Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA28
Belatacept, a selective costimulation blocker, is a soluble fusion protein consisting of a modified extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to a portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4.
Belatacept binds to CD80 and CD86 on antigen presenting cells. As a result, belatacept blocks CD28 mediated co-stimulation of T cells inhibiting their activation. Activated T cells are the predominant mediators of immunologic response to the transplanted kidney. Belatacept, a modified form of CTLA4-Ig, binds CD80 and CD86 more avidly than the parent CTLA4-Ig molecule from which it is derived. This increased avidity provides a level of immunosuppression that is necessary for preventing immune-mediated allograft failure and dysfunction.
In a clinical study, approximately 90% saturation of CD86 receptors on the surface of antigenpresenting cells in the peripheral blood was observed following the initial administration of belatacept. During the first month post-transplantation, 85% saturation of CD86 was maintained. Up to month 3 post-transplantation with the recommended dosing regimen, the level of CD86 saturation was maintained at approximately 70% and at month 12, approximately 65%.
The safety and efficacy of belatacept as part of an immunosuppressive regimen following renal transplantation were assessed in two randomised, partially-blinded, multicenter, 3 year studies with the primary endpoint specified at Year 1. These studies compared two dose regimens of belatacept (MI and LI) with ciclosporin in recipients of standard criteria (Study 1) or extended criteria (Study 2) donor organs. All patients received basiliximab, MMF, and corticosteroids. The more intensive (MI) regimen, which included higher and more frequent dosing during the first 6 months post transplant, resulted in 2-fold higher exposure to belatacept than the less intensive (LI) regimen during Months 2 through 7 post transplant. Efficacy was similar between MI and LI while the overall safety profile was better for the LI. Therefore, the recommended dose of belatacept is the LI dosage regimen.
Standard criteria donor organs were defined as organs from a living donor, or a deceased donor with anticipated cold ischemia time of <24 hours and not meeting the definition of extended criteria donor organs. Study 1 excluded (1) recipients undergoing a first transplant whose current PRA were ≥50%; (2) recipients undergoing a retransplantation whose current PRA were ≥30%; (3) recipients when previous graft loss was due to acute rejection and in case of a positive T-cell lymphocytotoxic cross match.
In this study, 666 patients were enrolled, randomised, and transplanted; 219 to belatacept MI, 226 to belatacept LI, and 221 to ciclosporin. The median age was 45 years; 58% of donor organs were from living patients; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorised as of other races; 16% had PRA ≥10%; and 41% had 4 to 6 HLA mismatches.
The dose of corticosteroids used in all treatment groups was tapered during the first 6 months following transplantation. The median corticosteroid doses administered with the belatacept recommended regimen up to months 1, 3, and 6 were 20 mg, 12 mg and 10 mg, respectively.
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 after cardiac death or (4) anticipated cold ischemia time of ≥24 hours. Study 2 excluded recipients with a current PRA ≥30%, re-transplanted patients, and in case of a positive T-cell lymphocytotoxic cross match.
In this study, 543 patients were enrolled, randomised, and transplanted; 184 to belatacept MI, 175 to belatacept LI, and 184 to ciclosporin. 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 categorised as of other races; 3% had PRA ≥10%; and 53% had 4 to 6 HLA mismatches.
The dose of corticosteroids used in all treatment groups was tapered during the first 6 months following transplantation. The median corticosteroid doses administered with the belatacept recommended regimen up to months 1, 3, and 6 were 21 mg, 13 mg and 10 mg, respectively.
Table 5 summarises results for belatacept LI compared with ciclosporin for the co-primary efficacy endpoints of death and graft loss, composite renal impairment, and acute rejection (defined as clinically suspected biopsy proven acute rejection). Patient and graft survival were similar between belatacept and ciclosporin. Fewer patients met the composite renal impairment endpoint and mean GFR was higher with belatacept compared to ciclosporin.
Acute rejection (AR) occurred more frequently with belatacept versus ciclosporin in Study 1 and with similar frequency with belatacept versus ciclosporin in Study 2. Approximately 80% of AR episodes occurred by Month 3 and were infrequent after Month 6. In Study 1, 11/39 belatacept and 3/21 ciclosporin acute rejections were Banff 97 grade ≥ IIb by Year 3. In Study 2, 9/33 belatacept and 5/29 ciclosporin acute rejections were Banff 97 grade ≥ IIb by Year 3. AR was treated more often with lymphocyte depleting therapy (a risk factor for PTLD; see section 4.4) in the belatacept group than the ciclosporin group. In both studies, in patients with AR by Year 2, donor-specific antibodies, one of the criteria for diagnosis of antibody-mediated rejection, were present in 6% (2/32, Study 2)-8% (3/39, Study 1) and 20% (4/20, Study 1)-26% (7/27, Study 2) in the belatacept and ciclosporin groups by year 3, respectively. By Year 3 recurrent AR was similar across groups (<3%) and subclinical AR identified on the 1 year protocol biopsy was 5% in both groups. In Study 1, 5/39 belatacept patients versus 1/21 ciclosporin patients with AR had experienced graft loss, and 5/39 belatacept patients and no ciclosporin patients with AR had died by Year 3. In Study 2, 5/33 belatacept patients versus 6/29 ciclosporin patients with AR had experienced graft loss, and 5/33 belatacept patients versus 5/29 ciclosporin patients with AR had died by Year 3. In both studies, mean GFR following AR was similar in belatacept and ciclosporin treated patients.
Table 5. Key efficacy outcomes at years 1 and 3:
| Study 1: living and standard criteria deceased donors | Study 2: extended criteria donors | |||
|---|---|---|---|---|
| Parameter | Belatacept LI | Ciclosporin | Belatacept LI | Ciclosporin |
| N=226 | N=221 | N=175 | N=184 | |
| Patient and Graft Survival (%) | ||||
| Year 1 [95% CI] | 96.5 [94.1-98.9] | 93.2 [89.9-96.5] | 88.6 [83.9-93.3] | 85.3 [80.2-90.4] |
| Year 3 [95% CI] | 92.0 [88.5-95.6] | 88.7 [84.5-92.9] | 82.3 [76.6-87.9] | 79.9 [74.1-85.7] |
| Death (%) | ||||
| Year 1 | 1.8 | 3.2 | 2.9 | 4.3 |
| Year 3 | 4.4 | 6.8 | 8.6 | 9.2 |
| Graft Loss (%) | ||||
| Year 1 | 2.2 | 3.6 | 9.1 | 10.9 |
| Year 3 | 4.0 | 4.5 | 12.0 | 12.5 |
| % of Patients meeting Composite renal impairment endpoint at | ||||
| Year 1a | 54.2 | 77.9 | 76.6 | 84.8 |
| P-value | <0.0001 | - | <0.07 | - |
| AR (%) | ||||
| Year 1 (%) [95% CI] | 17.3 [12.3-22.2] | 7.2 [3.8-10.7] | 17.7 [12.1-23.4] | 14.1 [9.1-19.2] |
| Year 3 (%) [95% CI] | 17.3 [12.3-22.2] | 9.5 [5.6-13.4] | 18.9 [13.1-24.7] | 15.8 [10.5-21.0] |
| Mean Calculated GFRb ml/min/1.73 m² | ||||
| Year 1 | 63.4 | 50.4 | 49.6 | 45.2 |
| Year 2 | 67.9 | 50.5 | 49.7 | 45.0 |
| Μέσος υπολογιζόμενος GFRγ ml/λεπτό/1.73 m² | ||||
| Month 1 | 61.5 | 48.1 | 39.6 | 31.8 |
| Year 1 | 65.4 | 50.1 | 44.5 | 36.5 |
| Year 2 | 65.4 | 47.9 | 42.8 | 34.9 |
| Year 3 | 65.8 | 44.4 | 42.2 | 31.5 |
a Proportion of Patients with Measured GFR < 60 ml/min/1.73 m² or with a Decrease in Measured GFR ≥ 10 ml/min/1.73 m² from Month 3 to
Month 12.
b Measured GFR was assessed by iothalamate at Year 1 and 2 only
c Calculated GFR was assessed by MDRD formula at Month 1, Years 1, 2, and 3
In Study 1 by Year 3, mean calculated GFR was 21 ml/min/1.73 m² higher with belatacept, and 10% and 20% of patients reached CKD stage 4/5 (GFR <30 ml/min/1.73 m²) with belatacept versus ciclosporin, respectively. In Study 2 by Year 3, mean calculated GFR was 11 ml/min/1.73 m² higher with belatacept, and 27% and 44% of patients reached CKD stage 4/5 (GFR <30 ml/min/1.73 m²) with belatacept versus ciclosporin, respectively.
The prevalence of CAN/IFTA at Year 1 in Studies 1 and 2, was numerically lower with belatacept than ciclosporin (~9.4% and 5%, respectively).
New Onset Diabetes Mellitus and Blood Pressure In a prespecified pooled analysis of Studies 1 and 2 at Year 1, the incidence of new onset diabetes mellitus (NODM), defined as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values >126 mg/dl (7.0 mmol/l) post-transplantation, was 5% with belatacept and 10% with ciclosporin. At Year 3, the incidence of NODM was 8% with belatacept and 10% with ciclosporin.
For Studies 1 and 2 at Years 1 and 3, belatacept was associated with 6 to 9 mmHg lower mean systolic blood pressure, approximately 2 to 4 mmHg lower mean diastolic blood pressure, and less use of antihypertensive medicinal products than ciclosporin.
A total of 321 belatacept (MI: 155 and LI: 166) and 136 ciclosporin patients completed 3 years of treatment in Study 1 and entered the 4-year long-term open label extension period (up to 7 years in total). More patients discontinued in the ciclosporin group (32.4%) versus each belatacept group (17.4% and 18.1% in MI and LI groups, respectively) during the long-term extension period. A total of 217 belatacept (MI: 104 and LI: 113) and 87 ciclosporin patients completed 3 years of treatment in Study 2 and entered the 4-year long-term open label extension period (up to 7 years in total). More patients discontinued in the ciclosporin group (34.5%) versus each belatacept group (28.8% and 25.7% for MI and LI groups, respectively) during the long-term extension period.
As compared to ciclosporin and assessed by the hazard ratio (HR) estimates (for death or graft loss) from an ad hoc Cox regression analysis, overall patient and graft survival was higher for belatacepttreated patients in Study 1, HR 0.588 (95% CI: 0.356-0.972) for the MI group and HR 0.585 (95% CI: 0.356-0.961) for the LI group, and comparable across treatment groups in Study 2, HR 0.932 (95% CI: 0.635-1.367) for the MI group and HR 0.944 (95% CI: 0.644-1.383) for the LI group. The overall proportion of patients with death or graft loss was lower in belatacept-treated patients (MI: 11.4%, LI: 11.9%) as compared to ciclosporin-treated patients (17.6%) in Study 1. The overall proportion of patients with death or graft loss was comparable across treatment groups (29.3%, 30.9%, and 28.3% for MI, LI and ciclosporin, respectively) in Study 2. In Study 1, in the MI, LI, and ciclosporin groups, respectively, death occurred in 7.8%, 7.5%, and 11.3% of patients, and graft loss occurred in 4.6%, 4.9%, and 7.7% of patients. In Study 2, in the MI, LI, and ciclosporin groups, respectively, death occurred in 20.1%, 21.1%, and 15.8% of patients, and graft loss occurred in 11.4%, 13.1%, and 15.8% of patients. The higher proportion of deaths in the LI group in Study 2 was mainly due to neoplasms (MI: 3.8%, LI: 7.1%, ciclosporin: 2.3%).
The higher calculated GFR observed in belatacept-treated patients relative to ciclosporin-treated patients during the first 3 years was maintained over the long-term extension period. In Study 1, mean calculated GFR at 7 years was 74.0, 77.9 and 50.7 mL/min/1.73 m² in the belatacept MI, belatacept LI and ciclosporin groups, respectively. In Study 2, mean calculated GFR at 7 years was 57.6, 59.1 and 44.6 mL/min/1.73 m², in the same groups, respectively. The time to death, graft loss, or GFR <30 mL/min/1.73 m² was analyzed over the 7-year period: in Study 1, approximately 60% reduction in the risk of death, graft loss, or GFR <30 mL/min/1.73 m² was observed among patients in the belatacept groups as compared with those assigned to ciclosporin. In Study 2, approximately 40% reduction in this risk was observed among patients in the belatacept groups as compared with those assigned to ciclosporin.
A single, randomised, multi-center, controlled Phase 2 trial of belatacept in de novo orthotopic liver transplant recipients was conducted. A total of 250 subjects were randomised to 1 of 5 treatment groups (3 belatacept and 2 tacrolimus groups). The belatacept dosing used in this liver study was higher in all 3 belatacept arms than the belatacept dosing used in the Phase 2 and 3 renal transplant studies.
An excess in mortality and graft loss was observed in the belatatacept LI + MMF group and an excess in mortality was observed in the belatacept MI + MMF group. No pattern was identified in the causes of death. There was an increase in viral and fungal infections in the belatacept groups versus the tacrolimus groups, however overall frequency of serious infections was not different among all treatment groups (see section 4.4).
Two hundred seventeen (217) patients 65 years and older received belatacept across one Phase 2 and two Phase 3 renal studies. Elderly patients demonstrated consistency with the overall study population for safety and efficacy as assessed by patient and graft survival, renal function, and acute rejection.
The European Medicines Agency has deferred the obligation to submit the results of studies with belatacept in one or more subsets of the paediatric population in renal transplantation (see section 4.2 for information on paediatric use).
The pharmacokinetics of belatacept in renal transplant patients and healthy subjects appeared to be comparable. The pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally in healthy subjects after a single intravenous infusion dose of 1 to 20 mg/kg. The mean (range) pharmacokinetic parameters of belatacept after multiple intravenous infusions at doses of 5 and 10 mg/kg in renal transplant subjects were: terminal half-life, 8.2 (3.1-11.9) and 9.8 (6.1-15.1) days, respectively; systemic clearance 0.51 (0.33-0.75) and 0.49 (0.23-0.70) ml/h/kg, respectively; and distribution volume at steady state, 0.12 (0.09-0.17) and 0.11 (0.067-0.17) l/kg, respectively. At the recommended dosing regimen, serum concentration generally reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. At Month 1, 4, and 6 post-transplant, the mean (range) trough concentrations of belatacept were 22.7 (11.1-45.2), 7.6 (2.1-18.0), and 4.0 (1.5-6.6) μg/ml, respectively.
Based on population pharmacokinetic analysis of 944 renal transplant patients up to 1 year posttransplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. The trough concentration of belatacept was consistently maintained up to 5 years post-transplant. Minimal systemic accumulation of belatacept occurred upon multiple infusions of 5 or 10 mg/kg doses in renal transplant patients every 4 weeks. The accumulation index for belatacept at steady state is 1.1.
Population pharmacokinetic analyses in renal transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. No clinically relevant effects of age, gender, race, renal function (calculated GFR), diabetes, or concomitant dialysis on clearance of belatacept was identified.
There is no data available in patients with hepatic impairment.
Belatacept has less activity in rodents than abatacept, a fusion protein that differs from belatacept by two amino acids in the CD80/86 binding domains. Because of abatacept’s similarity to belatacept in structure and mechanism of action and its higher activity in rodents, abatacept was used as a more active homolog for belatacept in rodents. Therefore, preclinical studies conducted with abatacept have been used to support the safety of belatacept in addition to the studies conducted with belatacept.
No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a six-month and one-year toxicity study in cynomolgus monkeys with belatacept and abatacept, respectively, no significant toxicity was observed. Reversible pharmacological effects consisted of minimal decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed in either study. This was despite the presence in the abatacept study of a virus, lymphocryptovirus, known to cause these lesions in immunosuppressed monkeys within the time frame of these studies. The viral status was not determined in the belatacept study but, as this virus is prevalent in monkeys, it was likely present in these monkeys as well.
In rats, belatacept had no undesirable effects on male or female fertility. Belatacept was not teratogenic when administered to pregnant rats and rabbits at doses up to 200 mg/kg and 100 mg/kg daily, respectively, representing approximately 16 and 19 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC. Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with infections in a small percentage of dams at all doses (≥20 mg/kg, ≥3 times the MRHD exposure based on AUC), and produced no adverse effects in offspring at doses up to 200 mg/kg representing 19 times the MRHD exposure based on AUC. Belatacept was shown to cross the placenta in rats and rabbits. Abatacept administered to female rats every three days during gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept or belatacept.
Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats) as well as inflammation of the thyroid and pancreas (both juvenile and adult rats). Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses.
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