SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Belatacept
  4. Alefacept (Amevive)
  5. Eculizumab (Soliris)
  6. References

There remains a need in solid-organ transplantation for an immunosuppressive agent with a novel mechanism of action and fewer adverse consequences to replace current immunosuppressive drugs and improve long-term patient and graft survival. There are several agents on the horizon, both small molecules and biologics, offering this promise along with ease and consistency of long-term administration. We discuss three biologic agents currently in advanced stages of clinical trials in kidney transplantation.

Agents referred to as “biologics” are playing increasingly important roles in clinical medicine. The term itself refers to medicinal products created or isolated from a variety of natural sources—humans, animals, microorganisms. They are protein based and are produced by biotechnological methods. These types of therapeutic agents have always played a key role in kidney transplantation. (Polyclonal antilymphocyte sera were first produced and utilized in the 1960 s, with OKT3, daclizumab, and basiliximab being more recent additions.) In looking forward, however, the term “biologics” is used more restrictively to describe medications produced by recombinant DNA technology. The current paradigm in transplantation is for biologics to be administered for a defined purpose (induction or antirejection therapy) over a limited period (several weeks at most). As in dermatology, rheumatology, and oncology, it seems likely that future use of biologics will be as maintenance therapy, spanning the life of the allograft.

Although outcomes in solid-organ transplantation have improved dramatically, allowing broad expansion of clinical applicability, with current immunosuppressants, there remains a recognized need for newer agents. This need is driven by both incomplete efficacy (demonstrated largely as late allograft failure) and untoward adverse effects, including infection, malignancy, and nephrotoxicity. It seems, thus far, that interventions intended to ease the impact of nephrotoxicity, such as drug minimization, increase the possibility of infection and malignancy, and vice versa. Against this backdrop, it is hoped that the new biologics will allow consistent long-term efficacy and ease of administration and will also produce fewer adverse consequences and long-term complications.

The new biologics undergoing development as transplant therapeutics are mainly humanized or chimeric monoclonal antibodies, targeted to a defined antigenic ligand with the goal of inhibiting a single pathway or cell type involved in the rejection process. While it is tempting to consider administration of these agents to donors before or during organ recovery, most (if not all) will be administered to transplant recipients. Many of these agents were initially developed for use in rheumatology, oncology, or dermatology, and some have already been approved by the Food and Drug Administration (FDA) for other indications. In this review, we will cover only those agents that are in advanced stages of clinical development. Efalizumab, an antiCD2 monoclonal, approved for psoriasis and with some clinical promise in transplantation, was withdrawn from the market in the U.S. in 2009 due to its association with progressive multifocal leukoencephalopathy after long-term use in a few psoriasis patients and will not be discussed further.

Belatacept

  1. Top of page
  2. Abstract
  3. Belatacept
  4. Alefacept (Amevive)
  5. Eculizumab (Soliris)
  6. References

It has been well established that CTLA4Ig blocks CD28-mediated co-stimulation and suppresses T cell-mediated responses in animal models of transplantation, autoimmunity, and inflammation. Bristol-Myers Squibb initially developed abatacept (CTLA4-Ig) a soluble fusion protein molecule now approved by the FDA for the treatment of rheumatoid arthritis and psoriasis. Belatacept is a humanized monoclonal antibody subsequently developed for use in kidney transplantation. It has a longer half-life and greater binding affinity than CTLA4-Ig, but acts via an identical mechanism: inhibiting co-stimulation of T cells by antigen-presenting cells via blockage of the CD80/86 interaction with CD28. The net result of blocking this pathway is thought to be anergy and apoptosis of T-cells undergoing antigen-specific activation via the T-cell receptor (TCR), and downregulation of the immune response. The agent is administered intravenously, at intervals ranging from 1 to 4 weeks in clinical trials, and the underlying rationale of the development program was to use belatacept as an alternative to calcineurin inhibitors.

The Phase 2 and 3 studies involved similar designs: All patients received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. The control arm in each study received standard doses of cyclosporine A (CyA), while two treatment arms received different dosings of belatacept (low and moderate intensity). In the Phase 2 trial involving 218 patients (NEJM 1 year and AJT 5 year), data after 1 year revealed nearly identical patient and graft survival, as well as acute rejection rates. However, there was better preservation of renal function, with 10–15% higher glomerular filtration rates (GFRs) in the belatacept arms, and less chronic allograft nephropathy in a 1-year protocol biopsy. A recent publication of data derived from 132 patients electing to participate in an extension phase of the trial documented that these same trends were evident after 5 years of follow-up.1 Unfortunately, only 76% (78/106) of those receiving belatacept and 61% (16/26) of the patients in the CyA arm completed the 5-year extension. Mean estimated GFR remained stable in the belatacept group between 12 (76 ± 20) and 60 months (77 ± 23 mL/min/1.73 m2) of follow-up, but declined in the CyA group (from 74 ± 24 to 59 ± 15 mL/min/1.73 m2) over the same period. Patient mortality was comparable between the groups at 3% (n = 3) in the belatacept group and 8% (n = 2) in the CyA group, and neoplasms also occurred at a similar frequency of 12% in both groups.

The successful Phase 2 experience led to recent completion of two large Phase 3 trials of belatacept-based maintenance therapy.2, 3 Although belatacept dosing changed slightly, both studies, conducted in differing patient populations all at relatively low immunologic risk, involved basiliximab induction, MMF, and corticosteroids. Again, subjects were randomized to CyA or one of two (low or moderate intensity) belatacept treatment regimens. In the BENEFIT trial, involving 686 randomized subjects receiving standard deceased-donor or living-donor kidneys, there was more acute rejection, including moderate to severe episodes by Banff grading, among those given belatacept. However, graft and patient survival at 1 year was identical, with, again, better GFR in the belatacepttreated patients.2 In the BENEFIT-EXT trial, 578 recipients of kidneys with prolonged cold ischemia times or otherwise meeting requirements for expanded criteria donor (ECD) placement had essentially identical rejection risk, graft, and patient survival among the three arms, with better preservation of eGFR among the belatacepttreated groups.3

In all three trials, overall rates of infection and malignancy were similar among treatment groups. However, post-transplant lymphoproliferative disease (PTLD), including central nervous system (CNS) lymphoma, occurred more frequently among belatacept-treated subjects. Those at greatest risk were naïve for Epstein-Barr virus before transplantation, and tended to have received more antilymphocyte therapy (ATG) for acute rejection. Overall, combining results from all three trials, 13 subjects receiving belatacept developed PTLD, including some after the first year (frequency of around 1–2%). In the Phase 2 extension, the only PTLD case that occurred after year 1 was in a CyA-treated patient.

In all three studies, belatacept-treated patients had better blood pressure control and lipid profiles compared with those receiving cyclosporine. Data after 1 year also suggest a possible beneficial impact of belatacept on antidonor antibody formation. Additional small pilot studies have been performed using belatacept in combination with either tacrolimus or sirolimus, with favorable short-term outcomes. An effective immunosuppressive agent that can maintain renal function and promote long-term allograft survival while decreasing the overall long-term mortality by reducing cardiovascular events and improving the metabolic profile of transplant recipients is an exciting prospect. However, the impact of early acute rejection, risk of PTLD, cost, and necessity for long-term IV injections will likely influence use of the drug even after approval for widespread usage by the FDA. Additionally, since memory T cells are less dependent on CD80/86 co-stimulation for activation, the agent may be less effective in sensitized patients. Three-year results of BENEFIT and BENEFIT-EXT should be available soon, with hopes for FDA approval early in 2011.

Alefacept (Amevive)

  1. Top of page
  2. Abstract
  3. Belatacept
  4. Alefacept (Amevive)
  5. Eculizumab (Soliris)
  6. References

Alefacept is a dimeric, humanized LFA-3Ig fusion protein that is an antagonist of the extracellular CD2 receptor expressed on T lymphocytes; by blocking the CD2/LFA-3 interaction, it inhibits lymphocte activation. It was initially developed for treatment of autoimmune diseases, and is just now undergoing clinical trials in transplantation. This drug appears to selectively eliminate memory T cells and when combined with a co-stimulation blockade-based regimen using CTLA4-Ig in nonhuman primates prevented renal allograft rejection and alloantibody formation.4 Treatment with alefacept reduces the circulating total CD4+ and CD8+ counts. As CD2 is also expressed on the surface of other lymphoid tissue (such as natural killer [NK] cells and some B cells), there may be additional effects as well. Alefacept, available for subcutaneous injection, is already FDA approved as treatment for chronic plaque psoriasis, with a known safety profile as monotherapy. A global Phase II trial to define the proper dosing and explore combination therapy in kidney transplantation for efficacy and tolerance has recently completed enrollment, with results expected in 2011.

Eculizumab (Soliris)

  1. Top of page
  2. Abstract
  3. Belatacept
  4. Alefacept (Amevive)
  5. Eculizumab (Soliris)
  6. References

Eculizumab is a recombinant humanized monoclonal IgG that specifically binds, with high affinity, to the complement component, C5, and prevents development of the terminal complement complex, C5b-9. It thus blocks complement-mediated cell lysis, and is FDA approved for treatment of paroxysmal nocturnal hemoglobinuria (intravascular hemolysis). Evidence that activated complement is a major contributor to the cellular damage that is observed in antibody-mediated rejection (AMR) implies benefit in the treatment of AMR. Anecdotal use in transplantation is to prevent (in patients at high risk), or treat, AMR.5 By blocking the terminal effector component of the injury response, preliminary data indicate that eculizumab is effective in preserving allograft function in highly sensitized kidney allograft recipients, at least for intermediate-term periods.6 Whether prevention or successful treatment of AMR will decrease the prevalence of chronic injury and improve long-term graft survival will require long-term studies. Like belatacept, eculizumab is also administered intravenously, at intervals of 1 to 4 weeks. The current cost of eculizumab at $20,000 per dose for a minimum of six doses per treatment cycle is also prohibitive. A single-center study is under way investigating the clinical efficacy of eculizumab in preventing AMR in sensitized renal transplant recipients with persistently elevated donor-specific anti-HLA antibodies post transplantation.7 It has not been approved by the FDA for use in kidney transplantation at the present time.

References

  1. Top of page
  2. Abstract
  3. Belatacept
  4. Alefacept (Amevive)
  5. Eculizumab (Soliris)
  6. References