Nulojix Belatacept 250 mg Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 0003-0371-13 (Billing 00003-0371-13)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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 (eg, 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.

12.3Pharmacokinetics 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 four 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 a AUC=AUC (INF) after single dose and AUC (TAU) after multiple dose, where TAU=4 weeks Peak concentration (C max ) [µg/mL] 300±77 (190-492) 247±68 (161-340) 139±28 (80-176) AUC a [μg•h/mL] 26398±5175 (18964-40684) 22252±7868 (13575-42144) 14090±3860 (7906-20510) Terminal half-life (t 1/2 ) [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) 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.… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 four 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 a AUC=AUC (INF) after single dose and AUC (TAU) after multiple dose, where TAU=4 weeks Peak concentration (C max ) [µg/mL] 300±77 (190-492) 247±68 (161-340) 139±28 (80-176) AUC a [μg•h/mL] 26398±5175 (18964-40684) 22252±7868 (13575-42144) 14090±3860 (7906-20510) Terminal half-life (t 1/2 ) [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) 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 one 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 three 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 C max and AUC 0-12 were approximately 20% and 40% higher, respectively, with NULOJIX coadministration than with cyclosporine coadministration [see Drug Interactions (7.1) ] .

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 three days and at seven 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 (7.2) ] .

12.2Pharmacodynamics 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 (eg, 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.

14 CLINICAL STUDIES

14.1Prevention 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 (2.1) ] 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 four 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 four weeks (plus or minus three days). NULOJIX was administered as an intravenous infusion over 30 minutes [see Dosage and Administration (2.1) ] .

Basiliximab 20 mg was administered intravenously on the day of transplantation and four 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 a Dosing in Studies 1 and 2 Day of Dosing Median (Q1–Q3) Daily Dose b,c Study 1 Study 2 a Corticosteroid = prednisone or prednisolone. b 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. c Q1 and Q3 are the 25 th and 75 th percentiles of daily corticosteroid doses, respectively.

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) 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 recipients undergoing a retransplantation whose current PRA were ≥30%; Study 2 excluded recipients with a 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 recommend… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A carcinogenicity study was not conducted with belatacept. However, a murine carcinogenicity study was conducted with abatacept (a more active analog in rodents) to determine the carcinogenic potential of CD28 blockade. Weekly subcutaneous injections of 20, 65, or 200 mg per kg of abatacept were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females) at clinically relevant exposures.

The mice in this study were infected with endogenous murine leukemia and mouse mammary tumor viruses which are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. Although the precise relevance of these findings to the clinical use of NULOJIX is unknown, cases of PTLD (a premalignant or malignant proliferation of B lymphocytes) were reported in clinical trials. Genotoxicity testing is not required for protein therapeutics; therefore, no genotoxicity studies were conducted with belatacept.

Belatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg per kg daily (25 times the MRHD exposure).

13.2Animal Toxicology and/or Pharmacology Abatacept, a fusion protein that differs from belatacept by two 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 (5.5) ] . 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 five 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, typic… [Excerpted — this section continues on DailyMed.]