Safety Population

1

CerticanCertican (everolimus) tablets (everolimus) tabletsProphylaxis of Rejection in Heart TransplantationProphylaxis of Rejection in Heart Transplantation

New Drug Application 21-628New Drug Application 21-628

Cardiovascular and Renal Drugs Advisory Committee Cardiovascular and Renal Drugs Advisory Committee November 16, 2005November 16, 2005

Clinical Safety ReviewClinical Safety Review

Arturo Hernandez, M.D. Arturo Hernandez, M.D. Marc Cavaille-Coll, M.D., Ph.D.Marc Cavaille-Coll, M.D., Ph.D.

Division of Special Pathogen and Transplant ProductsDivision of Special Pathogen and Transplant ProductsCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration

CerticanCertican (everolimus) tablets (everolimus) tabletsProphylaxis of Rejection in Heart TransplantationProphylaxis of Rejection in Heart Transplantation

New Drug Application 21-628New Drug Application 21-628

Cardiovascular and Renal Drugs Advisory Committee Cardiovascular and Renal Drugs Advisory Committee November 16, 2005November 16, 2005

Clinical Safety ReviewClinical Safety Review

Arturo Hernandez, M.D. Arturo Hernandez, M.D. Marc Cavaille-Coll, M.D., Ph.D.Marc Cavaille-Coll, M.D., Ph.D.

Division of Special Pathogen and Transplant ProductsDivision of Special Pathogen and Transplant ProductsCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration

2

Safety PopulationSafety PopulationSafety PopulationSafety 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.

• 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)

3

Targeted and Achieved Trough Targeted and Achieved Trough Cyclosporine Concentrations in Cyclosporine Concentrations in

Study B253Study B253

Targeted and Achieved Trough Targeted and Achieved Trough Cyclosporine Concentrations in Cyclosporine Concentrations in


0 1 2 3 4 5 6 7 8 9 10 11 120

50

100

150

200

250

300

350

400

Azathioprine Control

ERL 0.75 mg b.i.d.Lower Limit

ERL 1.5 mg b.i.d.

Upper Limit

Time Post Transplant (month)

Cy

clo

sp

ori

ne

Cm

in (

ng

/mL

)

0 1 2 3 4 5 6 7 8 9 10 11 120

50

100

150

200

250

300

350

400

Azathioprine Control

ERL 0.75 mg b.i.d.Lower Limit

ERL 1.5 mg b.i.d.

Upper Limit

Time Post Transplant (month)

Cy

clo

sp

ori

ne

Cm

in (

ng

/mL

)

4

Concomitant Administration of Concomitant Administration of Immunosuppressive Agents Other Immunosuppressive Agents Other than Randomized Study Medication than Randomized Study Medication

and Neoral by WHO Preferred Drug Nameand Neoral by WHO Preferred Drug Name(ITT Population - 24 Month Analysis)(ITT Population - 24 Month Analysis)

Concomitant Administration of Concomitant Administration of Immunosuppressive Agents Other Immunosuppressive Agents Other than Randomized Study Medication than Randomized Study Medication

and Neoral by WHO Preferred Drug Nameand Neoral by WHO Preferred Drug Name(ITT Population - 24 Month Analysis)(ITT Population - 24 Month Analysis)

RAD 1.5 (n=209)

RAD 3(n=211)

AZA(n=214)

Methylprednisolone Total

160 (76.5%)

142 (67%)

170 (79%)

Antibody Therapy Total

86(41%)

83 (39%)

95 (44%)

5

Premature Discontinuation from Study Medication Premature Discontinuation from Study Medication (Safety population - 12 and 24 Month Visits)(Safety population - 12 and 24 Month Visits)

Premature Discontinuation from Study Medication Premature Discontinuation from Study Medication (Safety population - 12 and 24 Month Visits)(Safety population - 12 and 24 Month Visits)

RAD 1.5(n=209)

RAD 3(n=211)

AZA(n=214)

12 month visit Time window: 312 - 415

days

Adverse events

62 (29.7%)

33(53.2%)

84 (39.8%)

46(54.8%)

61 (28.5%)

28(45.9%)

24 month visitTime window: up to 810 days

82 (39.2%)

104 (49.3%)

83 (38.8%)

Adverse events 43

(52.4%)58

(55.8%)40

(48.2%)

6

Patients Who Discontinue Study MedicationPatients Who Discontinue Study Medication(24 Months, Safety Population)(24 Months, Safety Population)


Patients Who Discontinue Study MedicationPatients Who Discontinue Study Medication(24 Months, Safety Population)(24 Months, Safety Population)


Reason for Discontinuation from Study Medication

RAD 1.5 mg (n=209)

RAD 3 mg(n=211)

AZA(n=214)

Adverse events 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%)

Total Discontinuation from Study Medication

82 (39%) 104 (49%) 83 (39%)

7

Dose Reductions from Study Medication Dose Reductions from Study Medication (Safety Population - 24 months analysis)(Safety Population - 24 months analysis)

Dose Reductions from Study Medication Dose Reductions from Study Medication (Safety Population - 24 months analysis)(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%)

8

Post Heart Transplant Morbidity in Post Heart Transplant Morbidity in the Safety Populationthe Safety Population

Post Heart Transplant Morbidity in Post Heart Transplant Morbidity in the Safety Populationthe 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.

• 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.

9

Infections: Safety Population - 24 Infections: Safety Population - 24 Month AnalysisMonth Analysis

Infections: Safety Population - 24 Infections: Safety Population - 24 Month AnalysisMonth Analysis

Type of Organism or preferred term

RAD 1.5 (n=209)

RAD 3(n=211)

AZA(n=214)

Any Infection 160 (77%)

169 (80%)

154 (72%)

Bacterial 78 (37%) 85 (40%) 55 (26%)

Fungal 18 (9%) 27 (13%) 19 (9%)

Viral 34 (16 %) 39 (19%) 69 (32%)

CMV infection 15 (7%) 15 (7%) 45 (21%)

Herpes simplex 17 (8%) 12 (6%) 23 (11%)

10

Pneumonias Pneumonias (Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Pneumonias Pneumonias (Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Preferred Term RAD 1.5 mg (n=209)

RAD 3 mg(n=211)

AZA(n=214)

Pneumonia NOS (AE) 29 (14%) 20 (10%) 6 (3%)

Bacterial pneumonia (AE) 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%)

*DAE=discontinued due to AE (adverse event)

**NSAE=non-fatal SAE (serious adverse event)

11

Wound Site Related ComplicationsWound Site Related Complications (Safety Population - 24 Month Analysis) (Safety Population - 24 Month Analysis)

Wound Site Related ComplicationsWound Site Related Complications (Safety Population - 24 Month Analysis) (Safety Population - 24 Month Analysis)

Preferred Term RAD 1.5 (n= 209)

RAD 3(n=211)

AZA(n=214)

Wound infection(AE) 15 (7%) 11 (5%) 6 (3%)

(NSAE) 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%)

(NSAE) 2 ( 1.0%) 3 (1.4%) 0

Pleural Effusion (NSAE) 4 ( 2%) 9 (4%) 2 ( 1%)

12

Pericardial ComplicationsPericardial Complications(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Pericardial ComplicationsPericardial Complications(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

System Organ Classification or Preferred Term

RAD 1.5 (n= 209)

RAD 3(n=211)

AZA(n=214)

Pericardial effusion (AE) 48 (23%) 49 (23%) 36 (17%)

(NSAE) 22 (11%) 16 (8%) 6 (3%)

Cardiac tamponade (AE) 6 (3%) 10 (5%) 3 (1%)

(NSAE) 4 (2%) 9 (4%) 3 (1%)

Pericarditis* (NSAE) 2 (1%) 5 (2%) 2 (1%)

Mediastinitis (NSAE) 5 (2%) 6 ( 3%) 3 (1%)

13

Gastrointestinal Hemorrhage Gastrointestinal Hemorrhage (Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Gastrointestinal Hemorrhage Gastrointestinal Hemorrhage (Safety Population - 24 Month Analysis)(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%)

(NSAE) 2 (1.0%) 5 (2.4%) 1 (0.5%)

(DAE) 0 3 (1%)* 0

Gastric ulcer hemorrhage and Hemorrhagic Gastritis

(AE) 3 (1%) 4 (2%) 0

(NSAE) 2 1 0

* One patient died from this cause

14

Hematological ToxicitiesHematological Toxicities(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Hematological ToxicitiesHematological Toxicities(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Preferred Term RAD 1.5 (n=209)

RAD 3(n=211)

AZA(n=214)

Anemia NOS AE 70 (34%) 93 (44%) 58 (27%)

DAE 0 5 (2%) 1 (0.5%)

NSAE 6 (2.9%) 17 (8%) 8 (4%)

Leukopenia NOS AE 43 (21%) 44 (21%) 63 (29%)

DAE 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

15

Mean Hemoglobin [g/dL] and Mean Hemoglobin [g/dL] and Mean Leukocyte count [10^9 /L] by Visit Mean Leukocyte count [10^9 /L] by Visit (Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Mean Hemoglobin [g/dL] and Mean Hemoglobin [g/dL] and Mean Leukocyte count [10^9 /L] by Visit Mean Leukocyte count [10^9 /L] by Visit (Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

5

6

7

8

9

10

11

12

13

14

15

Leuc

ocyt

es [1

0^9

/L]

0 3 6 9 12 15 18 21 24

Months Post-transplantation

Y RAD 1.5 RAD 3 AZA

9.5

10

10.5

11

11.5

12

12.5

13

Hem

oglo

bin

g/dL

0 3 6 9 12 15 18 21 24


16

Lipid AbnormalitiesLipid AbnormalitiesMean Mean TriglyceridesTriglycerides and and CholesterolCholesterol [mmol/L] by [mmol/L] by

Visit (Safety Population - 24 Month Analysis)Visit (Safety Population - 24 Month Analysis)

Lipid AbnormalitiesLipid AbnormalitiesMean Mean TriglyceridesTriglycerides and and CholesterolCholesterol [mmol/L] by [mmol/L] by

Visit (Safety Population - 24 Month Analysis)Visit (Safety Population - 24 Month Analysis)

1

1.4

1.8

2.22.4

2.8

3.23.4

Trigly

cerides m

mol/L

0 3 6 9 12 15 18 21 24


3

3.4

3.8

4.2

4.6

5

5.4

5.8

6.2

Cho

lest

erol

mm

ol/L

0 3 6 9 12 15 18 21 24


Y RAD 1.5 RAD 3 AZA

17

Mean Cockcroft-Gault Calculated Creatinine Mean Cockcroft-Gault Calculated Creatinine Clearance Study B253 Clearance Study B253

(Safety Population - 24-Month Analysis)(Safety Population - 24-Month Analysis)

Mean Cockcroft-Gault Calculated Creatinine Mean Cockcroft-Gault Calculated Creatinine Clearance Study B253 Clearance Study B253


45

50

55

60

65

70

75C

reatinin

e C

leara

nce m

L/m

in

0 3 6 9 12 15 18 21 24


Y RAD 1.5 RAD 3 AZA

18

Mean Cockcroft-Gault calculated Creatinine Mean Cockcroft-Gault calculated Creatinine Clearance Study B253 Clearance Study B253


Mean Cockcroft-Gault calculated Creatinine Mean Cockcroft-Gault calculated Creatinine Clearance Study B253 Clearance Study B253


Y RAD 1.5 RAD 3 AZA

50

52

54

56

58

60

62

64

66

68

70

72C

alc

ula

ted C

rC

l m

L/m

in

-1 0 1 2 3 4 5 6


19

Estimated Mean Creatinine Clearance Estimated Mean Creatinine Clearance (mL/min) Change from Baseline (mL/min) Change from Baseline

(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

Estimated Mean Creatinine Clearance Estimated Mean Creatinine Clearance (mL/min) Change from Baseline (mL/min) Change from Baseline

(Safety Population - 24 Month Analysis)(Safety Population - 24 Month Analysis)

-20

-15

-10

-5

0

5C

hange in C

rC

l fr

om

BL m

L/m

in

0 3 6 9 12 15 18 21 24


Y Change RAD 1.5 Change RAD 3

Change AZA

20

Study B253 and ISHLT Registry Data Study B253 and ISHLT Registry Data Percentage of Patients with Creatinine Percentage of Patients with Creatinine 2.5 mg/dL 2.5 mg/dL

Study B253 and ISHLT Registry Data Study B253 and ISHLT Registry Data Percentage of Patients with Creatinine Percentage of Patients with Creatinine 2.5 mg/dL 2.5 mg/dL

9.1 7.87.7

0.0

5.0

10.0

15.0

20.0

25.0

30.0

B-253 IS HLT 04/94to 12/99

IS HLT 01/00to 06/03

Per

cen

tag

e o

f P

atie

nts

O

bse

rved

Ever 1.5 m g

Ever 3.0 m g

AZA

21

Summary / ConclusionsSummary / ConclusionsSummary / ConclusionsSummary / 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.

• 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.

22


• 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.

• 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.

23


• 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.

• 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.

24

25

Lipid AbnormalitiesLipid AbnormalitiesMean Low Density Lipoprotein [mmol/L] by VisitMean Low Density Lipoprotein [mmol/L] by Visit(B-253 Safety Population - 24 Month Analysis)(B-253 Safety Population - 24 Month Analysis)

Lipid AbnormalitiesLipid AbnormalitiesMean Low Density Lipoprotein [mmol/L] by VisitMean Low Density Lipoprotein [mmol/L] by Visit(B-253 Safety Population - 24 Month Analysis)(B-253 Safety Population - 24 Month Analysis)

2.7

2.8

2.9

3

3.1

3.2

3.3

Low

Density

Lip

opro

tein

[m

mol/L

]

0 5 10 15 20 25


116 mg/dl

108 mg/dL

120 mg/dL

Y RAD 1.5 RAD 3 AZA

1.5

1.7

1.9

2.1

2.3

2.5

2.7

2.9

3.1

3.3

3.5

Low

Density

Lip

opro

tein

[m

mol/L

]

-5 0 5 10 15 20 25 30


Documents

Safety Population