Safety and Efficacy of Belatacept as Immunotherapy in Kidney Transplant Recipients

Cyclosporine and tacrolimus, calcineurin inhibitors (CNIs), are commonly used as immunosuppressive therapy in patients who have undergone kidney transplantation. According to Josep M. Grinyó, MD, PhD, and colleagues in Buenos Aires, Argentina, those agents may be associated with patient comorbidity via nephrotoxicity and cardiovascular risk (hypertension, hypercholesterolemia, and diabetes mellitus), as well as transplant loss via chronic transplant injury. The researchers contend that there is a need for immunosuppressive agents that control the alloimmune response as effectively as CNIs, but do not have the possible renal and cardiovascular adverse effects.

Some immunosuppressive regimens that avoid or minimize CNI involve the mammalian target of rapamycin (mTOR) inhibitors sirolimus or everolimus; those have been evaluated in earlier prospective studies of recipients of kidney transplant. In those studies, patients who switched from therapy based on CNIs to one based on a mTOR inhibitor had significant improvement in kidney function 12 months after the change compared with patients who continued with treatment with cyclosporine or tacrolimus. However, the patients in the mTOR inhibitor groups were more likely to experience adverse events, particularly dyslipidemia and proteinuria.

The immunosuppressive belatacept selectively inhibits activation of T cells via costimulation blockade. In a recent phase 2 trial, belatacept was studied as conversion therapy in patients maintained on immunosuppression based on CNI (cyclosporine or tacrolimus). The primary outcome of the trial was change in estimated glomerular filtration rate (eGFR). At 12 months, improvement in kidney function from baseline was statistically significant in patients who switched to belatacept-based immunosuppression compared with those who continued CNI therapy (7.0 vs 2.1 mL/min/1.73 m2; P=.006). Further, there was no association with increased risk for death or transplant loss in the patients who switched therapy.

Among those who remained in the trial beyond 12 months, mean change in eGFR from baseline remained greater than among those who did not switch. Between 12 and 24 months, no patient in the belatacept group experienced acute transplant rejection compared with three patients in the group that did not switch to belatacept. Dr. Grinyó et al. reported on outcomes at 36 months after randomization in the intention-to-treat population of this study [American Journal of Kidney Diseases. 2017;69(5):587-594].

Of 84 patients treated with belatacept, 74 (88%) were followed up for the full 36 months, as were 72 of the 89 (81%) patients in the CIN group. Reasons for discontinuation prior to the 36-month follow-up in the belatacept group were lack of efficacy (n=2), adverse events (n=1 [polyoma virus-associated nephropathy]), death (n=1) and other (n=1). In the CNI group, 14 patients discontinued treatment: unknown reasons (n=4), withdrawal of consent (n=3), adverse events (n=2 [pulmonary edema and nephropathy, n=1; cellulitis, n=1]), other (n=2), administrative reason (n=1), death (n=1), and lack of efficacy (n=1). There were also 16 patients in the CNI group who switched to belatacept after month 24, as permitted in the study protocol.

At the 36-month mark, the cumulative frequency of serious adverse events was similar for the two groups: 39% (33/84) in the belatacept group and 40% (36/89) in the CNI group. Incident rates of serious infections per 100 person-years of treatment exposure were also similar: 10.21 per 100 person-years in the belatacept group and 9.31 per 100 person-years in the CNI group. However, more patients in the belatacept group had any-grade viral infections compared with those in the CNI group (14.60 vs 11.00 per 100 person-years, respectively). There was no post-transplantation lymphoproliferative disorder reported in either group.

In the belatacept group, mean eGFR increased from month 1 to month 36; there was no increase in the CNI treatment group. At months 12, 24, and 36, mean eGFRs in the belatacept group were 60.3, 62.4, and 62.4 mL/min/1.73 m2, respectively. Corresponding eGFRs in the control group were 56.9, 55.0, and 55.6 mL/min/1.73 m2, respectively.

There was no significant difference in the probability of acute rejection for belatacept (8.38% vs 36.0%; hazard ratio [HR], 2.50; 95% confidence interval [CI], 0.65-9.65; P=.2). The HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=.9).

The researchers cited some limitations to the study, including the small sample sizes, the open-label design of the trial, and the large range of times between transplantation and conversion (6-36 months) which may have confounded
the results.

In conclusion, the researchers said, “Despite these limitations, our results suggest that the improvements in kidney function seen in patients who switched from CNI-based to belatacept-based immunosuppression were sustained over 36 months and may help preserve long-term transplant function. This exploratory analysis indicated that switching from a CNI-based to a belatacept-based regimen may represent a safe and effective clinical approach to long-term immunosuppression, one that is being further explored in an ongoing phase 3b trial (clinicaltrials.gov study number NCT01820572).”

Takeaway Points

  1. Results of a phase 2 study among kidney transplant recipients with low immunologic risk who switched form a calcineurin inhibitor (CIN) to belatacept are presented in this article.
  2. At 6 to 36 months following transplantation, treatment exposure-adjusted incidence rates for serious infections and malignancies were similar between the belatacept group and the CNI group.
  3. There were no significant differences between the two groups in the probability of acute rejection.