Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication • NULOJIX is a selective T cell costimulation blocker indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. (1.1) • Use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. (1.1) Limitations of Use : • Use only in patients who are EBV seropositive. FDA label
Also known as Nulojix, BMS-224818
belatacept · 12 trials · 13 indications
The number of participants in each group with donor-specific antibody formation at 36 months following randomization.
Percentage of participants who survive with a functional graft at 24 months post-randomization
Adverse events that will be counted in the total number include: Episodes of acute cellular rejection ≥ 2R/3A, antibody mediated rejection (AMR) ≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1, hemodynamically compromised rejection, development of cardiac allograft vasculopathy, graft failure occurring ≥ 14 days post-transplant, the need for re-transplant, serious infection requiring inpatient intravenous therapies, post-transplant lymphoproliferative disorder (PTLD), or death.
The Outcome Measure is a composite primary endpoint of the development of donor-specific HLA antibodies, re-transplantation, or death. Testing for donor-specifc HLA antibodies was performed at study-specified time points using the single antigen bead assay at the study core lab. Donor-specific HLA antibodies were defined as reactivity with a mean fluorescence intensity (MFI) ≥ 2,000.
Cmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Cmax was measured in micrograms per milliliter.
Tmax was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Tmax was measured in hours (h).
T-HALF was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). T-HALF was measured in hours (h).
AUC (0 - T) and AUC (0 - INF) were derived from serum concentration versus time data and measured in microgram hours per milliliter (µg\*h/mL). Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL).
CLT was the volume of abatacept cleared by the system, normalized by baseline body weight. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). CLT was measured in milliliters per hours per kilogram of body weight (mL/h/kg).
Vss was derived from serum concentration versus time data. Serum samples were analyzed for abatacept by a validated enzyme-linked immunosorbent assay (ELISA) and were obtained at: pre-dose (0 hours), 0.5 and 2 hours from Start of Infusion on Day 1, Day 29, and Day 57. The results were summarized. The lower limit of assay quantitation (LLOQ) was set to "zero" which was 0.003 micrograms per milliliter (ug/mL). Vss was measured in liters per kg body weight (L/kg).
Pharmacokinetic (PK) sampling started from pre-dose (0 hour) on Day 84 and ended at 672 hour (h) on Day 112 (between Weeks 12 to 16). The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method and measured as nanograms/milliliter (ng/mL). Less than the lower limit of quantification (LLQ), 3.000 ng/mL concentration value was treated as missing.
Cmax, Cmin are measured in micrograms per milliliter (µg/mL). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. Serum samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). Actual sampling times were used for PK calculations. The Cmax, and the Cmin were recorded directly from experimental observations. Using no weighting factor, the terminal log-linear phase of the concentration-time curve was identified by least-square linear regression of at least 3 data points that yielded a maximum G-criteria, which is also referred to as adjusted R-squared. Values below lower limits of quantification (LLQ), 0.003 µg/mL, were set to 0.0015 for computation of summary statistics.
Tmax measured in hours (h). At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 (h) on Day 112 . The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). Actual sampling times were used for PK calculations.
At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). The area under the concentration-time curve in one dose interval \[AUC(TAU), where TAU = 4 weeks\] were calculated using the mixed log-linear trapezoidal algorithm in Kinetica. Actual sampling times were used for PK calculations. AUC (TAU) was measured as micrograms multiplied by time(h) per milliliter (µg\*h/mL).
At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). Actual sampling times were used for PK calculations. CLT was calculated by dividing the dose by AUC(TAU) and was adjusted to body weight. CLT was measured as milliliter per time per kg body weight (mL/h/kg).
At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). Actual sampling times were used for PK calculations. Vss was calculated by dividing the dose by AUC and multiply the mean residence time (MRT). Vss was adjusted to body weight and measured as liter per kilogram body weight (l/kg).
At Day 84, blood samples obtained from pre-dose (0 hour) and ended at 672 hour (h) on Day 112. The samples were analyzed for belatacept by enzyme-linked immunosorbent assay (ELISA) using a validated method. Individual participant PK parameters were derived from serum concentration versus time data using a non-compartmental method, using a validated PK analysis program (KineticaTM 4.4.1 within the eToolbox \[version 2.6.1\]). Actual sampling times were used for PK calculations. T-HALF was calculated as ln2/Lz, where Lz is the absolute value of the slope of the terminal log-linear phase. T-HALF is measured in hours (h).
Calculated GFR assessment used the modification of diet in renal disease (MDRD) formula. GFR was measured as mL/min/1.73 m\^2. For death or graft loss participants, calculated GFR (cGFR) value 10 was used, for other participants who had a post baseline cGFR value missing, but had baseline value and at least 2 post baseline values available, which were at least 120 days apart, linear regression model was used to impute the cGFR value. Baseline = value at screening. Randomization/First Dose was on Day 1.
No participant was to receive treatment for acute rejection without a biopsy to confirm the diagnosis. CSPAR=Clinically-suspected rejection, defined as an increase in serum creatinine ≥0.5 mg/dL compared with the baseline value in the absence of other factors known to adversely affect renal function, and biopsy-proven rejection, which includes all cases in which a biopsy was read by the central pathologist as demonstrating acute rejection regardless of the reason why the biopsy was performed.
Proportion of subjects who have not met a subject stopping rule, and remain free of all of the following through 26 weeks after starting treatment or until receiving a transplant, whichever occurs earlier: 1. Grade 3 or higher infusion reaction 2. Grade 3 or higher infections 3. Any malignancy The study site will grade the severity of adverse events experienced by the study subjects according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Published November 27, 2017).
Proportion of subjects who meet any one of the following compared to Baseline (Visit 0): 1. Elimination of one human leukocyte antigen (HLA) antibody at Visit 12 (16 weeks ±7 days after starting treatment); 2. 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Visit 12 (16 weeks ±7 days after starting treatment); and/or 3. Kidney transplant with a previously incompatible donor within 26 weeks after starting treatment without graft loss due to acute antibody mediated rejection occurring within the first four weeks post-transplant and caused by an anamnestic response.
Proportion of subjects who meet any one of the following compared to Baseline (Visit 0): 1. Elimination of one human leukocyte antigen (HLA) antibody at Visit 14 (26 weeks ±7 days after starting treatment); 2. 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Visit 14 (26 weeks ±7 days after starting treatment); and/or 3. Kidney transplant with a previously incompatible donor within 52 weeks after starting treatment without graft loss due to acute antibody mediated rejection occurring within the first four weeks post-transplant and caused by an anamnestic response.
Time of maximum observed serum concentration (Tmax) values were derived from serum concentration versus time data for all participants treated with Belatacept.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUC(0-T)) was derived from serum concentration versus time data. Adjusted geometric means were reported in microgram hours per milliliter (ug\*h/mL).
Area under the serum concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) was derived from serum concentration versus time data. Adjusted geometric means were reported in microgram hours per milliliter (ug\*h/mL)
Serum half-life (T-HALF) was determined from serum concentration versus time data and was reported in hours.
Apparent total body clearance (CLT/F) was derived from serum concentration versus time data for all participants who received subcutaneous (SC) Belatacept injections. Units reported in milliliters per hour (mL/h).
Total body clearance (CLT) was derived from serum concentration versus time data for all participants that were treated with IV Belatacept. Units reported in milliliters per hour (mL/h)
Volume of distribution at steady state (VSS) was derived from serum concentration versus time data for all participants treated with IV Belatacept.
Apparent volume of distribution at steady state (Vss/F) was derived from concentration versus time data for all participants treated with subcutaneous (SC) Belatacept.
| Arm | Type | Description |
|---|---|---|
| Treatment | EXPERIMENTAL | Belatacept (Nulojix) IV |
| Control | ACTIVE_COMPARATOR | Calcineurin inhibitor based therapy (cyclosporine or tacrolimus) |
| Arm 1: Conversion from a CNI- to belatacept-based regimen after a period of overlap | EXPERIMENTAL | Conversion followed by tapering and discontinuation of the calcineurin inhibitor (CNI) |
| Arm 2: Continue calcineurin inhibitor-based regimen | ACTIVE_COMPARATOR | - |
| Belatacept | EXPERIMENTAL | Belatacept 5 mg/kg intravenous 30 minute infusion on Days 1, 15, 29, 43, 57 then every 28 days for 24 months |
| CNI | ACTIVE_COMPARATOR | Tacrolimus 4-11 ng/mL tablet orally according to package insert for 24 months Cyclosporine 50-250 ng/mL tablet orally according to package insert for 24 months |
| Standard of care | ACTIVE_COMPARATOR | Tacrolimus + Mycophenolate mofetil + prednisone from day 0 through day 365 |
| Belatacept-based immunosuppression | EXPERIMENTAL | Belatacept + Tacrolimus + prednisone from day 0 through day 89, then Belatacept + Mycophenolate mofetil + prednisone from day 90 through day 365 |
| A | ACTIVE_COMPARATOR | 10mg/kg 6 doses (Day 1, 5, week 2, 4, 8 and 12) for 12 weeks |
| B | ACTIVE_COMPARATOR | 5mg/kg 33 doses (every 4 weeks) for 144 weeks |
| A: Belatacept | EXPERIMENTAL | - |
| B: calcineurin inhibitor (CNI)-based immunosuppressive regimen | ACTIVE_COMPARATOR | - |
| Belatacept: More intensive (MI) regimen | EXPERIMENTAL | The MI regimen was designed to achieve projected serum trough concentrations of belatacept of approximately 20 μg/mL through Day 99, and approximately 5 μg/mL through Day 183 (10 mg/kg on Days 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, and 169). After Day 169, patients were reallocated and dosed to achieve projected trough serum concentrations of approximately 2 or 0.25 μg/mL (5 mg/kg every 4 or 8 weeks starting on Day 197). Those patients who received belatacept every 8 weeks received placebo infusions on scheduled treatment dates between infusions of active drug to maintain the blind between treatment regimens. Patients initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the patient was able to tolerate medications by mouth. Corticosteroids given daily. |
| Belatacept: Less intensive (LI) regimen | EXPERIMENTAL | The LI regimen was designed to achieve projected trough serum concentrations of belatacept of approximately 20 μg/mL through Day 29, and approximately 5 μg/mL through Day 99 (10 mg/kg on Days 1, 15, 29, 57 and 85). After Day 85, these subjects were reallocated and dosed to achieve projected trough serum concentrations of either approximately 2 or 0.25 μg/mL (5 mg/kg every 4 or 8 weeks starting on Day 113). Participants initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the participant was able to tolerate medications by mouth. Corticosteroids given daily. |
| Cyclosporine regimen | EXPERIMENTAL | The initial daily dose was 7±3 mg/kg. Subsequent doses were adjusted to maintain a predefined range of serum concentrations: 1st month, target level 150-400 ng/mL; after 1st month, target level of 150-300 ng/mL. Participants initially received mycophenolate mofetil (MMF), 2 g/d orally, unless the investigator chose to administer ≥1 doses intravenously The first MMF dose was administered preoperatively; subsequent doses were administered in 2 or 3 divided doses, every 8-12 hours, beginning as soon as the participant was able to tolerate medications by mouth. Corticosteroids given daily. |
| Cohort 1 (N=5 Subjects) | EXPERIMENTAL | Multiple intravenous infusions of daratumumab and belatacept over 10 weeks: * Daratumumab will be administered intravenously at a dose of 8 mg/kg weekly for 4 weeks, then every other week for 4 weeks (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, and 14). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit, and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. |
| Cohort 2 (N=10 Subjects) | EXPERIMENTAL | The enrollment of ten additional subjects is dependent on the results in Cohort 1. Multiple intravenous infusions of daratumumab and belatacept over 14 weeks:° * Daratumumab will be administered intravenously at a dose of 8 mg/kg for the first dose, then 16 mg/kg for subsequent given weekly for 3 weeks, then every 2 weeks for 2 doses (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, 14, 16 and 18). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. * Was modified based on the safety and efficacy analysis of Cohort 1. |
| Belatacept 50 mg Subcutaneous Injection | ACTIVE_COMPARATOR | Belatacept 50 mg subcutaneous (SC) injection |
| Belatacept 100 mg Subcutaneous Injection | ACTIVE_COMPARATOR | Belatacept 100 mg SC injection |
| Belatacept 125 mg Subcutaneous Injection | ACTIVE_COMPARATOR | Belatacept 125 mg SC injection |
| Belatacept 150 mg Subcutaneous Injections | ACTIVE_COMPARATOR | 2 SC injections of 75 mg Belatacept |
| Belatacept 200 mg Subcutaneous Injections | ACTIVE_COMPARATOR | 2 SC injections of 100 mg Belatacept |
| Belatacept 250 mg Subcutaneous Injections | ACTIVE_COMPARATOR | 2 SC injections of 125 mg Belatacept |
| Belatacept 125 mg Intravenous Infusion | ACTIVE_COMPARATOR | 125 mg Belatacept intravenous (IV) injection |
| Placebo | PLACEBO_COMPARATOR | SC injection of placebo solution |
| Name | Type | Description |
|---|---|---|
| Belatacept | DRUG | Belatacept, dosing 10mg/kg- day 0, 2 weeks, 1 month, 2 months, 3 months; subsequent doses 5mg/kg monthly through duration of trial or until retransplantation, whichever is first. |
| Calcineurin inhibitor therapy | DRUG | Upon enrollment, wean calcineurin inhibitor (CNI) to target tacrolimus trough of 3-5 nanogram/milliliter (ng/ml)or equivalent cyclosporine trough. Upon initiation of hemodialysis, discontinue CNI therapy over 5 days. |
| Mycophenolate mofetil | DRUG | Continue current dose at enrollment. Upon initiation of dialysis, decrease dose by half, then discontinue 2 weeks later |
| prednisone | DRUG | Begin steroid withdrawal one month after initiation of dialysis, with monthly reduction in dose by half, with plans to discontinue prednisone by 3 months after initiation of dialysis |
| Tacrolimus | DRUG | Specified dose on specified days |
| Cyclosporine A | DRUG | Specified dose on specified days |
| Enteric Coated Mycophenolate Sodium | DRUG | Specified dose on specified days |
| Corticosteroids | DRUG | Specified dose on Specified days |
| Cyclosporine | DRUG | - |
| Corticosteroid | DRUG | Non-experimental: CS is part of standard of care after heart transplant and will follow dosing recommendations as per standard clinical practice at a dose no less than 5mg/d. |
| ATG | DRUG | Anti-thymocyte globulin will be dosed intravenously at 3 mg/kg divided into 3 daily doses starting on day 0 after transplantation |
| Methylprednisolone | DRUG | Methylprednisolone 500 mg will be given intravenously before perfusion of the allograft during the transplant procedure, then methylprednisolone 0.5 mg/kg will be given intravenously twice daily for 6 total doses |
| Mycophenolate mofetil (MMF) | DRUG | Oral, capsule |
| daratumumab | BIOLOGICAL | Daratumumab is a CD38 (Cluster of Differentiation 38)-directed cytolytic monoclonal antibody indicated for the treatment of multiple myeloma. In this study, daratumumab will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant. Definition of highly sensitized: Potential kidney transplant recipients with either: * calculated panel reactive antibodies (cPRA) ≥99.9% awaiting deceased donor transplant, or * cPRA \>98% (with \>5 years of waiting time) awaiting living donor transplant |
| Bone marrow aspiration | PROCEDURE | Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 12 weeks after starting the study regimen. In subjects who undergo a kidney transplant during the study, another bone marrow aspiration will be done if it has been \>4 weeks since the previous bone marrow aspiration. |
| Placebo | DRUG | Subcutaneous injection of placebo solution (product ID: 224818-N000- 029) |
| Abatacept | DRUG | - |
Inclusion Criteria: * Signed written informed consent * Kidney transplant recipient (human leukocyte antigen (HLA) non-identical donor) who now has impaired renal allograft function with: * Estimated glomerular filtration rate (GFR) \< 35 with a decline in GFR of \> 10% in the 12 months prior to en...
Belatacept is an immunosuppressive agent studied in kidney transplantation, including maintenance therapy in adolescent and adult renal allograft recipients, highly sensitized prospective kidney transplant recipients, and failing renal allografts. It is also being evaluated in heart transplantation and in lung transplantation immunosuppression. Its development spans several transplant settings rather than a single indication.
Belatacept targets CD80 and CD86, two costimulatory ligands on antigen-presenting cells. It acts as an inhibitor of this costimulatory pathway, which is a mechanism intended to suppress T-cell activation and the immune response against a transplanted organ. Bristol-Myers Squibb Company (BMY) is the developer.
Belatacept is developed by Bristol-Myers Squibb Company, which trades under the ticker BMY. The company sponsors the clinical program evaluating belatacept across kidney, heart, and lung transplant settings, including the Phase 3 adolescent kidney transplant conversion study NCT04877288.
Belatacept is in Phase 3 clinical development. The Phase 3 study NCT04877288 is recruiting adolescent kidney transplant recipients aged 12 to under 18 years, comparing conversion to a belatacept-based immunosuppressive regimen with continuation of a calcineurin inhibitor-based regimen. Earlier phase work includes Phase 1 and Phase 2 trials in other transplant populations.
Belatacept trials include NCT04877288, a recruiting Phase 3 study in adolescent kidney transplant recipients across the United States and Europe; NCT04827979, a completed Phase 1 study of daratumumab and belatacept for desensitization in highly sensitized kidney transplant candidates; NCT04477629, a recruiting Phase 2 study in de novo heart transplantation; and NCT03388008, a completed Phase 2 pilot study in lung transplantation immunosuppression.
Belatacept is also known by the brand name Nulojix. Searches for either name refer to the same Bristol-Myers Squibb (BMY) compound, a CD80 and CD86 inhibitor studied in transplant immunosuppression, including kidney transplant maintenance and investigational use in heart and lung transplantation.