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Nulojix

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Nulojix

CLINICAL PHARMACOLOGY

Mechanism Of Action

Belatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection.

In non-human primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased the production of anti-donor antibodies, compared to vehicle.

Pharmacodynamics

Belatacept-mediated costimulation blockade results in the inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells. In clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to Month 6 and Month 12 post-transplant in belatacept-treated patients compared to cyclosporine-treated patients. In an exploratory subset analysis, a trend of decreasing IgG concentrations with increasing belatacept trough concentrations was observed at Month 6. Also in this exploratory subset analysis, belatacept-treated patients with CNS PTLD, CNS infections including PML, other serious infections, and malignancies were observed to have a higher incidence of IgG concentrations below the lower limit of the normal range ( < 694 mg/dL) at Month 6 than those patients who did not experience these adverse events. This observation was more pronounced with the higher than recommended dose of belatacept. A similar trend was also observed for cyclosporine-treated patients with serious infections and malignancies.

However, it is unclear whether any causal relationship between an IgG concentration below the lower level of normal and these adverse events exists, as the analysis may have been confounded by other factors (e.g., age greater than 60 years, receipt of an extended criteria donor kidney, exposure to lymphocyte depleting agents) which were also associated with IgG below the lower level of normal at Month 6 in these trials.

Pharmacokinetics

Table 5 summarizes the pharmacokinetic parameters of belatacept in healthy adult subjects after a single 10 mg per kg intravenous infusion; and in kidney transplant patients after the 10 mg per kg intravenous infusion at Week 12, and after 5 mg per kg intravenous infusion every 4 weeks at Month 12 post-transplant or later.

Table 5: Pharmacokinetic Parameters (Mean±SD [Range]) of Belatacept in Healthy Subjects and Kidney Transplant Patients After 5 and 10 mg per kg Intravenous Infusions Administered Over 30 Minutes

Pharmacokinetic Parameter Healthy Subjects (After 10 mg per kg Single Dose)
N=15
Kidney Transplant Patients (After 10 mg per kg Multiple Doses)
N=10
Kidney Transplant Patients (After 5 mg per kg Multiple Doses)
N=14
Peak concentration (Cmax) [μg/mL] 300 ± 77
(190-492)
247 ± 68
(161-340)
139 ± 28
(80-176)
AUC*[μg•h/mL] 26398 ± 5175
(18964-40684)
22252 ± 7868
(13575-42144)
14090 ± 3860
(7906-20510)
Terminal half-life (t½) [days] 9.8 ± 2.8
(6.4-15.6)
9.8 ± 3.2
(6.1-15.1)
8.2 ± 2.4
(3.1-11.9)
Systemic clearance (CL) [mL/h/kg] 0.39 ± 0.07
(0.25-0.53)
0.49 ± 0.13
(0.23-0.70)
0.51 ± 0.14
(0.33-0.75)
Volume of distribution (Vss) [L/kg] 0.09 ± 0.02
(0.07-0.15)
0.11 ± 0.03
(0.067-0.17)
0.12 ± 0.03
(0.09-0.17)
* AUC=AUC (INF) after single dose and AUC (TAU) after multiple dose, where TAU=4 weeks

In healthy subjects, the pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally after a single intravenous infusion dose of 1 to 20 mg per kg. The pharmacokinetics of belatacept in de novo kidney transplant patients and healthy subjects are comparable. Following the recommended regimen, the mean belatacept serum concentration reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. Following once monthly intravenous infusion of 10 mg per kg and 5 mg per kg, there was about 20% and 10% systemic accumulation of belatacept in kidney transplant patients, respectively.

Based on population pharmacokinetic analysis of 924 kidney transplant patients up to 1 year post-transplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. In clinical trials, trough concentrations of belatacept were consistently maintained from Month 6 up to 3 years post-transplant. Population pharmacokinetic analyses in kidney transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. Age, gender, race, renal function (measured by calculated glomerular filtration rate [GFR]), hepatic function (measured by albumin), diabetes, and concomitant dialysis did not affect the clearance of belatacept.

Drug Interactions

Mycophenolate Mofetil

In a pharmacokinetic substudy of Studies 1 and 2, the plasma concentrations of MPA were measured in 41 patients who received fixed MMF doses of 500 to 1500 mg twice daily with either 5 mg per kg of NULOJIX or cyclosporine. The mean dose-normalized MPA Cmax and AUC0-12 were approximately 20% and 40% higher, respectively, with NULOJIX coadministration than with cyclosporine coadministration [see DRUG INTERACTIONS].

Cytochrome P450 Substrates

The potential of NULOJIX to alter the systemic concentrations of drugs that are CYP450 substrates was investigated in healthy subjects following administration of a cocktail of probe drugs given concomitantly with, and at 3 days and at 7 days following a single intravenous 10 mg per kg dose of NULOJIX. NULOJIX did not alter the pharmacokinetics of drugs that are substrates of CYP1A2 (caffeine), CYP2C9 (losartan), CYP2D6 (dextromethorphan), CYP3A (midazolam), and CYP2C19 (omeprazole) [see DRUG INTERACTIONS].

Animal Toxicology And/Or Pharmacology

Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents may be predictive of adverse effects in humans treated with belatacept.

Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (observed in juvenile rats and pregnant rats) as well as autoimmunity of the thyroid and pancreas (observed in rats exposed in utero, as juveniles or as adults). Studies of abatacept in adult mice and monkeys, as well as belatacept in adult monkeys, have not demonstrated similar findings.

The increased susceptibility to opportunistic infections observed in juvenile rats is likely associated with the exposure to abatacept before the complete development of memory immune responses. In pregnant rats, the increased susceptibility to opportunistic infections may be due to the inherent lapses in immunity that occur in rats during late pregnancy/lactation. Infections related to NULOJIX have been observed in human clinical trials [see WARNINGS AND PRECAUTIONS].

Administration of abatacept to rats was associated with a significant decrease in T-regulatory cells (up to 90%). Deficiency of T-regulatory cells in humans has been associated with autoimmunity. The occurrence of autoimmune events across the core clinical trials was infrequent. However, the possibility that patients administered NULOJIX could develop autoimmunity (or that fetuses exposed to NULOJIX in utero could develop autoimmunity) cannot be excluded.

In a 6-month toxicity study with belatacept in cynomolgus monkeys administered weekly doses up to 50 mg per kg (6 times the MRHD exposure) and in a 1-year toxicity study with abatacept in adult cynomolgus monkeys administered weekly doses up to 50 mg per kg, no significant drug-related toxicities were observed. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes.

Following 5 doses (10 mg per kg or 50 mg per kg, once a week for 5 weeks) of systemic administration, belatacept was not detected in brain tissue of normal healthy cynomolgus monkeys. The number of cells expressing major histocompatibility complex (MHC) class-II antigens (potential marker of immune cell activation) in the brain were increased in monkeys administered belatacept compared to vehicle control. However, distribution of some other cells expressing CD68, CD20, CD80, and CD86, typically expressed on MHC class II-positive cells, was not altered and there were no other histological changes in the brain. The clinical relevance of the findings is unknown.

Clinical Studies

Prevention Of Organ Rejection In Kidney Transplant Recipients

The efficacy and safety of NULOJIX in de novo kidney transplantation were assessed in two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of NULOJIX, the recommended dosage regimen [see DOSAGE AND ADMINISTRATION] and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. All treatment groups also received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids.

Treatment Regimen

The NULOJIX recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every 4 weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, NULOJIX was administered at the maintenance dose of 5 mg per kg every 4 weeks (plus or minus 3 days). NULOJIX was administered as an intravenous infusion over 30 minutes [see DOSAGE AND ADMINISTRATION].

Basiliximab 20 mg was administered intravenously on the day of transplantation and 4 days later.

The initial dose of MMF was 1 gram twice daily and was adjusted, as needed based on clinical signs of adverse events or efficacy failure.

The protocol-specified dosing of corticosteroids in Studies 1 and 2 at Day 1 was methylprednisolone (as sodium succinate) 500 mg IV on arrival in the operating room, Day 2, methylprednisolone 250 mg IV, and Day 3, prednisone 100 mg orally. Actual median corticosteroid doses used with the NULOJIX recommended regimen from Week 1 through Month 6 are summarized in the table below (Table 6).

Table 6: Actual Corticosteroid* Dosing in Studies 1 and 2

Day of Dosing Median (Q1-Q3) Daily Dose†,‡
Study 1 Study 2
Week 1 31.7 mg (26.7-50 mg) 30 mg (26.7-50 mg)
Week 2 25 mg (20-30 mg) 25 mg (20-30 mg)
Week 4 20 mg (15-20 mg) 20 mg (15-22.5 mg)
Week 6 15 mg (10-20 mg) 16.7 mg (12.5-20 mg)
Month 6 10 mg (5-10 mg) 10 mg (5-12.5 mg)
* Corticosteroid = prednisone or prednisolone.
† The protocols allowed for flexibility in determining corticosteroid dose and rapidity of taper after Day 15. It is not possible to distinguish corticosteroid doses used to treat acute rejection versus doses used in a maintenance regimen.
‡ Q1 and Q3 are the 25th and 75th percentiles of daily corticosteroid doses, respectively.

Study 1 enrolled recipients of living donor and standard criteria deceased donor organs and Study 2 enrolled recipients of extended criteria donor organs. Standard criteria donor organs were defined as organs from a deceased donor with anticipated cold ischemia time of < 24 hours and not meeting the definition of extended criteria donor organs. Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥ 60 years; (2) donor age ≥ 50 years and other donor comorbidities ( ≥ 2 of the following: stroke, hypertension, serum creatinine > 1.5 mg/dL); (3) donation of organ after cardiac death; or (4) anticipated cold ischemia time of the organ of ≥ 24 hours. Study 1 excluded recipients undergoing a first transplant whose current Panel Reactive Antibodies (PRA) were ≥ 50% and recipientsundergoing a retransplantation whose current PRA were ≥ 30%; Study 2 excluded recipients witha current PRA ≥ 30%. Both studies excluded recipients with HIV, hepatitis C, or evidence of current hepatitis B infection; recipients with active tuberculosis; and recipients in whom intravenous access was difficult to obtain.

Efficacy data are presented for the NULOJIX recommended regimen and cyclosporine regimen in Studies 1 and 2.

The NULOJIX regimen with higher cumulative doses and more frequent dosing of belatacept was associated with more efficacy failures. Higher doses and/or more frequent dosing of NULOJIX are not recommended [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].

Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys

In Study 1, 666 patients were enrolled, randomized, and transplanted: 226 to the NULOJIX recommended regimen, 219 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyclosporine control regimen. The median age was 45 years; 58% of organs were from living donors; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ≥ 10%; 41% had 4 to 6 HLA mismatches; and 27% had diabetes prior to transplant. The incidence of delayed graft function was similar in all treatment arms (14% to 18%).

Premature discontinuation from treatment at the end of the first year occurred in 19% of patients receiving the NULOJIX recommended regimen and 19% of patients on the cyclosporine regimen. Among the patients who received the NULOJIX recommended regimen, 10% discontinued due to lack of efficacy, 5% due to adverse events, and 4% for other reasons. Among the patients who received the cyclosporine regimen, 9% discontinued due to adverse events, 5% due to lack of efficacy, and 5% for other reasons.

At the end of three years, 25% of patients receiving the NULOJIX recommended regimen and 34% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 12% discontinued due to lack of efficacy, 7% due to adverse events, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 15% discontinued due to adverse events, 8% due to lack of efficacy, and 11% for other reasons.

Assessment of Efficacy

Table 7 summarizes the results of Study 1 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed separately.

Table 7: Efficacy Outcomes by Years 1 and 3 for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Parameter NULOJIX Recommended Regimen
N=226
n (%)
Cyclosporine (CSA)
N=221
n (%)
NULOJIX-CSA (97.3% CI)
Efficacy Failure by Year 1 49 (21.7) 37 (16.7) 4.9 (-3.3, 13.2)
  Components of Efficacy Failure*
    Biopsy Proven Acute Rejection 45 (19.9) 23 (10.4)  
    Graft Loss 5 (2.2) 8 (3.6)  
    Death 4 (1.8) 7 (3.2)  
    Lost to follow-up 0 1 (0.5)  
Efficacy Failure by Year 3 58 (25.7) 57 (25.8) -0.1 (-9.3, 9)
  Components of Efficacy Failure*
    Biopsy Proven Acute Rejection 50 (22.1) 31 (14)  
    Graft Loss 9 (4) 10 (4.5)  
    Death 10 (4.4) 15 (6.8)  
    Lost to follow-up 2 (0.9) 5 (2.3)  
Patient and graft survival †
    Year 1 218 (96.5) 206 (93.2) 3.2 (-1.5, 8.4)
    Year 3 206 (91.2) 192 (86.9) 4.3 (-2.2, 10.8)
* Patients may have experienced more than one event.
† Patients known to be alive with a functioning graft.

In Study 1, the rate of BPAR at one year and three years was higher in patients treated with the NULOJIX recommended regimen than the cyclosporine regimen. Of the patients who experienced BPAR with NULOJIX, 70% experienced BPAR by Month 3, and 84% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups ( < 3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

Patients treated with the NULOJIX recommended regimen experienced episodes of BPAR classified as Banff grade IIb or higher (6% [14/226] at one year and 7% [15/226] at three years) more frequently compared to patients treated with the cyclosporine regimen (2% [4/221] at one year and 2% [5/221] at three years). Also, T-cell depleting therapy was used more frequently to treat episodes of BPAR in NULOJIX-treated patients (10%; 23/226) compared to cyclosporine­treated patients (2%; 5/221). At Month 12, the difference in mean calculated glomerular filtration rate (GFR) between patients with and without history of BPAR was 19 mL/min/1.73 m² among NULOJIX-treated patients compared to 7 mL/min/1.73 m² among cyclosporine-treated patients. By three years, 22% (11/50) of NULOJIX-treated patients with a history of BPAR experienced graft loss and/or death compared to 10% (3/31) of cyclosporine-treated patients with a history of BPAR; at that time point, 10% (5/50) of NULOJIX-treated patients experienced graft loss and 12% (6/50) of NULOJIX-treated patients had died following an episode of BPAR, whereas 7% (2/31) of cyclosporine-treated patients experienced graft loss and 7% (2/31) of cyclosporine­treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 5% and 11% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

While the difference in GFR in patients with BPAR versus those without BPAR was greater in patients treated with NULOJIX than cyclosporine, the mean GFR following BPAR was similar in NULOJIX (49 mL/min/1.73 m²) and cyclosporine treated patients (43 mL/min/1.73 m²) at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see INDICATIONS AND USAGE].

In Study 1, approximately 87% of patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 21% (42/202) in patients treated with the NULOJIX recommended regimen and 17% (31/184) in patients treated with cyclosporine (difference=4%, 97.3% CI [-4.8, 12.8]). Patient and graft survival was 98% (198/202) in NULOJIX-treated patients and 92% (170/184) in cyclosporine-treated patients (difference=5.6%, 97.3% CI [0.8, 10.4]).

By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in NULOJIX-treated patients compared with 88% (162/184) in cyclosporine­treated patients (difference=4.6%, 97.3% CI [-2.1, 11.3]).

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 8, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 1, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between three and 36 months demonstrated an increase of 0.8 mL/min/year (95% CI [-0.2, 1.8]) for NULOJIX-treated patients and a decrease of 2.2 mL/min/year (95% CI [-3.2, -1.2]) for cyclosporine-treated patients.

Table 8: Measured and Calculated GFR for Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Parameter NULOJIX Recommended Regimen
N=226
Cyclosporine (CSA)
N=221
NULOJIX-CSA (97.3% CI)
Measured GFR* mL/min/1.73 m² mean (SD)
Year 1 63.4 (27.7) (n=206) 50.4 (18.7) (n=199) 13.0 (7.3, 18.7)
Year 2f 67.9 (29.9) (n=199) 50.5 (20.5) (n=185) 17.4 (11.5, 23.4)
Calculated GFR‡ mL/min/1.73 m² mean (SD)
Year 1 65.4 (22.9) (n=200) 50.1 (21.1) (n=199) 15.3 (10.3, 20.3)
Year 2 65.4 (25.2) (n=201) 47.9 (23) (n=182) 17.5 (12, 23.1)
Year 3 65.8 (27) (n=190) 44.4 (23.6) (n=171) 21.4 (15.4, 27.4)
* GFR was measured using the cold-iothalamate method.
† Measured GFR was not assessed at Year 3.
‡ GFR was calculated using the MDRD formula.

Figure 1: Calculated (MDRD) GFR through Month 36; Study 1: Recipients of Living and Standard Criteria Deceased Donor Kidneys

Calculated (MDRD) GFR through Month 36 - Illustration

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff '97 classification system, was 24% (54/226) in patients treated with the NULOJIX recommended regimen and in 32% (71/219) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

Study 2: Recipients of Extended Criteria Donor Kidneys

In Study 2, 543 patients were enrolled, randomized, and transplanted: 175 to the NULOJIX recommended regimen, 184 to the NULOJIX regimen with higher cumulative doses and more frequent dosing than recommended, and 184 to the cyclosporine control regimen. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ≥ 10%; 53% had 4 to 6 HLA mismatches; and 29% had diabetes prior to transplantation. The incidence of delayed graft function was similar in all treatment arms (47% to 49%).

Premature discontinuation from treatment at the end of the first year occurred in 25% of patients receiving the NULOJIX recommended regimen and 30% of patients receiving the cyclosporine control regimen. Among the patients who received the NULOJIX recommended regimen, 14%discontinued due to adverse events, 9% due to lack of efficacy, and 2% for other reasons. Among the patients who received the cyclosporine regimen, 17% discontinued due to adverse events, 7% due to lack of efficacy, and 6% for other reasons.

At the end of three years, 35% of patients receiving the NULOJIX recommended regimen and 44% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the NULOJIX recommended regimen, 20% discontinued due to adverse events, 9% due to lack of efficacy, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 25% discontinued due to adverse events, 10% due to lack of efficacy, and 10% for other reasons.

Assessment of Efficacy

Table 9 summarizes the results of Study 2 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed.

Table 9: Efficacy Outcomes by Years 1 and 3 for Study 2: Recipients of Extended Criteria Donor Kidneys

Parameter NULOJIX Recommended Regimen
N=175
n (%)
Cyclosporine (CSA)
N=184
n (%)
NULOJIX-CSA (97.3% CI)
Efficacy Failure by Year 1 51 (29.1) 52 (28.3) 0.9 (-9.7, 11.5)
  Components of Efficacy Failure*
     Biopsy Proven Acute Rejection 37 (21.1) 34 (18.5)  
     Graft Loss 16 (9.1) 20 (10.9)  
     Death 5 (2.9) 8 (4.3)  
     Lost to follow-up 0 2 (1.1)  
     Efficacy Failure by Year 3 63 (36) 68 (37) -1.0 (-12.1, 10.3)
  Components of Efficacy Failure*
     Biopsy Proven Acute Rejection 42 (24) 42 (22.8)  
     Graft Loss 21 (12) 23 (12.5)  
     Death 15 (8.6) 17 (9.2)  
     Lost to follow-up 1 (0.6) 5 (2.7)  
Patient and graft survival†
Year 1 155 (88.6) 157 (85.3) 3.2 (-4.8, 11.3)
Year 3 143 (81.7) 143 (77.7) 4.0 (-5.4, 13.4)
* Patients may have experienced more than one event.
† Patients known to be alive with a functioning graft.

In Study 2, the rate of BPAR at one year and three years was similar in patients treated with NULOJIX and cyclosporine. Of the patients who experienced BPAR with NULOJIX, 62% experienced BPAR by Month 3, and 76% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups ( < 3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups.

A similar proportion of patients in the NULOJIX recommended regimen group experienced BPAR classified as Banff grade IIb or higher (5% [9/175] at one year and 6% [10/175] at three years) compared to patients treated with the cyclosporine regimen (4% [7/184] at one year and 5% [9/184] at three years). Also, T-cell depleting therapy was used with similar frequency to treat any episode of BPAR in NULOJIX-treated patients (5% or 9/175) compared to cyclosporine-treated patients (4% or 7/184). At Month 12, the difference in mean calculated GFR between patients with and without a history of BPAR was 10 mL/min/1.73 m² among NULOJIX-treated patients compared to 14 mL/min/1.73m² among cyclosporine-treated patients. By three years, 24% (10/42) of NULOJIX-treated patients with a history of BPARexperienced graft loss and/or death compared to 31% (13/42) of cyclosporine-treated patients with a history of BPAR; at that time point, 17% (7/42) of NULOJIX-treated patients experienced graft loss and 14% (6/42) of NULOJIX-treated patients had died following an episode of BPAR, whereas 19% (8/42) of cyclosporine-treated patients experienced graft loss and 19% (8/42) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 6% and 15% for the NULOJIX recommended regimen and cyclosporine, respectively, up to 36 months post-transplant.

The mean GFR following BPAR was 36 mL/min/1.73m² in NULOJIX patients and 24 mL/min/1.73m² in cyclosporine-treated patients at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR.

Assessment of Efficacy in the EBV Seropositive Subpopulation

NULOJIX is recommended for use only in EBV seropositive patients [see INDICATIONS AND USAGE].

In Study 2, approximately 91% of the patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied.

By one year, the efficacy failure rate in the EBV seropositive population was 29% (45/156) in patients treated with the NULOJIX recommended regimen and 28% (47/168) in patients treated with cyclosporine (difference=0.8%, 97.3% CI [-10.3, 11.9]). Patient and graft survival rate in the EBV seropositive population was 89% (139/156) in the NULOJIX-treated patients and 86% (144/168) in cyclosporine-treated patients (difference=3.4%, 97.3% CI [-4.7, 11.5]).

By three years, efficacy failure was 35% (54/156) in NULOJIX-treated patients and 36% (61/168) in cyclosporine-treated patients. Patient and graft survival was 83% (130/156) in NULOJIX-treated patients compared with 77% (130/168) in cyclosporine-treated patients (difference=5.9%, 97.3% CI [-3.8, 15.6]).

Assessment of Glomerular Filtration Rate (GFR)

Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 10, both measured and calculated GFR was higher in patients treated with the NULOJIX recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 2, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between Month 3 and Month 36 demonstrated a decrease of 0.8 mL/min/year (95% CI [-1.9, 0.3]) for NULOJIX-treated patients and a decrease of 2.0 mL/min/year (95% CI [-3.1, -0.8]) for cyclosporine-treated patients.

Table 10: Measured and Calculated GFR for Study 2: Recipients of Extended Criteria Donor Kidneys

Parameter NULOJIX Recommended Regimen
N=175
Cyclosporine (CSA)
N=184
NULOJIX-CSA (97.3% CI)
Measured GFR* mL/min/1.73 m² mean (SD)
Year 1 49.6 (25.8) (n=151) 45.2 (21.1) (n=154) 4.3 (-1.5, 10.2)
Year 2† 49.7 (23.7) (n=139) 45.0 (27.2) (n=136) 4.7 (-1.8, 11.3)
Calculated GFR‡ mL/min/1.73 m² mean (SD)
Year 1 44.5 (21.8) (n=158) 36.5 (21.1) (n=159) 8.0 (2.5, 13.4)
Year 2 42.8 (24.1) (n=158) 34.9 (21.6) (n=154) 8.0 (1.9, 14)
Year 3 42.2 (25.2) (n=154) 31.5 (22.1) (n=143) 10.7 (4.3, 17.2)
* GFR was measured using the cold-iothalamate method.
† Measured GFR was not assessed at Year 3.
‡ GFR was calculated using the MDRD formula.

Figure 2: Calculated (MDRD) GFR through Month 36; Study 2: Recipients of Extended Criteria Donor Kidneys

Calculated (MDRD) GFR through Month 36 - Illustration

Assessment of Chronic Allograft Nephropathy (CAN)

The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff '97 classification system, was 46% (80/174) in patients treated with the NULOJIX recommended regimen and 52% (95/184) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown.

Last reviewed on RxList: 10/14/2014
This monograph has been modified to include the generic and brand name in many instances.

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