Publication:
Author Interview: Professor Lionel ROSTAING, MD, PhD

Belatacept- versus Cyclosporine-based Immunosuppression in Renal Transplant Recipients with Pre-existing Diabetes.

Rostaing L, Neumayer HH, Reyes-Acevedo R, Bresnahan B, Florman S, Vitko S,
 Heifets M, Xing J, Thomas D, Vincenti F.
Toulouse, France;
Clin J Am Soc Nephrol. 2011 Sep 15. [Epub ahead of print]

What is belatacept?

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, is the basis of abatacept, which conserves the natural structure of CTLA4, belatacept, which has enhanced activity thanks to two amino acid substitutions. Abatacept and belatacept both block CD86-CD28 interaction, but belatacept blocks it more powerfully. Abatacept has already been approved for many years for the treatment of rheumatoid arthritis and is marketed as Orencia® (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept has been approved only recently in the US and in Europe as Nulojix® (Bristol-Myers Squibb, Princeton, NJ, USA).

What were the main findings of belatacept-based phase III studies in kidney transplantation?

In phase III kidney-transplantation trials comparing cyclosporine (CsA)-based immunosuppression vs. belatacept (either more intensive: MI; or less intensive: LI)-based immunosuppression at 1 year, belatacept was associated with similar patient/graft survival, better renal function, and an improved cardiovascular/metabolic risk profile as compared to CsA in the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT; n=666 patients) and Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT; n=543 patients) studies.

Acute rejection was more frequent with belatacept in BENEFIT but without consequences with respect to kidney allograft function by one year posttransplantation. Post-transplant lymphoproliferative disorder (PTLD), and specifically central nervous system PTLD, was observed more frequently in belatacept-treated patients. 493 of 666 patients (74%) in BENEFIT and 347 of 543 (64%) in BENEFIT-EXT completed two years of treatment. The proportion of patients who survived with a functioning graft was similar across groups (BENEFIT: 94% MI, 95% LI, and 91% CsA; BENEFIT-EXT: 83% MI, 84% LI, and 83% CsA). Belatacept's renal benefits were sustained, as evidenced by a 16 to 17 mL/min (BENEFIT) and an 8 to 10 mL/min (BENEFIT-EXT) higher calculated glomerular filtration rate (cGFR) in the belatacept groups versus CsA.

There were few new acute rejection episodes in either study between years 1 and 2. Because PTLD risk was highest in Epstein-Barr virus (EBV) seronegative patients, an efficacy analysis of EBV seropositive patients was performed and was consistent with the overall population results. There were two previously reported cases of PTLD in each study between years 1 and 2 in the belatacept groups. The overall balance of safety and efficacy favored the LI over the MI regimen. Of note, the registered belatacept dose is that used in the LI arm of the phases III studies.

Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors (CNIs). Will belatacept-treated patients provide a better cardiovascular/metabolic risk profile than current immunosuppressants?

With regards to cardiovascular and metabolic endpoints, the two phase III studies (BENEFIT and BENEFIT-EXT) had at month 12 prespecified secondary endpoints, such as changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT). Across the two studies the mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups vs. CsA (p≤ 0.002) at month 12. Non-HDL cholesterol was lower in the belatacept groups vs. CsA (p<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups vs. CsA (p<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups vs. CsA in a prespecified pooled analysis (p<0.05 MI or LI vs. CsA).

Q3. What are the main findings of belatacept-based phase III studies in transplant patients with pre-existing diabetes mellitus?

It has been demonstrated that renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. For type 2 diabetes, the use of calcineurin inhibitors might increase the amount of antidiabetic medications.

Moreover, it has also been demonstrated that kidney transplant patients developing NODAT have the same impaired patient/allograft outcome as do have patients with pre-existing diabetes. A post hoc analysis assessed the effect of belatacept in this high-risk group of patients with pre-existing diabetes, by evaluating pooled data from BENEFIT and BENEFIT-EXT. Of 1209 intent-to-treat patients, 336 had PD. At 12 months, the belatacept LI arm demonstrated a numerically higher rate of patients surviving with a functioning graft (90.4% MI [103 of 114], 92.8% LI [90 of 97], and 80.8% CsA [101 of 125]),i.e. a difference of 12% between belatacept LI and CsA, and fewer serious adverse events than CsA or MI patients.

Three cases of post-transplant lymphoproliferative disorder were reported in LI patients, one involving the central nervous system. Higher rates (% [95% confidence interval]: 22.8% MI [15.1 to 30.5]; 20.6% LI [12.6 to 28.7]; 14.4% CsA (8.2 to 20.6]) and grades of acute rejection were observed with belatacept. Measured GFR (mL/min per 1.73 m2, 59.8 MI; 62.5 LI; 45.4 CsA, i.e. a difference of 14.4 mL/min per 1.73 m2 between CsA and belatacept LI), and cardiovascular risk profile were better for belatacept vs. CsA.

We also have to keep in mind that NODAT incidence in BENEFIT and BENEFIT-EXT occurred less often in the belatacept groups vs. CsA in a prespecified pooled analysis (p<0.05 MI or LI vs. CsA).

Q4. Were any findings unexpected?

Overall, in both belatacept-based phase III studies, patient survival was similar across the three protocols—not the case in the PD population where those randomized to belatacept have a much lower mortality at 1 year as compared to those randomized on CsA.

Hence, PD patients on belatacept therapy have at 1 year post-transplantation a similar survival rate as compared to those without PD but being treated by calcineurin inhibitors.

Q5. What should clinicians and patients take away from this study?

NODAT incidence occurred less often in the belatacept groups vs. CsA group. Kidney transplant recipients with pre-existing diabetes experience a very good 1 year patient and graft survival when they receive from the transplantation onwards belatacept less intensive regimen which is the one approved by the FDA and by the EMEA.

Moreover, in this high risk group of patients regarding cardiovascular mortality/morbidity, the use of belatacept resulted in a better allograft function (despite higher rate of acute rejections) at 1 year post-transplantation and in a better cardiovascular profile as compared to CsA.

We can hypothesize that it will be translated in the mid-term to an improved patient/allograft survival.

Q6. What should clinicians and patients take away from this study?

Because most kidney transplant recipients with pre-existing diabetes suffer from type 2 and because the use of calcineurin inhibitors in this setting might be harmful by increasing blood pressure and blood lipids, the replacement of calcineurin inhibitors by belatacept LI from transplantation onwards is of outstanding value.
Moreover, those patients on belatacept-based therapy have a much better allograft function at 1-year post-transplantation as compared to those receiving CsA.

Moreover, it has been previously demonstrated that a better kidney allograft function at 1 year is associated with a significant better allograft survival in the long term.

Hence, for all the above mentioned reasons, the use of belatacept in kidney recipients with pre-existing diabetes might result in the long term with higher rates of patient/allograft survival, good renal function, and less cardiovascular-targeted medications.

Finally, belatacept-based immunosuppression will result in less NODAT, the latter being a poor condition whit regards to cardiovascular morbidity/mortality.

SummaryBackground and objectives Renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. To assess the effect of belatacept in this high-risk group, we evaluated outcomes of the subpopulation with PD from previously published BENEFIT and BENEFIT-EXT trials.

Design, setting, participants, & measurements A post hoc analysis evaluated pooled data from BENEFIT (living donors or standard criteria donors) and BENEFIT-EXT (extended criteria donors). Patients were randomized to receive cyclosporine or a more intensive (MI) or less intensive (LI) belatacept regimen.Results Of 1209 intent-to-treat patients, 336 had PD.

At 12 months, the belatacept LI arm demonstrated a numerically higher rate of patients surviving with a functioning graft (90.4% MI [103 of 114], 92.8% LI [90 of 97], and 80.8% cyclosporine [101 of 125]), and fewer serious adverse events than cyclosporine or MI patients.

Three cases of posttransplant lymphoproliferative disorder were reported in LI patients, one involving the central nervous system. Higher rates (% [95% confidence interval]: 22.8% MI [15.1 to 30.5]; 20.6% LI [12.6 to 28.7]; 14.4% cyclosporine (8.2 to 20.6]) and grades of acute rejection were observed with belatacept. Measured GFR (ml/min per 1.73 m(2), 59.8 MI; 62.5 LI; 45.4 cyclosporine), and cardiovascular risk profile were better for belatacept versus cyclosporine.

Conclusions In post hoc analysis of patients with PD, patient/graft survival and renal function at 12 months were numerically higher with belatacept versus cyclosporine, but not statistically significant. Further study is necessary to confirm the benefits belatacept may provide in these patients.