MEMORANDUM

DATE: July 19, l999

TO: Antiviral Drugs Advisory Committee members

FROM: Rosemary Tiernan, M.D., Medical Officer

Cheryl Dixon, Ph.D., Statistician

VIA: Mark Goldberger, M.D., M.P.H., Director

Division of Special Pathogens and Immunologic Drug Products

SUBJECT: Clinical/Statistical Background Information for 27 July l999 Advisory Committee Meeting

Drug name: Rapamune® (sirolimus) Oral Solution

NDA-21-083

Indication: Prevention of acute rejection in renal transplantation

Applicant: Wyeth-Ayerst Laboratories

 

  1. Introduction:
  2. This section of the FDA briefing package will focus on several

    specific safety issues that arose during the sirolimus Phase III trials i.e. pivotal studies 301 and 302. Comments regarding the design and conduct of the clinical studies will be rendered, and specific safety issues will be addressed in order to assist in a final risk/benefit analysis of the two proposed sirolimus doses.

    Please refer to the Applicant’s summary of safety data as presented in their Advisory Committee briefing package. Please also refer to the FDA Statistical Review which addresses the overall safety and efficacy of sirolimus oral solution, when used in conjunction with cyclosporine (CsA) and corticosteroids, to prevent acute rejection in the renal transplant recipient.

    The recommended fixed maintenance dose for sirolimus is 2 mg/day (SRL 2). In addition, the Applicant is recommending a fixed maintenance dose of 5 mg/day (SRL 5) for patients with a "high risk for acute rejection" such as African-American patients, highly HLA mismatched patients, those with high panel reactive antibodies (PRA) and patients with a second transplant.

  3. Design of Clinical Studies

The Applicant’s briefing package summarizes the differences between pivotal studies 301 and 302. It is important to note that both studies were randomized, double-blind, controlled trials. The U.S. trial, study 301 (719 patients), utilized azathioprine as an active control. Study 302 (576 patients), which included sites in the U.S., Europe and Canada, utilized a placebo control. The objective endpoints for both study 301 and 302 included a composite endpoint of acute rejection, graft loss (defined as nephrectomy or dialysis for 56 or more consecutive days ) or death at 6 months and patient and graft survival at 12 months.

Reviewer’s Note: A strength of study 301 was its enrollment of adequate numbers of African-American patients. The African-American segment of the U.S. transplant population is 21.3% according to 1998 UNOS data. In study 301, African-Americans comprised 23.1% of the study population.

One potential weakness of U.S. study 301 was that, although the randomization at 48 hours post-transplant may have eliminated patients who sustained surgical site complications, it also may have eliminated "higher risk" patients such as those with "delayed graft function" (maintained on dialysis for at least one week post-transplant). However, study 302 randomized patients prior to transplantation and thus should capture those with delayed graft function.

Additional important points regarding studies 301 and 302:

Trial Design

  1. Antibody induction was prohibited in study 301 and 302.
  2. 2) Antibody therapy (OKT3 or Anti-thymocyte globulin) was used for episodes of acute rejection, if the patient had failed an initial steroid "pulse". No mycophenolate mofetil or tacrolimus was allowed.

    3) Study drug was administered as a loading dose of 15 mg and a fixed dose of 5 mg/day or as a loading dose of 6 mg with a fixed dose of 2 mg/day. Refer to section 7.10.8 through 7.10.8.3 of the Applicant’s Advisory briefing package for a complete discussion of the issues related to drug exposure, dose reduction and discontinuations for Rapamune.

    4) In the initial NDA submission, fourteen patients had been "lost-to follow-up" in study 301. However, over the past 6 months, the Applicant was able to obtain follow-up data on all patients except 5 in study 301: one in the SRL 2mg arm , two in the SRL 5 mg arm and one in the azathioprine arm. If patients were lost to follow-up, they were counted as efficacy failures. No patients were lost to follow-up in study 302.

    5) The Division of Scientific Investigations inspected three U.S. study sites and one overseas study site and found several minor problems with the conduct of studies 301 and 302. No major protocol deviations or violations were identified that would preclude accepting data from any individual study site. However, it should be noted that one study 301 investigator had a high rate of discontinuations at his site because he felt that when the patient’s renal function began to worsen, it was imperative to discontinue study drug and initiate an alternative immunosuppressive regimen. There were also some difficulties in adhering to the time of randomization in study 302. Consequently, 67 of the 576 (12%) study 302 patients were assigned to treatment at one or more days after transplantation—as opposed to being randomized prior to transplantation. The Applicant states that an analysis of the primary endpoint, after these patients were excluded, did not show a difference in the overall results. Consequently, it is doubtful that this will bias the study results.

    6) Concomitant dosing for cyclosporine and corticosteroids was rendered as outlined in the Applicant’s briefing package. The target cyclosporine troughs were slightly different for the first month in studies 301 and 302.

    Target cyclosporine troughs were:

    Study 301 Study 302

    Month 1 200-350 ng/ml 200-400 ng/ml

    Month 2-3 200-300 ng/ml 200-300 ng/ml

    >Month 3 150-250 ng/ml 150-250 ng/ml

    Corticosteroids were dosed as :

    pulse corticosteroids on days 1-4

    tapering to 10mg/day by month 6

    between 5-10 mg/day by month 12

    Azathioprine, the active comparator in study 301, was dosed at 2-3mg/kg/day.

    7) Prophylaxis for Pneumocystis carinii pneumonia was mandated for one year post- transplant during this trial. CMV prophylaxis for the "high risk" patient i.e. the CMV negative recipient of a CMV positive donor kidney, was mandated for 3 months post transplant (using center-specific therapy such as ganciclovir or acyclovir) and was also recommended for lower risk renal transplant recipients. Prophylaxis for urinary tract infection was routinely utilized for 6 weeks post-transplant and the study centers chose the antibiotic according to their standard practice.

    Demographics

    1) Multi-organ transplants and high risk patients, as defined by the criteria of high PRA or second transplant were excluded from studies 301 and 302.

  3. Study 301 had 35.2% living related (LRT) and living unrelated donors (LURT).

Study 302 had 23% LRT and LURT.

3) Studies 301 and 302 enrolled different ethnic populations and thus there may be differences in dietary habits and reporting of adverse events.

4) A significantly higher proportion of African-Americans and females was assigned to the azathioprine arm in study 301.

5) The majority of renal allograft donors were of white ethnic background and were CMV positive.

6) Glomerulonephritis and hypertension were the most common etiologies for end stage renal disease in renal tranplant recipients.

 

  1. EFFICACY ISSUES

Please refer to the FDA statistical review on efficacy for further discussion regarding the results presented in the tables outlined below.

 

 

Table 2

Efficacy Failure at 6 months (Study 301)

 

SRL 2 mg/day

(n=284)

SRL 5 mg/day

(n=274)

Azathioprine

(n=161)

Overall rate of efficacy failure, n(%)

Acute rejection

Graft loss

Death

Lost to follow-up

53 (18.7)

47 (16.5)

3 (1.1)

2 (0.7)

1 (0.4)

46 (16.8)

31 (11.3)

8 (2.9)

5 (1.8)

2 (0.7)

52 (32.3)

47 (29.2)

4 (2.5)

0

1 (0.6)

CMH p-value

0.002

0.001

 

Relative risk (stratified)

(97.5% CI)

0.61

(0.42, 0.88)

0.58

(0.39, 0.85)

 

Stratified differences in rates

(97.5% CI)

-13.3

(-23.2, -3.4)

-14.6

(-24.5, -4.7)

 

Breslow-Day p-value

0.290

0.310

 

Reviewer’s note: Sirolimus 2 mg/day and sirolimus 5 mg/day both significantly reduced the incidence of efficacy failure compared to azathioprine and placebo during the first 6 months post-transplant.

Table 3

Efficacy Failure at 6 months Stratified by Race (Study 301)

 

SRL 2 mg/day

(n=284)

SRL 5 mg/day

(n=274)

Azathioprine

(n=161)

Overall rate of efficacy failure, n(%)

Blacks

Non-blacks

53 (18.7)

22/63 (34.9)

31/221 (14.0)

46 (16.8)

11/61 (18.0)

35/213 (16.4)

52 (32.2)

14/42 (33.3)

36/119 (30.3)

CMH p-value

0.002

0.001

 

Breslow-Day p-value

0.024

0.928

 

Reviewer’s note: The rate of efficacy failure is slightly higher in African-American patients treated with sirolimus 2 mg/day ( 34.9%) when compared to azathioprine (33.3%).

Table 4

Patient and Graft Survival at 12 months (Study 301)

 

SRL 2 mg/day

(n=284)

SRL 5 mg/day

(n=274)

Azathioprine

(n=161)

Patient and Graft survival, n(%)

Graft loss

Death

269 (94.7)

8

7

254 (92.7)

12

8

151 (93.8)

8

2

Fisher’s exact p-value

0.674

0.845

 

Relative risk

(97.5% CI)

0.85

(0.35, 2.07)

1.175

(0.51, 2.72)

 

Differences in rates

(97.5% CI)

0.9

(-4.8, 6.6)

-1.1

(-7.1, 4.9)

 

 

 

Table 12

Patient and Graft Survival at 12 months (study 302)

 

RapamuneÒ 2 mg/day

(n=227)

RapamuneÒ 5 mg/day

(n=219)

Placebo

(n=130)

Patient and Graft survival, n(%)

Graft loss

Death

204 (89.9)

15

8

199 (90.9)

11

9

114 (87.7)

9

7

Fisher’s exact p-value

0.597

0.366

 

Relative risk

(97.5% CI)

0.82

(0.41, 1.64)

0.74

(0.37, 1.51)

 

Differences in rates

(97.5% CI)

2.2

(-6.3, 10.7)

3.2

(-5.2, 11.6)

 

Reviewer’s note: Sirolimus 2 mg/day demonstrated equivalence to azathioprine and placebo controls in 1 year patient and graft survival. However, please note in Table 4, that for study 301 in the sirolimus 5 mg/day arm, the lower limit of the 97.5% confidence interval is between a delta of –5 and –10 and not between the target 0 and –5 . In study 302, the lower limits of the 97.5 % confidence intervals were –6.3 and

–5.2 for sirolimus 2mg and 5mg , respectively. Therefore, one can exclude no more than a 7% overall decrease in survival for the sirolimus. In addition, for sirolimus 5 mg in study 301, the relative risk for efficacy failure is also slightly greater than 1.0 (1.175). Thus, the overall treatment effects observed on acute rejection were not associated with a detectable improvement in patient or graft survival at one year.

Table 7

Efficacy Failure at 6 months

Selected subgroups (Study 301)

Subgroup

SRL 2 mg/day

(n=284)

SRL 5 mg/day

(n=274)

Azathioprine

(n=161)

Recipient Gender

Female

Male

14/76 (18.4)

39 /208 (18.8)c

20/103 (19.4)

26/171 (15.2)c

17/71 (23.9)

35/90 (38.9)

Donor Source

Cadaver

Living Related

Living Unrelated

39/180 (21.7)

10/86 (11.6)c

4/18 (22.2)

28/167 (16.8)a

15/83 (18.1)b

3/24 (12.5)

34/119 (28.6)

14/33 (42.4)

4/9 (44.4)

Number of HLA mismatches

0 to 2

3 to 6

12/69 (17.4)

41/215 (19.1)c

8/69 (11.6)

38/205 (18.5)c

7/42 (16.7)

45/119 (37.8)

a: Comparison with azathioprine statistically significant at less than 0.05.

b: Comparison with azathioprine statistically significant at less than 0.01

c: Comparison with azathioprine statistically significant at less than 0.001.

 

 

 

 

 

 

Table 15

Efficacy Failure at 6 months

Selected subgroups (Study 302)

Subgroup

SRL 2 mg/day

(n=227)

SRL 5 mg/day

(n=219)

Placebo

(n=130)

Recipient Race

Blacks

Non-blacks

8/26 (30.8)

60/201 (29.9)c

9/27 (33.3)

47/192 (24.5)c

5/13 (38.5)

57/117 (48.7)

Recipient Gender

Female

Male

27/79 (34.2)

41/148 (27.7)c

21/70 (30.0)

35/149 (23.5)c

16/39 (41.0)

46/91 (50.6)

Donor Source

Cadaver

Living Related

Living Unrelated

54/173 (31.2)a

14/39 (35.9)

0/15 (0.0)b

48/174 (27.6)b

5/29 (17.2)b

3/16 (18.8)

43/99 (43.4)

16/27 (59.3)

3/4 (75.0)

Number of HLA mismatches

0 to 2

3 to 6

13/51 (25.5)

55/176 (31.3)c

10/60 (16.7)

46/159 (28.9)c

7/30 (23.3)

55/100 (55.0)

a: Comparison with azathioprine statistically significant at less than 0.05.

b: Comparison with azathioprine statistically significant at less than 0.01

c: Comparison with azathioprine statistically significant at less than 0.001.

Reviewer’s note: Among women in study 301, there was not a statistically significant difference in efficacy failure between treatment groups. Though not statistically significant, a larger proportion of subjects in study 301 received organs from living donors in the sirolimus treatment groups compared to the azathioprine control group: sirolimus 2 mg (104/284 or 36.6%), sirolimus 5 mg (107/274 or 39.1%) and azathioprine (42 /161 or 26.1%)

Patients with >3- 6 HLA mismatches had significant improvement with either dose of sirolimus when compared to azathioprine in study 301 or to placebo in study 302. Please see Table 15 which has the study 302 results. However, recipients at higher risk for acute rejection, including recipients of cadaveric kidneys and those with more than 2 HLA mismatches, did not significantly benefit from the 5 mg dose compared to the 2 mg dose of sirolimus.

Additional points regarding the efficacy of sirolimus include:

1) Pharmacodynamic analysis does not demonstrate that African-American patients had lower trough levels of either cyclosporine or sirolimus. The Applicant proposes that there may be an efficacy benefit in monitoring sirolimus blood levels and attempting to achieve a higher trough i.e. closer to 20 ng/ml. The mean trough levels achieved with sirolimus 2 mg/day were 8.59 ng/ml and with sirolimus 5 mg/day were 17.3 ng/ml. A trough level of 10 ng/ml may be necessary in order to attain a significant efficacy benefit. This issue of how to optimally dose a "high risk patient" requires further investigation especially since studies 301 and 302 were not designed to address the issue of efficacy in the "high risk population". Monitoring of sirolimus trough levels is recommended for patients with hepatic disease, reduced or elevated sirolimus clearance, pediatric age, necessity of cyclosporine dose reduction or discontinuation or the need to administer concomitant medications that may have a substantial effect on sirolimus metabolism. Sirolimus trough levels greater than 30 ng/ml have been associated with an increased rate of side effects.

2) Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and

p-glycoprotein. Please refer to the Applicant’s briefing package for a full description of the metabolism and drug interactions with this product.

Reviewer’s note: Additional studies are needed to ascertain the factors that contribute to the higher rate of efficacy failure in the black patients who received sirolimus 2 mg/day. The Applicant is recommending that the higher dose of sirolimus 5 mg/day be used in black patients as well as other "high risk" groups. However, the factors that cause this reduced efficacy in black patients do not appear to be related to differences in sirolimus pharmacokinetics. Consequently, any recommendations for an increased sirolimus or cyclosporine dose must be weighed against the side-effects of these drugs i.e. the problems with "over-immunosuppression" and drug toxicity.

  1. In studies 301 and 302, the use of anti-T-lymphocyte antibody therapies to treat the first biopsy-confirmed acute rejection during the first 6 months post-transplant was significantly reduced for sirolimus 5 mg compared to the control groups.

Reviewer’s note: This decrement in the use of anti- T-lymphocyte antibody preparations was a secondary study endpoint and did not translate into improved survival, decreased rate of infection or decreased rate of post-transplant lymphoproliferative disease (PTLD). In fact, the incidence of PTLD was highest in the sirolimus 5 mg study arm.

 

  1. Safety

Of the 1295 patients enrolled in studies 301 and 302, 1260 patients received randomized treatment and were considered evaluable for safety.

  1. Please refer to the Applicant’s briefing package for more detailed information regarding deaths and graft loss.
  2. The most common reasons for deaths were vascular (cardiovascular or cerebrovascular) and infection. The overall death rate in study 301 and 302 was 3.7%. This included death rates of : 3.1% sirolimus 2 mg/day

    4.5% sirolimus 5 mg/day

    1.9% Azathioprine

    5.4% Placebo

     

     

     

     

     

     

     

     

    Table 3 Study 301

    Summary of Deaths, Graft Loss, Malignancy, Life-Threatening Adverse Events

    Event

    SRL

    2 mg/day

    (n=284)

    SRL

    5 mg/day

    (n=274)

    Aza

    (n=161)

    Death

    3 (1.1)

    8 (2.9)

    3 (1.9)

    Graft Loss

    4 (1.4)

    12 (4.3)

    7 (4.3)

    Malignancy

    1 (0.4)

    2 (0.7)

    3 (1.9)

    Life-Threatening Adverse Event

    6 (2.1)

    4 (1.5)

    0

           

     

    Table 4 Study 302

    Summary of Deaths, Graft Loss, Malignancy, Life-Threatening Adverse Events

     

    Event

    SRL

    2 mg/day

    (n=227)

    SRL

    5 mg/day

    (n=219)

    Placebo

    (n=130)

    Death

    5 (2)

    8(4)

    6 (5)

    Graft Loss

    16 (7)

    16 (7)

    15 (12)

    Malignancy

    3 (1)

    2 (1)

    1 (1)

    Life-Threatening Adverse Event

    1 (<1)

    2 (1)

    1 (1)

     

  3. The most common etiology of graft loss was death with a functioning graft and the second most common etiology was acute rejection. Please refer to the Applicant’s briefing package for a full discussion.
  4. The incidence of malignancy (post-transplant lymphoproliferative disease PTLD/lymphoma) during the first year post-transplant was higher in the sirolimus 5 mg/day group with an overall incidence of 1.4%. The rates of PTLD in this trial were similar to that which has been reported in other trials of immunosuppressive agents.

Reviewer’s note: Epstein-Barr virus (EBV) serologies were not collected on patients at study onset and thus I can not comment on whether the cases of PTLD were in "high risk" EBV-negative transplant recipients of EBV-positive donor kidneys.

  1. Please refer to the Applicant’s briefing package regarding a discussion on discontinuation of study drug. The most frequent reason for discontinuation in the sirolimus 2 mg/day group was an unsatisfactory response and in the sirolimus 5 mg group it was an adverse event. Tables 5 and 6 below (and Tables 18 and 21 of the FDA statistical review) outline the clinically important treatment emergent adverse events (TEAE) that occur in studies 301 and 302 respectively. These tables also demonstrate the side effects that appear to be dose-dependent. Hypertension, diarrhea, anemia, leukopenia, thrombocytopenia and hyperlipidemia show an increased frequency at the higher dose of sirolimus.

Table 5

Number (%) of Study 301 Patients Reporting Clinically Important TEAE

Excluding Infection and Malignancy

Body system

Event

SRL

2 mg/day

(n=281)

SRL

5 mg/day

(n=269)

Azathio-prine

(n=159)

p-value

Body as a whole

Headache

Lymphocele

44 (16)

33 (12)

50 (19)

36 (13)

12 (8)

4 (3)

0.005*

<0.001*

Cardiovascular system

Hypertension

96 (34)

89 (33)

35 (22)

0.017*

Digestive system

Diarrhea

Liver function tests abnormal

50 (18)

24 (9)

74 (28)

26 (10)

18 (11)

14 (9)

<0.001*

0.381

Endocrine system

Diabetes mellitus

14 (5)

22 (8)

8(5)

0.256

Hemic and lymphatic system

Anemia

Leukopenia

Thrombocytopenia

Thrombotic thrombocytopenia purpura (TTP)

56 (20)

14 (5)

25 (9)

2 (<1)

73 (27)

28 (10)

47 (17)

4 (1)

32 (20)

17 (11)

9 (6)

0

0.096

0.027*

<0.001*

0.283

Metabolic and nutritional

Creatinine increased

Healing abnormal

Hypercholesteremia

Hyperglycemia

Hyperkalemia

Hyperlipemia

Peripheral edema

61 (22)

22 (8)

84 (30)

34 (12)

34 (12)

83 (30)

137 (49)

64 (24)

24 (9)

94 (35)

39 (14)

22 (8)

103 (38)

134 (50)

32 (20)

6 (4)

34 (21)

18 (11)

30(19)

29 (18)

68 (43)

0.669

0.120

0.012*

0.581

0.005*

<0.001*

0.343

Musculoskeletal system

Arthralgia

40 (14)

53 (20)

18 (11)

0.053

Nervous system

Hypotonia

Insomnia

Tremor

14 (5)

28(10)

60 (21)

14 (5)

51 (19)

64 (24)

1 (<1)

19 (12)

25 (16)

0.022*

0.008*

0.136

Respiratory system

Epistaxis

8 (3)

13 (5)

1 (<1)

0.043*

Skin and appendages

Acne

Hirsutism

Rash

67 (24)

14 (5)

23 (8)

49 (18)

32 (12)

19 (7)

18 (11)

3 (2)

3 (2)

0.004*

<0.001*

0.016*

*Overall difference among treatment groups assessed by Fisher’s exact test.

 

Reviewer’s note: Some adverse events commonly associated with cyclosporine such as hypertension, tremor, headache and hirsutism were more frequently reported in the sirolimus treatment groups in study 301.

Table 6

Number (%) of Study 302 Pts. Reporting Clinically Important TEAE

Excluding Infection and Malignancy

Body system

Event

SRL

2 mg/day

(n=218

SRL

5 mg/day

(n=208)

Placebo

(n=124)

p-value

Body as a whole

Headache

Lymphocele

55 (25)

20 (9)

57 (27)

25 (12)

23 (19)

6 (5)

0.184

0.091

Cardiovascular system

Hypertension

80 (37)

84 (40)

51 (41)

0.611

Digestive system

Diarrhea

36 (16)

50 (24)

17 (14)

0.038*

Endocrine system

Diabetes mellitus

9 (4)

16 (8)

3 (2)

0.082

Hemic and lymphatic system

Anemia

Leukopenia

Thrombocytopenia

Thrombic thrombocytopenia purpura (TTP)1

36 (16)

15 (7)

25 (11)

4 (2)

56 (27)

18 (9)

47 (23)

7 (3)

16 (13)

3 (2)

4 (3)

2 (2)

0.003*

0.069

<0.001*

0.586

Metabolic and nutritional

ALT increased

AST increased

Creatinine increased

Healing abnormal

Hypercholesteremia

Hyperglycemia

Hyperkalemia

Hyperlipemia

Peripheral edema

19 (9)

9 (4)

56 (26)

15 (7)

81 (37)

23 (11)

29 (13)

76 (35)

93 (42)

20 (10)

15 (7)

65 (31)

22 (11)

91 (44)

25 (12)

23 (11)

103 (50)

98 (47)

9 (7)

6 (5)

40 (32)

7 (6)

25 (20)

12 (10)

28 (23)

22 (18)

43 (35)

0.777

0.369

0.295

0.224

<0.001*

0.786

0.016*

<0.001*

0.086

*Overall difference among treatment groups assessed by Fisher’s exact test.

1All patiens with hemolytic uremic syndrome (HUS) were coded to this term.

 

 

  1. The major toxicities that I will now focus on will include: infection, hyperlipidemia, post-transplant diabetes mellitus, elevated liver function tests , hematologic toxicity, HUS/TTP and renal function.

Reviewer’s note: The applicant recommends that "high risk patients" be administered the sirolimus 5 mg/day dose. They infer that the African-American population incurred less side effects/less risk from sirolimus. Please keep in mind that there were only 166 black patients in study 301. Regarding complications from cytomegalovirus infection—the African-American patients may have been a lower risk population to develop serious CMV infection and serious CMV disease.

 

  1. INFECTION
  1. There was a decreased incidence of CMV in studies 301 and 302 that the Applicant partially attributed to the use of CMV prophylaxis. However, assessment of the degree of CMV donor and recipient mismatch for study 301 demonstrated that the majority of the black and non-black patients in study 301 were not at high risk to develop serious CMV infection or disease i.e. they were not CMV negative recipients (R-) of CMV positive donor kidneys (D+) i.e. (CMV D+R-).
  2. Reviewer’s note: The applicant recommends that "high risk patients" be administered the sirolimus 5 mg/day dose. They claim that the black population incurred less side effects/less risk from sirolimus. Please keep in mind that there were only 166 African-American patients in study 301. Regarding complications from cytomegalovirus infection—the African-American patients may have been a low risk population to develop serious CMV infection and serious CMV disease.

    Table 7 Analysis Black patients with "high risk" to develop serious CMV infection and disease (CMV D+R-)

    Study 301

    Treatment Arms

    Black

    Pts. in 301

    Black patients

    CMV D+/R-

    "high risk"

    Black Pts. with unknown D/R serologic status for CMV

    AZA

    42

    5/42 (11.9%)

    4

    SRL 2

    63

    4/63 (6.3%)

    4

    SRL 5

    61

    2/61 (3.3%)

    3

    Total Black patients

    166

    11/166 (6.6%)

    11 (6.6%)

     

     

     

     

     

     

     

     

     

     

     

     

     

     

    Table 8 Analysis Non-Black patients with "high risk" to develop serious CMV infection and disease (CMV D+R-)

    Study 301

    Treatment

    Arms

    Non-Black Pts. in 301

    Non-Black patients

    CMV D+/R-

    "high risk"

    Non-Black with unknown serologic status for CMV

    AZA

    119

    21/119 (17.6%)

    0

    SRL 2

    221

    55 /221 (25.0%)

    3

    SRL 5

    213

    46 /213 (21.6%)

    5

    Total Non-Black patients

    553

    122/553 (22.1%)

    8 (1.5%)

    Reviewer’s note: As one can see in the above tables, the percentage of black patients in study 301, who were at high risk to develop CMV infection and disease, was only 6.6%. The non-black patients in study 301 carried a "high risk" of 22.1%. Study 302 enrolled less black patients. However, once again, of the 66 black patients enrolled in study302, only 2 were CMV negative recipients of CMV positive donor kidneys. Many different host and epidemiologic factors, as well as the level of immunosuppression, contribute to the development of post-transplant infection. One must be careful not to overlook these factors and falsely assume that the black population "better tolerated" the sirolimus or that this population is "under-immunosuppressed" because they developed fewer problems with CMV infection, opportunistic infection and PTLD.

  3. There was no increase in the rates of sepsis, pyelonephritis, wound infection and pneumonia across treatment groups in studies 301 and 302.
  4. There was no increase in the incidence of opportunistic infection in either of the sirolimus treatment groups compared to the control groups in studies 301 and 302, except for a higher incidence of mucosal Herpes simplex in the sirolimus 5 mg group.
  5. Despite differences between treatment groups, with respect to episodes of acute

rejection requiring additional high doses of immunosuppression, there were no significant differences between treatment groups with respect to serious infection.

Reviewer’s note: The increased incidence of mucosal herpes simplex is quite unusual considering many of these patients were receiving either acyclovir or ganciclovir prophylaxis for CMV infection. Either of these two antiviral drugs has efficacy against Herpes simplex virus. Please note that the diagnosis of Herpes simplex infection can be problematic in that it was not confirmed by laboratory tests such as culture.

 

 

B) HYPERLIPIDEMIA

Reviewer’s note: The following tables pertain to an analysis of treatment emergent abnormalities in serum cholesterol and triglycerides that developed in transplant recipients in Studies 301 and 302 .Data was not collected for HDL, LDL or apolipoproteins during Studies 301 and 302. Consequently, the following analysis utilizes a threshold for "normal cholesterol" as < 200 mg/dl and "elevated cholesterol" as >240 mg/dl. Keep in mind that the National Cholesterol Education Program (NCEP) guidelines for intervention utilizing lipid-lowering agents relies on data that was not available for our review such as LDL values and cardiac risk factors. The threshold values utilized for the triglyceride analysis include a "normal triglceride" value of <200 mg/dl and "elevated triglyceride" value of >500 mg/dl.

The lipid analysis below differs from the Applicant’s analysis in that it evaluates a cohort of patients who had normal cholesterol and triglyceride levels prior to initiation of study drug and who developed hyperlipidemia while on study drug. Hyperlipidemia has been identified as a major side-effect with sirolimus and has surfaced in all Phase II and Phase III studies.

TABLE 9 Study 301 patients who developed hypercholesterolemia on study drug

# study 301 patients

Azathioprine

Sirolimus 2mg

Sirolimus 5mg

Total # study patients in each treatment arm

161

284

274

Pts. with pre-study chol.<200mg/dl

116/161 (72.1%)

204/284 (71.8%)

195/274 (71.2%)

Pts. with normal baseline cholesterol who developed chol. >240 mg/dl on study drug

55/116 (47.4%)

131/204 (64.2%)

133/195 (68.2%)

Fisher’s exact p-value

 

0.005

0.0003

 

 

 

 

 

 

 

 

 

 

 

 

TABLE 10 Study 302 Patients who developed hypercholesterolemia on study drug

# study 302 patients

Placebo

Sirolimus 2 mg

Sirolimus 5 mg

Total # patients in each treatment arm

130

227

219

Pts. with pre-study chol.<200mg/dl

95/130 (73.1%)

163/227 (71.8%)

165/219 (75.3%)

Pts. with normal baseline cholesterol who developed chol. >240 mg/dl on study drug

39/95 (41.1%)

123/163 (75.5%)

120/165 (72.7%)

Fisher’s exact p-value

 

<0.0001

<0.0001

Reviewer’s note: A significant risk to develop new onset hypercholesterolemia , above and beyond the risk anticipated from cyclosporine, exists in the sirolimus treatment arm and was identified in both study 301 and 302.

 

TABLE 11 Study 301 patients who developed hypertriglyceridemia on study drug

Study 301 patients

AZA

Sirolimus 2 mg

Sirolimus 5 mg

Total # patients in each treatment arm

161

284

274

Pts. with pre-study TG<200mg/dl

121/161 (75.2%)

207/284 (72.9%)

229/274

(83.6%)

Pts. with normal baseline TG who developed TG >500 mg/dl on study drug

6/121 (5.0%)

30/207 (14.5%)

41/229(17.9%)

Fisher’s exact p-value

 

0.01

0.0005

 

 

 

 

 

 

 

 

 

 

 

TABLE 12 Study 302 patients who developed hypertriglyceridemia on study drug

Study 302 patients

Placebo

Sirolimus 2 mg

Sirolimus 5 mg

Total # patients in each treatment arm

130

227

219

Pts. with pre-study TG<200mg/dl

89 (68.5%)

168 (74.0%)

170 (77.6%)

Pts. with normal baseline TG who developed TG >500 mg/dl on study drug

2 (2.2)

26 (15.5)

40 (23.5)

Fisher’s exact p-value

 

0.0006

<0.0001

Reviewer’s note: A significant risk to develop new onset hypertriglyceridemia, above and beyond the risk anticipated from cyclosporine, exists in the sirolimus treatment arms and has been identified in both study 301 and 302.

 

 

 

Table 13 Analysis of the use of lipid lowering agents Study 301

Study 301

AZA

SRL 2 mg

SRL 5 mg

Patients with normal cholesterol pre-study

116

204

195

Patients initiated on lipid -lowering drug

25(21.6%)

93 (45.6%)

101 (51.8%)

Patients who continued on lipid lowering drug at 6-12 months

23(20%)

59 (29%)

69 (35%)

 

Table 14 Analysis of the use of lipid lowering agents Study 302

Study 302

Placebo

SRL 2 mg

SRL 5 mg

Patients with normal cholesterol pre-study

95

163

165

Patients initiated on lipid -lowering drug

15 (15.8%)

69 (42.3%)

77 (46.7%)

Patients who continued on lipid lowering drug at 6-12 months

11 (12%)

47 (29%)

64 (39%)

Reviewer’s note: In study 301, approximately 22% of the patients with normal cholesterol at study onset who developed hypercholesterolemia on azathioprine as did 46 to 52 %. In study 302, approximately 16% of the azathioprine patients were initiated on lipid-lowering agents and 42-47% of the patients on sirolimus. Once initiated on a lipid lowering agent, at least 60 % of the patients continued on the lipid lowering agent at study’s end. The majority of the lipid- lowering agents used were HMG-CoA reductase inhibitors.

Table 15

Demographics for patients who developed elevated chol. while on study 301

 

Azathioprine

N=55

Sirolimus 2 mg

N=131

Sirolimus 5 mg

N=133

Black

16 (29%)

24 (18.3%)

26 (19.5%)

Non-Black

39 (71%)

107 (81.7%)

107 (80.5%)

Male

25 (45.5%)

94 (72%)

77 (56%)

Female

30 (54.5%)

37 (28%)

56 (42%)

 

Reviewer’s comment: As seen in the above tables, it is obvious that a significant proportion of patients who entered these trials with normal lipid profiles, and were treated with sirolimus, developed a new problem with either elevated cholesterol and/or elevated triglycerides. The Applicant states that this problem was manageable with diet, exercise, lipid -lowering agents, reduction in corticosteroids and cyclosporine and that there was no evidence of major vascular disease at the end of one year. However, one year is too early to assess the major sequelae of this hyperlipidemia. Please also keep in mind that these patients may carry additional risk factors for heart disease such as family history, diabetes and hypertension. Values for HDL, LDL and the apolipoproteins were not collected during this trial and consequently it was not possible to include these parameters in the assessment of hyperlipidemia. We looked at the potential role of elevated cyclosporine/sirolimus levels contributing to hyperlipidemia, but found no data to substantiate a correlation. There was no significant increase in hyperlipidemia, in this group of patients with normal baseline lipid values, when the higher sirolimus dose was utilized. The demographics showed that non-Black male patients tended more often to develop hypercholesterolemia on sirolimus 2 mg and 5 mg. Non-Black females developed more problems with hypercholesterolemia on azathioprine. If a patient with a normal pre-study cholesterol developed hypercholesterolemia on any study drug and was initiated on lipid lowering therapy, greater than 60% of those patients continued to require the lipid lowering agent at 6-12 months post- transplant.

  1. Post-transplant diabetes mellitus (PTDM)
  2. PTDM was defined as a patient, without a prior history of IDDM or NIDDM, and who requires the use of insulin for 30 or more consecutive days with less than 5 days of interruption to maintain a normal, fasting blood glucose concentration.

    Twenty seven patients fit the above criteria.

     

     

     

     

    TABLE 16. 27 Patients who developed PTDM on study 301 & 302

     

    Placebo

    N= 84

    Azathioprine

    N= 98

    (23 Black

    75 Non-Black)

    Sirolimus 2 mg

    N= 334

    (51 Black

    283 Non-black )

    Sirolimus 5 mg

    N= 327

    (52 Black

    275 Non-black)

             

    Male

    0

    2

    9

    7

    Female

    0

    0

    1

    8

    Black

    0

    2

    3

    6

    Non-Black

    0

    0

    7

    9

    Total # pts.

    0

    2

    10

    15

    Incidence PTDM

    0%

    2%

    3%

    4.6%

    Reviewer’s note: Overall, the incidence of PTDM was uncommon in study 301 and 302. However, despite greater rates of acute rejection and use of additional steroids to treat the episodes of rejection in the control arms, there was no corresponding increase in PTDM. In fact, the incidence of PTDM is greater in the sirolimus 5 mg study arm, noting that there were 8 patients whose status regarding the use of insulin was unclear ( 2 in the azathioprine arm and 6 in the sirolimus 5 arm).

  3. Liver function Tests (LFT’s)
  4. Reviewer’s note: Please note that information regarding the serologic status of study patients for Hepatitis B or C was not reported in this study. The LFT’s that were assessed included alkaline phosphatase, AST,and ALT . Bilirubin levels were not collected. Please refer to table 8.71a in the Applicant’s briefing package. Essentially the percentage of patients who developed elevations of these LFT parameters to 5 and 10 times the upper limit of normal were equally distributed among the study drug groups in studies 301 and 302 . The overall percentage of LFT elevations was small and no significant trends were identified by race or gender.

     

  5. Renal Function as measured by Nankivell GFR and serum creatinine
  6. Reviewer’s comment : Sirolimus is believed to lack inherent nephrotoxicity as data indicates in animal models and in the phase 2 trials in de novo renal transplants and in phase 2 monotherapy psoriasis trials. In the following tables, one can see that in black and non-black patients the GFR was better in the group on AZA at 12 months. In the briefing package, the Applicant notes that patients on CsA and sirolimus have higher creatinine levels over time vs patients treated with full dose CsA in conjunction with placebo or azathioprine. These creatinine levels show a dose relationship with higher levels of creatinine found in patients treated with SRL 5 mg. The Applicant believes that this is mainly due to CsA nephrotoxicity. Additional study is needed to assess whether sirolimus will truly allowaa "cyclosporine –sparing"regimen without incurring an increased risk of rejection. Our analysis is different than that of the Applicant which was an "on treatment" analysis. Rather, our study population encompasses both those with and without rejection and patients both on and off study drug at 12 months. Our analysis includes patients similar to the general transplant populations on study 301 and 302. Although patients on azathioprine had an increased rate of rejection, we did not find a bias in our analysis that could be ascribed to an increased number of azathioprine "dropouts" with rejection which would have eliminated azathioprine patients with poor renal function and thus led to a bias with retention of only azathioprine patients with good renal function at 12 months.

     

    Table XII Study 301 GFR Results at 12months (337-393 days)

    Treatment

    N (observed) /N (total)

    Mean GFR

    (cc/min)

    p-value

    Azathioprine

    127/161 (78.9%)

    65.9 +/- 19

    ----------

    SRL 2 mg

    233/284 (82.0%)

    57.4 +/- 19.6

    0.001

    SRL 5 mg

    226/274 (82.5%)

    55.1 +/- 19.3

    0.001

     

    Table XIII Study 301 Creatinine at 12 months (337-393 days)

    Treatment

    N(observed)

    Mean creatinine mg/dl

    p-value

    Azathioprine

    127

    1.6 +/- 0.63

     

    Sirolimus 2

    233

    2.17 +/- 1.49

    0.0001

    Sirolimus 5

    227

    2.09 +/- 1.36

    0.0002

    Reviewer’s note: In study 301 both GFR and serum creatinine are significantly better in the azathioprine arm at 12 months.

     

    Table XIV Study 301 Creatinine at 12 months by Race

    Treatment

    Race

    N obs

    Mean creatinine (mg/dl)

    Azathioprine

    Black

    36

    1.75 +/- 0.79

     

    Non-Black

    91

    1.54 +/- 0.55

    Sirolimus 2

    Black

    49

    2.69 +/- 2.32

     

    Non-Black

    184

    2.04 +/- 1.15

    Sirolimus 5

    Black

    51

    2.54 +/- 2.35

     

    Non-Black

    176

    1.96 +/- 0.87

    Reviewer’s note: The serum creatinine is better for both blacks and non-blacks in the azathioprine arm at 12 months. There is no statistical improvement in the serum creatinine with sirolimus 5 in the African-American population at 12 months.

     

     

     

    Table XV Study 302 GFR results at 12 months (337-393 days)

    Treatment

    N observed /N total

    Mean GFR (cc/min)

    p-value

    Placebo

    101/130 (77.7%)

    61.7 +/- 18.18

    -----

    SRL 2 mg

    190/227 (83.7%)

    54.9 +/- 17.36

    0.0022

    SRL 5 mg

    175/219 (79.9%)

    52.9 +/- 18.29

    0.001

     

    Table XVI Study 302 Creatinine at 12 months

    Treatment

    N observed

    Mean creatinine mg/dl

    p-value

    placebo

    102

    1.96 +/- 1.77

     

    SRL 2

    191

    2.11 +/- 1.65

    0.4295

    SRL 5

    180

    2.11 +/- 1.32

    0.4357

    Reviewer’s note: The GFR was significantly better for placebo vs sirolimus in study 302. However, the serum creatinine was not significantly different in the treatment arms in study 302 at 12months.

    Table XVII Comparison of patients with rejection in the GFR analysis Study 301

    Study 301

    Time to 1st rejection (days) in first 6 months post transplant for pts. in FDA GFR analysis

    Time to 1st rejection (days) in first 6 months post transplant for overall study 301 pts.

    AZA

    N= 30 FDA

    N= 47 study 301

    Mean 16.8

    Median 12.5

    Mean 13.0

    Median 18.8

    SRL 2

    N= 37 FDA

    N = 47 study 301

    Mean 42.1

    Median 23.0

    Mean 43.3

    Median 25.0

    SRL 5

    N = 21 FDA

    N= 35 study 301

    Mean 88.0

    Median 77.0

    Mean 67.3

    Median 43.0

     

    Table XVIII GFR analysis study 301 @12 months (337-393 days post transplant)

    Study

    301

    # Pts. in 301 GFR analysis

    12 mos.

    # pts.with first rejection at 0-6 months

    # pts. with first rejection at 7-12 months

    Rejection rate at 12 mos. for pts. in our 12 mo. GFR analysis

    0verall Study 301 Rejection Rate at 12 months

    AZA

    N=161

    127/161

    (78.9%)

    30

    2

    32/127

    (25.2%)

    49/161

    (30.4%)

    SRL 2 N= 284

    233/284(82.0%)

    37

    9

    46/233

    (19.9%)

    59/284

    (20.8%)

    SRL 5

    N=274

    226/274

    (82.5%)

    21

    6

    27/226

    (11.9%)

    38/274

    (13.9%)

     

    Table XIV Analysis of population with rejection in the GFR analysis for Study 302

    Study 302

    Time to rejection (days) in first 6 months post-transplant for pts. in our GFR analysis

    Time to rejection (days) in first 6 months post-transplant for pts. in overall study 302

    Placebo

    N= 37 FDA

    N= 54 overall

    Mean 18.3

    Median 13.3

    Mean 21.4

    Median 12.0

    SRL 2

    N=42 FDA

    N = 56 overall

    Mean 31.0

    Median 10.5

    Mean 32.8

    Median 12.0

    SRL 5

    N = 31 FDA

    N = 42 overall

    Mean 32.7

    Median 14.0

    Mean 30.3

    Median 12.5

    Table GFR analysis study 302 @12 months (337-393 days post transplant)

    Study

    302

    # Pts. in 302 GFR analysis12 mos.

    # pts.with 1st rejection at 0-6 months

    (N= 110)

    our analysis

    # pts. with 1st rejection at 7-12 months

    (N=4)

    our analysis

    Rejection rate at 12 mos. for pts. in our 12 mo. GFR analysis

    0verall Study 302 Rejection Rate at 12 months

    Placebo

    N=130

    101/130

    (77.7%)

    37

    0

    37/101

    (36.6%)

    54/130

    (41.5%)

    SRL 2

    N= 227

    190/227

    (83.7%)

    42

    1

    43/190

    (22.6%)

    58/227

    (25.5%)

    SRL 5

    N=219

    175/219

    (79.9%)

    31

    3

    34/175

    (19.4%)

    47/219

    (21.5%)

     

    Reviewer’s note: In comparing the study populations for the FDA GFR analysis with that of the overall study 301 and 302 population , for the patients who had rejection in the first year, the mean and median times to first rejection for all groups were equivalent. Consequently, we do not believe that an unfair bias was created whereby patients with early rejection were excluded from the analysis and thus the GFR would have been better than expected for any one study drug group at one year.

     

     

     

     

     

  7. HUS/TTP
  8. There were 43 cases of HUS/TTP/ thrombotic microangiopathy in studies 301 and 302.

    Reviewer’s note: Rates for thrombotic microangiopathy are quoted in the literature as being:

    1 % for FK 506 and 3% for CsA.

    The applicant believes that CsA is the major contributer to this process, as no reports of

    HUS/TTP have been reported in the sirolimus monotherapy trials. However we don’t

    know the exact size of the entire sirolimus monotherapy trial safety data base.

    In the table below, please note that the rates of HUS are higher for SRL 5 mg and that

    the rates for SRL 2mg approximates placebo but is greater than AZA.

    No patient deaths occurred due to HUS and 3 patients (SRL 5 =2, SRL 2 = 1) lost grafts.

    Rate(%) of HUS/TTP at >12 months

    study

    SRL 2 mg

    n=281 study 301

    n=218 study 302

    SRL 5 mg

    n=269 study 301

    n=208 study 302

    Placebo n=130

    AZA

    n=161

    301

    1.4

    2.6

    -----

    1.9

    302

    2.7

    8.2*

    3.2

    -------

    p-value*

    <0.05 SRL 5 vs

    SRL 2

       

     

     

  9. Hematologic

Please refer to the Applicant briefing package for further discussion of this topic.

Important points:

1)Thrombocytopenia was significantly higher in SRL 5 compared to SRL 2 and AZA and placebo. The thrombocytopenia is a dose-related reversible decrease in platelet count—mean counts are still within the normal range. The applicant states that there were no

platelet counts under 50 x 109/L after month 3..

Severe thrombocytopenia was rare (0.2%) and although epistaxis is reported in this trial there was only one episodes of epistaxis associated with thrombocytopenia.

2) Leukopenia was significantly more frequent in the SRL 5 vs SRL 2 group but lower than in AZA. There were no cases of neutropenia. Leukopenia resolved with discontinuation of study medication . No white blood cell count was less than 1x 109/L (1000 mm3).

Reviewer’s note: Leukopenia was not associated with an increased risk of infection. Neutropenia was not an adverse event noted in the sirolimus arms.

 

V. SUMMARY OF MAJOR SAFETY ISSUES

  1. Hyperlipidemia is a major issue and will need to be closely followed. It is difficult to ascertain exactly what proportion of patients can be successfully treated with diet and exercise vs lipid-lowering therapy. It is difficult to make any specific recommendations regarding management since treatment decisions will depend on LDL values that we didn’t have and risk factor stratification/modification.
  2. The elevated GFR and serum creatinine at the end of 12 months in the sirolimus groups is of concern. The Applicant ascribes this to cyclosporine toxicity however, there was no evidence of elevated cycosporine troughs in this population. Studies are planned to assess outcomes utilizing sirolimus in a cyclosporine sparing regimens.
  3. It would be risky to conclude that 166 black patients encountered less difficulty with infectious disease complications in this study and had decreased efficacy with SRL 2 mg/day because they are "under-immunosuppressed". Factors that predispose immunosuppressed transplant patients for infection are multi-factorial and encompass more than just the type of immunosuppressive agent that they are receiving. To suggest merely that "more sirolimus" is better for this subset of patients is concerning and decisions on the use of the sirolimus 5 mg/day dose must be weighed against the price of hyperlipidemia and vascular disease. The answer may be to monitor trough levels more stringently—further study is warranted.
  4. The number of African-American patients in Study 301 may be too small to exclude an unacceptable increase in less common adverse events associated with a 5 mg maintenance dose of sirolimus over the long term.