Transcript Document 7120352

FDA Presentation
Rafia Bhore, PhD
Statistician
Tan Nguyen, MD, PhD
Medical Reviewer
1
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
2
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
3
Efficacy Data Assessment
4
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.
5
Necroinflammatory Score
Study 437
6
Necroinflammatory Score
Study 438
7
Fibrosis Score
Study 437
8
Fibrosis Scores
Study 438
9
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
10
Serum HBV DNA
Study 437
9
PLACEBO to 10mg
10mg ADV to 10mg
10mg ADV to PLACEBO
30mg ADV to PLACEBO
Mean Log10 HBVDNA (copies/mL)
8
7
6
5
4
3
2
1
0
Week
0 4 8
16
24
32
40
48
56
64
72
80
88
96
104
133
83
68
136
136
80
68
134
133
80
66
139
133
84
66
140
134
82
68
133
135
78
68
136
131
81
68
130
134
80
68
130
129
77
66
131
123
76
66
117
95
53
53
96
72
37
36
66
n=
PLACEBO to 10mg 138 136 136
10mgADV to 10mg 85 81 85
10mgADV to PLA
70 69 70
30mgADV to PLA
142 141 140
11
Serum HBV DNA
Study 438
9
PLACEBO to 10mg
10mg ADV to 10mg
10mg ADV to PLACEBO
Mean Log10 HBVDNA (copies/mL)
8
7
6
5
4
3
2
1
0
0
4
8
PLACEBO to 10mg 60
10mgADV to 10mg 80
60
79
38
56
77
36
Week
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
n=
10mgADV to PLA
40
57
76
36
57
80
39
57
75
40
55
76
38
58
80
39
59
77
40
57
78
39
59
79
40
60
80
40
56
79
39
60
77
39
57
79
39
59
80
40
49
71
35
39
55
25
28
37
18
19
24
11
12
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.
13
Serum ALT
Study 437
220
PLACEBO to
10mg ADV to
10mg ADV to
30mg ADV to
200
10mg
10mg
PLACEBO
PLACEBO
180
Mean ALT (U/L)
160
140
120
100
80
60
40
20
0
Week
0 4 8
16
24
32
40
48
56
64
72
80
88
96 104 112 120
PLACEBO to 10mg
138 137 137
136
137
133
131
134
133
129
132
127
126
113
94
66
27
10mgADV to 10mg
85 83 85
82
80
83
83
82
78
79
80
77
80
67
53
33
12
10mgADV to PLA
70 69 70
68
66
67
67
68
64
65
69
66
65
64
49
34
14
30mgADV to PLA
70 69 70
68
66
67
67
68
64
65
69
66
65
64
49
34
14
n=
14
Serum ALT
Study 438
220
PLACEBO to 10mg
10mg ADV to 10mg
10mg ADV to PLACEBO
200
180
Mean ALT (U/L)
160
140
120
100
80
60
40
20
0
Week
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
PLACEBO to 10mg 60
60
60
55
57
59
56
55
59
59
59
60
56
60
60
59
57
48
35
25
10mgADV to 10mg
80
78
79
77
80
76
77
76
78
77
79
80
80
77
79
80
79
65
51
34
10mgADV to PLA
40
40
37
38
40
40
38
36
40
39
39
40
39
39
40
40
39
34
25
14
n=
15
Treatment Effect on Fibrosis
Study 437
Study 437
Treatment Group
ADV 30 ADV 10
Placebo
Number of biopsy pairs
147
152
149
Ishak fibrosis score*:
- Improved  1 point 61 (41%) 52 (34%) 28 (19%)
- Unchanged
71 (48%) 83 (55%) 89 (60%)
- Worsened  1 point 15 (10%) 17 (11%) 32 (21%)
*
Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).
16
Treatment Effect on Fibrosis
Study 438
Study 438
Number of biopsy pairs
Ishak fibrosis score*:
- Improved by  1 point
- Unchanged
- Worsened by  1 point
*
Treatment Group
ADV 10
Placebo
113
56
38 (34%)
70 (62%)
5 (4%)
8 (14%)
28 (50%)
20 (36%)
Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).
17
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.
18
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.”
19
Safety Data Assessment
20
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
21
“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 ½ months after discontinuing
adefovir (30 mg daily) because of nephrotoxicity.
22
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
23
Estimated Creatinine Clearance:
0.3 versus 0.5 mg/dL Cutoff
Study
437
- Men
- Women
438
- Men
- Women
Baseline Reduction in Creatinine Clearance*
Creatinine†   0.3 mg/dL‡   0.5 mg/dL‡
0.9
0.6
26%
33%
36%
45%
0.8
0.6
24%
33%
35%
46%
*
Cockcroft and Gault, 1976.
† Mean baseline value, mg/dL; ‡ increase from baseline.
24
Nephrotoxicity
Study 437
Study 437
(First 48 Weeks)
Treatment Group
ADV 30 ADV 10 Placebo
Number ITT patients
173
309
167
Creatinine   0.3 mg/dL* 69 (40%) 13 (4%) 1 (<1%)
- Resolved to  0.2†
27 (39%) 10 (77%)
0
Phosphorus  < 2.0 mg/dL 9 (5%)
0
2 (1%)
9 (100%)
N/A
2 (100%)
- Resolved to  2.0
*
Increase from baseline.
† From baseline.
25
Nephrotoxicity
Study 438
Study 438
(First 48 Weeks)
Number ITT patients
Creatinine   0.3 mg/dL*
- Resolved to  0.2†
Phosphorus  < 2.0 mg/dL
Treatment Group
ADV 10
Placebo
183
61
5 (3%)
3 (5%)
2 (40%)
1 (33%)
0
0
* Increase
from baseline.
† From baseline.
26
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.
27
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
28
Estimated Creatinine Clearance:
0.3 versus 0.5 mg/dL Cutoff
Study 435
- Men
- Women
Baseline
Creatinine†
A
1.3
1.1
B
0.9
0.5
Reduction in Creatinine Clearance*
  0.3 mg/dL‡
A
B
18%
25%
22%
30%
  0.5 mg/dL‡
A
B
27%
36%
31%
42%
*
Cockcroft and Gault, 1976.
† Mean value, mg/dL. ‡ From baseline.
29
Nephrotoxicity
Study 435
Kaplan-Meier Estimate
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
*
Treatment Cohort
A
B†
205
139
45 (26%)
56 (37%)
25 (30%)
-
8 (4%)
10 (6%)
5 (5%)
-
From baseline; † Insufficient data after week 48.
30
Nephrotoxicity
Study 435
Kaplan-Meier Estimate
Treatment Cohort
A
B*
Number of patients at risk
205
139
Creatinine   0.5 mg/dL†
- by week 48
- by week 96
16 (9%)
28 (23%)
15 (19%)
-
*
Insufficient data after week 48.
† From baseline
31
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.
32
Resolution of Creatinine
Abnormality
Study 435
Number of patients with
creatinine   0.5 mg/dL
- Resolved to  0.3 mg/dL*
- Not resolved†
*
Treatment Cohort
A
B
28
4 (14%)
24 (86%)
15
3 (20%)
12 (80%)
From baseline; † At the last follow-up visit.
33
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.
34
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
Creatinine*
1.5 1.5 1.8 2.0 2.1 2.1
Cr. clearance† 51.0 49.5 40.8 37.8 34.9 37.3
Phosphorus‡
2.6 3.1 3.1 2.4 1.8 2.6
*
mg/dL; † Cockcroft and Gault, mL/min; ‡ mg/dL.
8/01
2.2
36.4
2.8
1/02
2.2
37.6
3.0
35
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
Creatinine*
1.9
1.8
2.3
Cr. clearance† 40.3 43.1 33.1
*
5/00
3.0
25.2
8/00 11/00 12/00
3.1
4.7
6.0
25.3 16.0 12.6
mg/dL; † Cockcroft and Gault, mL/min.
36
PK of Adefovir in Non-CHB
Patients with Renal Dysfunction
Renal Function Impairment Measured by
Creatinine Clearance (mL/min)
PK Study 473
Mean AUC0-*
Mean Cmax†
Normal
Mild
Moderate
> 80
50-79
30-49
(109 ± 25) (66 ± 16) (40 ± 9)
200 ± 41
18 ± 3
Severe
< 30
(18 ± 6)
266 ± 56 455 ± 176 1244 ± 629
22 ± 4
28 ± 9
52 ± 10
*
ng.hr/mL
† ng/mL.
37
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.
38
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).
39
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 wildtype 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).
40
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).
41
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.
42
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
43
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
44
Questions to the Advisory
Committee
45
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.
2. Has the applicant demonstrated the effectiveness
of adefovir 10 mg daily dose for the treatment of
CHB?
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.
46
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 (postmarketing) 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.
47
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
48
49