- | --- | --- |
|  |  |   0.3 mg/dL‡ |   0.5 mg/dL‡ |
| 437
  - Men   
  - Women | 
0.9
0.6 | 
26%
33% | 
36%
45% |
| 438
  - Men
  - Women | 
0.8
0.6 | 
24%
33% | 
35%
46% |

- * Cockcroft and Gault, 1976.
- † Mean baseline value, mg/dL; ‡ increase from baseline.

## NephrotoxicityStudy 437

| Study 437
(First 48 Weeks) | Treatment Group |  |  |
| --- | --- | --- | --- |
|  | ADV 30 | ADV 10  | Placebo |
| Number ITT patients
Creatinine   0.3 mg/dL*
  - Resolved to  0.2†
Phosphorus  < 2.0 mg/dL 
  - Resolved to  2.0  | 173
69 (40%)
27 (39%)
9 (5%)
9 (100%) | 309
13 (4%)
10 (77%)
0
N/A | 167
1 (<1%)
0
2 (1%)
2 (100%) |

- * Increase from baseline.
- † From baseline.

## NephrotoxicityStudy 438

| Study 438
(First 48 Weeks) | Treatment Group |  |
| --- | --- | --- |
|  | ADV 10 | Placebo  |
| Number ITT patients
Creatinine   0.3 mg/dL* 
  - Resolved to  0.2† 
Phosphorus  < 2.0 mg/dL    | 183
5 (3%)
2 (40%)
0 | 61
3 (5%)
1 (33%)
0 |

- * Increase from baseline.
- † From baseline.

## Nephrotoxicity in Year 2Studies 437, 438

- By K-M estimate, 9% of patients in adefovir 10 mg daily group in study 437 and 10% in study 438 developed increase in creatinine  0.3 mg/dL from baseline by week 96.
- Due to study design, no placebo control data beyond week 48 were available for comparison.

## NephrotoxicityStudy 435

- Study 435: open-label study of adefovir (10 mg or 5 mg) in post-liver transplantation (cohort A) and waitlisted for liver transplantation patients (cohort B) with 3TC-resistant HBV
- Complicated nephrotoxicity analysis
- Uncontrolled study design
- Advanced liver disease/liver transplantation
- Concomitant use of nephrotoxic antirejection drugs
- Abnormal renal dysfunction at baseline (cohort A)
- Limited data beyond week 48

##  Estimated Creatinine Clearance: 0.3 versus 0.5 mg/dL Cutoff

| Study 435 | Baseline
Creatinine† |  | Reduction in Creatinine Clearance* |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  |  |   0.3 mg/dL‡ |  |   0.5 mg/dL‡ |  |
| 
 - Men
 - Women | A | B | A | B | A | B |
|  | 1.3
1.1 | 0.9
0.5 | 18%
22% | 25%
30% | 27%
31% | 36%
42% |

- * Cockcroft and Gault, 1976.
- † Mean value, mg/dL. ‡ From baseline.

## NephrotoxicityStudy 435

| Kaplan-Meier Estimate | Treatment Cohort |  |
| --- | --- | --- |
|  | A | B† |
| Patients at risk, n
Creatinine   0.3 mg/dL*
  - by week 48
  - by week 96
Phosphorus  < 2.0 mg/dL
  - by week 48
  - by week 96 | 205

45 (26%)
56 (37%)

8 (4%)
10 (6%) | 139

25 (30%)
-

5 (5%)
- |

- * From baseline; † Insufficient data after week 48.

## NephrotoxicityStudy 435

| Kaplan-Meier Estimate | Treatment Cohort |  |
| --- | --- | --- |
|  | A | B* |
| Number of patients at risk
Creatinine   0.5 mg/dL†
  - by week 48
  - by week 96 | 205

16 (9%)
28 (23%) | 139

15 (19%)
- |

- * Insufficient data after week 48.
- † From baseline

## Profile of Patients with Creatinine Abnormality 

- 28 patients in cohort A had  0.5 mg/dL increase from baseline in creatinine.
- 100% in cohort A were on immunosuppressive drugs.
- 20 patients (71%) had renal dysfunction at baseline (creatinine clearance < 80 mL/min).
- 15 patients in cohort B had similar abnormality.
- 4 patients (27%) had renal dysfunction at baseline (creatinine clearance < 80 mL/min).
- 12 (80%) had increased creatinine levels shortly after liver transplantation and use of immunosuppressants.

## Resolution of Creatinine Abnormality

| Study 435 | Treatment Cohort |  |
| --- | --- | --- |
|  | A | B |
| Number of patients with  creatinine   0.5 mg/dL
  - Resolved to  0.3 mg/dL*
  - Not resolved†  | 
28
4 (14%)
24 (86%) | 
15
3 (20%)
12 (80%) |

- * From baseline; † At the last follow-up visit.

## Nephrotoxicity AssessmentStudy 435

- Confounding factors were present in patients with  0.5 mg/dL increase from baseline in creatinine.
- Concurrent use of nephrotoxic drugs, hepatic decompensation, hepatorenal syndrome, dehydration, acute post-op renal insult, etc.
- Nevertheless, the contributory role of adefovir could not be completely ruled out in:
- 22 cases (85%) in cohort A.
- 2 cases (13%) in cohort B.

## Nephrotoxicity: Case # 1Study 435

- 69 y/o man s/p liver transplant (1995) started adefovir 10 mg in 4/00.  Concurrent meds: cyclosporine, 3TC, nifedipine.  Adefovir was interrupted in 08/01, then restated at 5 mg.

| Date | 4/00 | 7/00 | 12/00 | 1/01 | 2/01 | 6/01 | 8/01 | 1/02 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Creatinine*
Cr. clearance†
Phosphorus‡ | 1.5
51.0
2.6 | 1.5
49.5
3.1 | 1.8
40.8
3.1 | 2.0
37.8
2.4 | 2.1
34.9
1.8 | 2.1
37.3
2.6 | 2.2
36.4
2.8 | 2.2
37.6
3.0 |

- * mg/dL; † Cockcroft and Gault, mL/min; ‡ mg/dL.

## Nephrotoxicity: Case # 2Study 435

- 65 y/o male s/p liver transplant (1991) started adefovir 10 mg in 11/99.  Concurrent meds: 3TC, cyclosporine, sirolimus, furosemide, antihypertensives, antibiotics.  Adefovir was reduced to 5 mg in 5/00.  Patient was hospitalized in late 11/00 with hepatorenal syndrome requiring dialysis, and died in 12/00.

| Date | 11/99 | 12/99 | 3/00 | 5/00 | 8/00 | 11/00 | 12/00 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Creatinine*
Cr. clearance†   | 1.9
40.3 | 1.8
43.1 | 2.3
33.1 | 3.0
25.2 | 3.1
25.3 | 4.7
16.0 | 6.0
12.6 |

- * mg/dL; † Cockcroft and Gault, mL/min.

## PK of Adefovir in Non-CHB Patients with Renal Dysfunction

| 

PK Study 473 | Renal Function Impairment Measured by Creatinine Clearance (mL/min) |  |  |  |
| --- | --- | --- | --- | --- |
|  | Normal
> 80
(109 ± 25) | Mild
50-79
(66 ± 16) | Moderate
30-49
(40 ± 9) | Severe
< 30
(18 ± 6) |
| Mean AUC0-*
Mean Cmax† | 200 ± 41
18 ± 3 | 266 ± 56
22 ± 4 | 455 ± 176
28 ± 9 | 1244 ± 629
52 ± 10 |

- * ng.hr/mL
- † ng/mL.

## Adefovir in CHB Patients with Renal Dysfunction

- Extrapolating from the PK study 473, adefovir 10 mg daily dose may result in significantly higher plasma levels in these patients than those with intact renal function.
- The applicant has proposed various dose modifications using the 10 mg-strength tablet based on the patient’s baseline creatinine clearance.
- Dose modification could be optimized with the availability of a lower strength formulation of the drug.

## Deaths

- Studies 437 and 438
- Four patients died after the clinical data cutoff date or after completion of 96 weeks of treatment.
- Study 435 (as of data cutoff date)
- Cohort A: 18 patients (9%) died.
- Cohort B: 24 (19%) died.
- Two of these patients (1 in cohort A and 1 in cohort B), also had treatment-emergent nephrotoxicity, in which the contributory role of adefovir could not be completely ruled out (*see* Appendix A, AC briefing document).

## HBV Viral Resistance

- Genotypic analysis of DNA sequences from clinical specimens may not detect all viral variants present at < 30% of a mixture of mutant and wild-type viruses.
- Resistance may be slow to emerge during treatment of HBV.
- It is possible that adefovir-resistant HBV mutants may emerge during longer-term treatment (> 48 weeks).

## Viral Resistance Issues

- Study 437
- The IC50 of H582Q, a mutant of conserved site (adefovir 10 mg group) was 3.6-fold higher than that of wild-type HBV.
- Patient had -5.9 log10 HBV DNA reduction at week 48.
- 2 patients with polymorphic site substitutions (E349E/Q, K487K/N) had only -1.3 and -1.8 log10 HBV DNA reduction at week 48.
- No compliance issues in these patients
- Other patients with 349Q (n = 9) or 487N (n = 225) substitution at baseline had adequate viral suppression.
- Study 460i
- 7 of 20 patients had R462G mutation in study 460i
- 2 of 20 had a substitution at N470 (T or L).

## HBV/HIV Co-infectionStudy 460i

- Historically*, *2 adefovir-resistant HIV mutations, K65R and K70E, were identified *in vitro.*
- Conferring 12-16 and 9-fold *in vitro* resistance, respectively.
- Of 13 patients in study 460i with available HIV RT genotype data:
- None harbored K65R or K70E.
- 5 patients had ZDV- or d4T-associated mutations (D67N, K70R, L210W).
- All had persistent M184V (3TC-associated HIV resistant) mutation.

## Risk-Benefit Assessment of Adefovir Treatment

- Relevant benefits of adefovir (10 mg daily) treatment compared with placebo:
- Improvement in liver biopsy histology at week 48
- Suppression of wild-type HBV and 3TC-resistant HBV replication (limited data on the latter) during treatment
- Improvement in transaminases during treatment
- Higher HBeAg seroconversion rate
- Lower incidence of significant ALT/AST elevations and hepatic flare during treatment
- No definitive adefovir-associated resistance mutations identified by week 48

## Risk-Benefit Assessment of Adefovir Treatment

- Relevant risks of adefovir (10 mg daily) treatment:
- Relatively low risk of nephrotoxicity in CHB patients with intact renal function and compensated liver disease by week 48, but increased risk with longer treatment duration
- Potentially significant risk of nephrotoxicity in patients with pre-existing renal dysfunction
- No data yet on PK, safety, and effectiveness of the dose modification scheme proposed by the applicant for CHB patient with renal dysfunction
- Potentially serious “flare” of disease associated with drug discontinuation

## Questions to the Advisory Committee

- 1.  Has the applicant demonstrated the safety of adefovir 10 mg daily dose for the treatment of CHB?
- Please discuss the safety of adefovir in patients with decompensated liver disease and patients with renal dysfunction at baseline.
- Please comment on the effectiveness of adefovir in patients with: compensated liver disease; decompensated liver disease; lamivudine-resistant hepatitis B virus; presumed pre-core mutation, and HBV/HIV co-infection.

- 3.  Based on the risk-benefit profile, does the Committee recommend approval of adefovir 10 mg daily dose for the treatment of CHB in adults?
- 4.  Are there any issues with the safety and effectiveness data that should be highlighted in the drug label?
- In particular, please discuss the use of adefovir in HBV/HIV coinfection and the potential risk of inducing NRTI resistance.
- 5.  Please recommend appropriate Phase 4 (post-marketing) studies for adefovir in CHB patients.
- Please discuss the adequacy of the applicant’s current program to detect the emergence of adefovir-resistant HBV and the optimal strategy for long-term resistance surveillance.

## Adefovir Review Team

**Marsha Holloman, Project Manager**
**Tan Nguyen, Clinical**
**Katie Laessig, Clinical Team Leader**
**Robert Kumi, Clinical Pharmacology **
**Kellie Reynolds, Clinical Pharmacology Team Leader**
**Rafia Bhore, Statistical**
**Greg Soon, Statistical Team Leader**
**Pritam Verma, Pharmacology**
**Jim Farrelly, Pharmacology Team Leader**
**Rao Kambhampati, Chemistry**
**Steve Miller, Chemistry Team Leader**
**Lalji Mishra, Microbiology**
**Jules O’Rear, Microbiology Team Leader**

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