Transcript Certican (everolimus) tablets Prophylaxis of Rejection in Heart Transplantation

Certican (everolimus) tablets
Prophylaxis of Rejection in Heart Transplantation
New Drug Application 21-628
Cardiovascular and Renal Drugs Advisory Committee
November 16, 2005
Clinical Safety Review
Arturo Hernandez, M.D.
Marc Cavaille-Coll, M.D., Ph.D.
Division of Special Pathogen and Transplant Products
Center for Drug Evaluation and Research
Food and Drug Administration
1
Safety Population
• All subjects who received at least one
dose of study medication: RAD* 1.5 mg,
n=209; RAD 3 mg, n=211; AZA, n=214.
• Adverse events were reported while
subjects were still on study medication,
serious adverse events while subjects
were still on study medication and up to
30 days after discontinuation.
*RAD = Certican (everolimus)
2
Targeted and Achieved Trough
Cyclosporine Concentrations in
Study B253
Cyclosporine Cmin (ng/mL)
400
350
Upper Limit
300
250
200
150
Azathioprine Control
100
ERL 0.75 mg b.i.d.
50
Lower Limit
ERL 1.5 mg b.i.d.
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time Post Transplant (month)
3
Concomitant Administration of
Immunosuppressive Agents Other
than Randomized Study Medication
and Neoral by WHO Preferred Drug Name
(ITT Population - 24 Month Analysis)
Methylprednisolone
Total
Antibody Therapy
Total
RAD 1.5
(n=209)
RAD 3
(n=211)
AZA
(n=214)
160
(76.5%)
142
(67%)
170
(79%)
86
(41%)
83
(39%)
95
(44%)
4
Premature Discontinuation from Study Medication
(Safety population - 12 and 24 Month Visits)
12 month visit
Time window: 312 - 415 days
Adverse events
24 month visit
Time window: up to 810 days
Adverse events
RAD 1.5
(n=209)
RAD 3
(n=211)
AZA
(n=214)
62
(29.7%)
33
(53.2%)
84
(39.8%)
46
(54.8%)
61
(28.5%)
28
(45.9%)
82
(39.2%)
104
(49.3%)
83
(38.8%)
43
(52.4%)
58
(55.8%)
40
(48.2%)
5
Patients Who Discontinue Study Medication
(24 Months, Safety Population)
Study B253
Reason for Discontinuation from
Study Medication
RAD 1.5 mg
(n=209)
RAD 3 mg
(n=211)
AZA
(n=214)
43 (52%)
58 (56%)
40 (48%)
Abnormal laboratory value(s)
9 (11%)
18 (17%)
10 (12%)
Unsatisfactory therapeutic effect
15 (18%)
3 (3%)
18 (22%)
Withdrawn consent
6 (7%)
11 (11%)
3 (4%)
Death
7 (5%)
9 (9%)
7 (8%)
82 (39%)
104 (49%)
83 (39%)
Adverse events
Total Discontinuation
from Study Medication
6
Dose Reductions from Study Medication
(Safety Population - 24 months analysis)
RAD 1.5 mg
(n= 209)
RAD 3 mg
(n=211)
AZA
(n=214)
Any Dose Reduction Total
121
(58%)
134
(64%)
112
(52%)
Adverse Event
56
(26.8%)
68
(32.2%)
20
(9.3%)
WBC Abnormality
51
(24.4%)
58
(27.5%)
71
(33.2%)
Platelet Abnormality
22
(10.5%)
25
(11.8%)
3
(1.4%)
7
Post Heart Transplant Morbidity in
the Safety Population
• Morbidity associated with immunosuppression:
infections, pneumonia
• Morbidity potentially associated with antiproliferative
effect of mTOR inhibition: wound site complications,
gastrointestinal hemorrhage, bone marrow effects,
lymphocele, pericardial and pleural complications.
• Morbidity potentially associated with the concurrent
use of mTOR inhibitors and cyclosporine: lipid
abnormalities, HUS, renal function impairment.
8
Infections: Safety Population - 24
Month Analysis
Type of Organism or
preferred term
RAD 1.5
(n=209)
RAD 3
(n=211)
AZA
(n=214)
160
(77%)
169
(80%)
154
(72%)
78 (37%)
85 (40%)
55 (26%)
18 (9%)
27 (13%)
19 (9%)
34 (16 %)
39 (19%)
69 (32%)
CMV infection
15 (7%)
15 (7%)
45 (21%)
Herpes simplex
17 (8%)
12 (6%)
23 (11%)
Any Infection
Bacterial
Fungal
Viral
9
Pneumonias
(Safety Population - 24 Month Analysis)
Preferred Term
RAD 1.5 mg
(n=209)
RAD 3 mg
(n=211)
AZA
(n=214)
29 (14%)
20 (10%)
6 (3%)
12(6%)
9 (4%)
3 (1%)
All types of pneumonia
(AE)
47 (23%)
38 (18%)
11 (5%)
Pneumonia (Severe )
13 (6%)
21 (10%)
4 (2%)
Pneumonia (DAE*)
1 (0.5%)
6(3%)
2 (1%)
Pneumonia (NSAE**)
33 (16%)
36 (17%)
11(5%)
Pneumonia NOS (AE)
Bacterial pneumonia (AE)
*DAE=discontinued due to AE (adverse event)
**NSAE=non-fatal SAE (serious adverse event)
10
Wound Site Related Complications
(Safety Population - 24 Month Analysis)
Preferred Term
RAD 1.5
(n= 209)
RAD 3
(n=211)
AZA
(n=214)
15 (7%)
11 (5%)
6 (3%)
9 (4%)
7 (3%)
5 (2%)
Wound dehiscence / wound
complication NOS (NSAE)
4 (2%)
5 (2%)
1(0.5%)
Incisional hernia nos (AE)
9 (4%)
8 (4%)
3 (1%)
Lymphocele
(AE)
10 (5%)
9 (4%)
2 (1%)
2 ( 1.0%)
3 (1.4%)
0
4 ( 2%)
9 (4%)
2 ( 1%)
Wound infection
(AE)
(NSAE)
(NSAE)
Pleural Effusion (NSAE)
11
Pericardial Complications
(Safety Population - 24 Month Analysis)
RAD 1.5
(n= 209)
RAD 3
(n=211)
AZA
(n=214)
48 (23%)
49 (23%)
36 (17%)
22 (11%)
16 (8%)
6 (3%)
6 (3%)
10 (5%)
3 (1%)
4 (2%)
9 (4%)
3 (1%)
Pericarditis* (NSAE)
2 (1%)
5 (2%)
2 (1%)
Mediastinitis (NSAE)
5 (2%)
6 ( 3%)
3 (1%)
System Organ Classification
or Preferred Term
Pericardial effusion
(AE)
(NSAE)
Cardiac tamponade
(AE)
(NSAE)
12
Gastrointestinal Hemorrhage
(Safety Population - 24 Month Analysis)
Preferred Term
RAD 1.5
(n=209)
RAD 3
(n=211)
AZA
(n=214)
GI HEMORRHAGE TOTAL (AE)
7 (3%)
16 (8%)
4 (2%)
Gastrointestinal hemorrhage NOS
(AE)
2 (1 %)
9 (4%)
3 (1%)
2 (1.0%)
5 (2.4%)
1 (0.5%)
0
3 (1%)*
0
3 (1%)
4 (2%)
0
2
1
0
(NSAE)
(DAE)
Gastric ulcer hemorrhage and
Hemorrhagic Gastritis
(AE)
(NSAE)
* One patient died from this cause
13
Hematological Toxicities
(Safety Population - 24 Month Analysis)
Preferred Term
RAD 1.5
(n=209)
RAD 3
(n=211)
AZA
(n=214)
70 (34%)
93 (44%)
58 (27%)
0
5 (2%)
1 (0.5%)
6 (2.9%)
17 (8%)
8 (4%)
43 (21%)
44 (21%)
63 (29%)
4 (2%)
5 (2%)
7 (3%)
NSAE
1 (0.5%)
4 (2%)
5 (2%)
Thrombocytopenia
AE
21 (10%)
37 (18%)
16(8%)
DAE
1 (0.5%)
4 (2%)
1 (0.5%)
NSAE
1 (0.5%)
1 (0.5%)
0
Anemia NOS
AE
DAE
NSAE
Leukopenia NOS
AE
DAE
14
Mean Hemoglobin [g/dL] and
Mean Leukocyte count [10^9 /L] by Visit
(Safety Population - 24 Month Analysis)
13
15
14
Leucocytes [10^9 /L]
Hemoglobin g/dL
12.5
12
11.5
11
10.5
13
12
11
10
9
8
7
10
6
5
9.5
0
3
6
9
12
15
18
21
0
24
RA D 1.5
RA D 3
6
9
12
15
18
21
24
Months Post-transplantation
Months Post-transplantation
Y
3
A ZA
15
Lipid Abnormalities
Mean Triglycerides and Cholesterol [mmol/L] by
Visit (Safety Population - 24 Month Analysis)
6.2
5.8
Cholesterol mmol/L
Triglycerides mmol/L
3.4
3.2
2.8
2.4
2.2
1.8
1.4
5.4
5
4.6
4.2
3.8
3.4
1
3
0
3
6
9
12
15
18
21
24
0
Months Post-transplantation
Y
RA D 1.5
RA D 3
3
6
9
12
15
18
21
Months Post-transplantation
A ZA
16
24
Mean Cockcroft-Gault Calculated Creatinine
Clearance Study B253
(Safety Population - 24-Month Analysis)
Creatinine Clearance mL/min
75
70
65
60
55
50
45
0
3
6
9
12
15
18
21
24
Months Post-transplantation
Y
RA D 1.5
RA D 3
AZA
17
Mean Cockcroft-Gault calculated Creatinine
Clearance Study B253
(Safety Population - 24-Month Analysis)
Calculated CrCl mL/min
72
70
68
66
64
62
60
58
56
54
52
50
-1
0
1
2
3
4
5
6
Months Post-transplantation
Y
RA D 1.5
RA D 3
AZA
18
Estimated Mean Creatinine Clearance
(mL/min) Change from Baseline
(Safety Population - 24 Month Analysis)
Change in CrCl from BL mL/min
5
0
-5
-10
-15
-20
0
3
6
9
12
15
18
21
24
Months Post-transplantation
Y
Change RA D 1.5
Cha nge A ZA
Change RA D 3
19
Study B253 and ISHLT Registry Data
Percentage of Patients with Creatinine  2.5 mg/dL
Percentage of Patients
Observed
30.0
25.0
20.0
Ever 1.5 mg
15.0
Ever 3.0 mg
7.7
10.0
9.1
7.8
AZA
5.0
0.0
B-253
ISHLT 04/94 ISHLT 01/00
to 12/99
to 06/03
20
Summary / Conclusions
• The impact of full dose cyclosporine plus everolimus
on renal function impairment was early and
persistent, and may not be reversible if renal toxicity
is sustained for a period of time sufficient to allow
irreversible changes to take place.
• Complications potentially related to antiproliferative
effects of everolimus such as wound healing
problems, pericardial complications and
gastrointestinal bleeding were also more common in
the everolimus arms.
21
Summary / Conclusions
• Pneumonias were more frequently
observed in the everolimus arms.
• Dyslipidemias occurred early or worsen
after drug exposure and persisted despite
the use of statins and attempts to optimize
lipid lowering therapy.
22
Summary / Conclusions
• Overall, the potential risks associated with
the use of the everolimus-cyclosporine
combinations studied in B-253 were felt to
outweigh the potential benefits.
• There is a need to develop regimens that
could minimize these toxicities while
providing adequate protection against
allograft rejection.
23
24
Lipid Abnormalities
Mean Low Density Lipoprotein [mmol/L] by Visit
(B-253 Safety Population - 24 Month Analysis)
3.3
Low Density Lipoprotein [mmol/L]
Low Density Lipoprotein [mmol/L]
3.5
3.3
3.1
2.9
2.7
2.5
2.3
2.1
1.9
1.7
1.5
3.2
3.1
120 mg/dL
3
116 mg/dl
2.9
2.8
108 mg/dL
2.7
-5
0
5
10
15
20
25
30
0
Months Post-transplantation
Y
RAD 1.5
RAD 3
5
10
15
20
25
Months Post-transplantation
AZA
25