The immunosuppression Paradox Controlling Rejection And Optimizing patient health

Editors

Gabriel Danovitch, MD Director, Kidney and Pancreas Transplant Program David Geffen School of Ronald Reagan UCLA Medical Center Los Angeles, CA

Robert S. Gaston, MD Medical Director, Kidney and Kidney Transplant Service University of Alabama at Birmingham Birmingham, AL Jointly sponsored by CTI Clinical Trial and Consulting Christian P. Larsen, MD, Dphil Services and the University of Kentucky Colleges of Joseph Brown Whitehead Professor and Chairman and Medicine Department of Emory University School of Medicine Atlanta, GA Release Date June 10, 2010 • Expiration Date June 9, 2011

1 Learning Objectives By the completion of this enduring material, the participants will be able to: I. Identify the outstanding medical opportunities II. Discuss the potential of pipeline for improving long-term renal function and immunosuppressive agents to optimize renal cardiovascular risk in kidney transplant recipients, function and to limit cardiovascular and metabolic while maintaining control of rejection. risk following .

Target Audience This enduring material is intended for transplant candidates and post-transplant care of kidney surgeons, , nephrologists, pharmacists transplant recipients. and nurses involved in the referral of transplant

Medicine Accreditation Statement This activity has been planned by the ACCME to provide The University of Kentucky and implemented in accordance continuing College of Medicine presents this with the Essential Areas and for physicians. activity for educational purposes policies of the Accreditation only. Participants are expected Council for Continuing Medical The University of Kentucky to utilize their own expertise and Education through the joint College of Medicine designates judgment while engaged in the sponsorship of the University this educational activity for a practice of medicine. The content of Kentucky College of maximum of 1.0 AMA PRA of this newsletter is provided Medicine and CTI Clinical Trial Category 1 CreditTM. Physicians solely by faculty who have been and Consulting Services. The should only claim credit selected because of recognized University of Kentucky College commensurate with the extent of expertise in their field. of Medicine is accredited their participation in the activity.

Pharmacy Accreditation Statement The University of 022-999-10-036-H04-P and will activity. Successful completion Kentucky College award up to one (1.0) contact hour includes signing in at registration, of Pharmacy is (0.1 CEU) of continuing pharmacy attending the entire session accredited by the Accreditation education credit in states that for which credit is claimed, Council for Pharmacy Education recognize ACPE providers. completing the activity evaluation as a provider of continuing and requesting credit online pharmacy education. Statements of credit will indicate at conclusion of the activity. hours and CEUs based on The College complies with the This knowledge-based activity participation and will be issued Accreditation Standards for has been assigned ACPE # online at the conclusion of the Continuing Pharmacy Education. Equal Opportunity Needs Assessment Statement The turn of the millennium inhibitors on rejection and renal The University of Kentucky is an equal ushered in a new era of vasoconstriction. opportunity University. transplantation science, equipped with novel immunosuppressive Parallel lines of research Recognition agents and innovative strategies have established the role “The Immunosuppression Paradox: to improve organ allocation. In the of calcineurin inhibitors Controlling Rejection and Optimizing first decade, the adoption of new and other maintenance Patient Health” immunosuppressive regimens immunosuppressive agents in is supported by has resulted in improved control exacerbating cardiovascular an unrestricted of acute rejection. Over the same risk. Control of cardiovascular educational grant from period, the transplant community risk is a clinical priority since it Bristol-Myers Squibb. has realized that acute rejection is the primary cause of death is only one aspect of ensuring with function, responsible Faculty excellent graft survival. Indeed, for approximately half of all Disclosure early renal function has been graft loss after the first post- shown to correlate with the transplant year. The close All faculty members of continuing education activities sponsored by maintenance of graft function relationship between renal the University of Kentucky Colleges long term. function and cardiovascular of Pharmacy and Medicine are health is underscored by the expected to disclose any real or Interestingly, while rejection demonstration that kidney perceived conflict of interest related can be deleterious to allograft disease and poor renal function to the content of their presentation. function, at least two lines are major risk factors for Detailed faculty disclosures are of evidence derived from the cardiovascular events. provided below: United States Renal Data Dr. Gabriel Danovitch has no System and the Scientific This newsletter will review disclosures to report. Registry of Transplant the requirement for new Recipients suggests that immunosuppressive Dr. Robert Gaston is a paid consultant to Novartis rejection and renal function may management strategies in Pharmaceuticals and Astellas be disassociated. The findings light of evolving definitions Pharma and is a paid consultant and revealed a relative lack of of rejection. The newsletter receives grant support from LifeCycle improvement in chronic allograft will then address our Biopharma and Bristol-Myers Squibb. failure despite a marked current understanding of

Dr. Christian Larsen is a reduction in acute rejection the relationship between consultant to Bristol-Myers Squibb. incidence. Later analysis also rejection and short- and revealed a minimal impact of long-term renal function. acute rejection on graft survival, Finally, the demonstrated and provided that glomerular potential impact of newer filtration rate returned to immunosuppressive agents on baseline. These data reflect rejection, renal function and the seemingly paradoxical cardiovascular and metabolic effects of the calcineurin risk will be discussed.

3 Introduction The American Transplant Congress convened in San Diego, California on May 1, 2010. Among the many scientific offerings, the satellite Continuing Medical Education (CME) symposium entitled “The Immunosuppression Paradox: Controlling Rejection and Optimizing Patient Health” was held on May 3, drawing the attendance of approximately 1,100 congress delegates. The present newsletter summarizes the proceedings of the activity.

The immunosuppression Paradox Gabriel Danovitch, MD

To introduce the immunosuppression cardiovascular and nephrotoxic paradox, Dr. Danovitch summarized adverse events is the central paradox the immunologic and non-immunologic of long-term patient management. Dr. stressors affecting long-term kidney Danovitch primed the attendees with Professor of Medicine allograft function. He focused on the first in a series of questions related David Geffen School of cellular and humoral allograft rejection to long-term renal outcomes to be Medicine at UCLA and the activation of latent CMV addressed by Faculty over the course Medical Director, and BK viral as examples of the symposium: Kidney Transplant of immunologic stressors. He then Program introduced a list of non-immunologic Ronald Reagan UCLA stressors, including recurrent kidney Current Questions Medical Center disease and cardiovascular disease. He Related to Long-Term Renal Allograft pointed out that cardiovascular disease, Outcome often an underlying comorbidity among kidney recipients, and nephrotoxicity Is there a gap in correlation between the incidence of rejection are exacerbated by maintenance and long-tern renal function? immunosuppressive agents including • Are all rejection episodes , calcineurin inhibitors created equal? (CNIs) and cyclosporine • What is the impact of rejection (CsA), and mammalian target of on graft survival? rapamycin inhibitors (mTOR inhibitors) and .1 With current immunosuppressive agents can we

The requirement for lifelong • Control rejection and immunosuppression to control the • Optimize renal function and alloimmune response and the impact • Limit cardiovascular and of immunosuppressive agents on metabolic risk? Optimizing Renal Function and controlling cardiovascular and metabolic risk Robert s. gaston, MD

Dr. Gaston addressed these questions in A poll of the audience revealed an even turn, beginning with the evidence that the split concerning their clinical impressions Endowed Professor of ultimate effects of rejection are tied to the of the effects of acute rejection kidney Transplant impact on renal allograft function. Citing the allograft outcome. Of all respondents, Professor of Medicine, classic pivotal study of the USRDS database one-third said acute rejection negatively Division of Nephrology published by Terasaki and colleagues in impacts graft survival when it is most 1995, Dr. Gaston noted that recognition of the severe ( resistant), one- Professor of association between good kidney function third said when it is antibody mediated, Surgery, Division of 2 Transplantation and graft survival is not new. He then went one one-third when it impacts GFR or on to present the more recent evidence SCr. All rejection episodes are not equal, Medical Director, that high first year serum creatinine (SCr) is and the phenotypes seem to be evolving Kidney, Pancreas, and associated with, but not predictive of, long- with new . Islet Transplantation term graft failure.3, 4 Continuing the argument, Senior Scientist, he explained that acute rejection has been Next, Dr. Gaston turned to the evidence Nephrology Research shown to have the most pronounced impact that renal and cardiovascular/metabolic and Training Center on graft survival when accompanied by poor function are interdependent. First

University of Alabama renal function (Figure 1). described in the general population, at Birmingham

Impact of Acute Rejection is Greatest in Recipients with Poor Renal Function3 – Figure 1

25 20

OPTN/UNOS database N=105,742 transplanted 15 1988-1998

SCr values evaluated at 10 12 months post-trans- plant; ∆SCr evaluated 5 between 6 months and

12 months GRAFT HALF-LIFEYEARS – 0 P-values not reported ∆SCr<0.3 ∆SCr>0.3 ∆SCr<0.3 ∆SCr>0.3

SCr ≤ 1.5mg/dL SCr ≥ 1.5mg/dL

5 Optimizing Renal Function and controlling cardiovascular and metabolic risk Robert s. gaston, MD the link between cardiovascular death and poor immunosuppressive management. Indeed, these agents renal function is now also documented in transplant are required to suppress the alloimmune response but recipients, with the risk proportional to an incremental may also contribute to poor outcomes due to renal and increase in serum creatinine levels (Figure 2).3, 5, 6 In metabolic dysfunction.11-13 the study cited, each 100 μmoL/L (1.1 mg/dL) increase in SCr was associated with a relative risk of 1.89 for Dr. Danovitch commented on Dr. Gaston’s presentation a major adverse cardiac event and 2.94 for cardiac by reviewing the cardiovascular and survival benefits death.6 Despite the risks, Dr. Gaston pointed out that of controlling blood there is wide variability in the use of cardioprotective pressure, atherogenic medications including statins, beta-blockers and aspirin lipid levels and blood Summary: among different transplant programs.7 glucose in the general Optimizing Renal population.14-17 However, Function and Recent attention has focused on the metabolic syndrome, he cautioned that Controlling a constellation of cardiovascular risk factors highly confounding factors Cardiovascular and Metabolic Risk prevalent not only in the general population, but also including underlying estimated to affect between one-quarter and almost and pre-existing Effective two-thirds of selected kidney transplant recipients.8-10 disease, the pressure immunosuppression remains essential Integral components of the metabolic syndrome, of immunosuppression, Better understanding of including elevated blood glucose, atherogenic lipid levels and dialysis history do immunologic mechanisms is and high blood pressure are all exacerbated by CNIs, not allow transplant changing our understanding corticosteroids and/or mTOR inhibitors, implicating professionals to directly of the relationship between rejection and graft failure the mainstays of current immunosuppression as extrapolate the results prime ingredients of the central paradox of long-term to transplant recipients. All rejection episodes are not created equal

Ongoing immunologic Cardiac and all-case mortality increase with poor injury is a major cause of late 6 post-transplant renal function – Figure 2 graft failure

Good renal function is SCR VALUES 50 **P<0.0001 a corollary of long term <200 µ mol/L (<2.3 mg/dL); n=946 graft survival 40 >200 µ mol/L (>2.3 mg/dL); n=106 ** 30 Cardiovascular and metabolic risk ** 20 ** Is impacted by ** immunosuppressant choices 10 and renal function

0 Modifiable variables MI Stroke MACE Cardiac Non-CVD All-Cause should be addressed in Death Death Mortality each recipient ALERT CLINICAL TRIAL UNIVARIATE COX REGRESSION ANALYSIS Avoiding the Calcineurin Pathway Christian P. Larsen, MD, Dphil

To propose a potential resolution of the prevent organ allograft rejection in a paradox explored by Dr. Gaston, in his murine model of commentary Dr. Danovitch speculated and in cynomolgus monkey recipients of on the feasibility of developing new kidney allografts.20 immunosuppressive agents that fulfill the criteria outlined below. A recent exploratory Phase 2 study in kidney allograft recipients was designed to replace CsA as a maintenance Requirements for new immunosuppressive agent.21 Compared Joseph Brown immunosuppressive Whitehead Professor to CsA, tasocitinib provided good and Chairman of the agents rejection prophylaxis and preservation of Department of Surgery Adequately control immunologic renal function. Over-immunosuppression risk to the allograft and safety signals included an increased Emory University risk of CMV and BK as well as School of Medicine Preserve renal function and cardiovascular health mild neutropenia and anemia, possibly Director of Surgical due to a crossover JAK2 effect. Services, Emory Limit introduction of new, potentially threatening Healthcare adverse effects An update of clinical progress with Surgeon-in-Chief, tasocitinib, introduced by Dr. Larsen and Emory University presented by Dr. Flavio Vincenti at an Hospital Dr. Christian Larsen responded to alternate ATC scientific session, revealed the challenge by focusing attention non-inferiority in the incidence of biopsy- on novel agents at varied stages of proven acute rejection at 6 months clinical development. These include (15.06% and 9.55% vs. 18.62%) and immunosuppressants that target non- statistically significantly higher measured calcineurin pathways including the Signal GFR in each of the tasocitinib treatment 3 JAK-STAT and Signal 2 co-stimulation arms compared with the CsA control and adhesion pathways. group.22 Interim results revealed a trend to improved glycemic control and lower Discussing first the JAK-STAT pathway, blood pressure values among tasocitinib- Dr. Larsen described the action of treated patients. Safety signals included tasocitinib (CP-690,550), an inhibitor of a higher incidence of serious infections JAK3-signaling cytokines sharing the and opportunistic viral infections, as common gamma chain (Γc cytokines: well as a higher incidence of anemia, IL-2, IL-4, IL-7, IL-9, IL-15 and IL- neutropenia, and . 21).18, 19 Cytokines that signal through Γc affect T, B and NK cell maturation, Focusing next on Signal 2 inhibition, Dr. proliferation and function. Inhibition of Larsen described the development path the JAK3 pathway was first shown to of , a CD28 co-stimulation

7 Avoiding the Calcineurin Pathway Christian P. Larsen, MD, Dphil blocker that has currently completed arms (one more intense, the second at an alternate scientific session at two Phase 3 clinical trials.23, 24 less intense) compared to the ATC, demonstrated consistency at 2 A second generation CTLA4 Ig CsA group. Across both clinical years of follow up.26, 27 derivative, belatacept has improved trials, patients receiving belatacept avidity for CD80/CD86, increasing experienced significantly improved Safety signals associated with its immunosuppressive potency as renal function, as determined by belatacept treatment included an demonstrated in early non-human measured GFR, over the follow up increased incidence and more primate models of transplantation.25 period. Importantly, in both studies, severe grade of acute rejection in the time to progression to Stage the more intense (MI) regimen arm The results of two Phase 3 clinical 4/5 chronic kidney disease was of the BENEFIT study, perhaps trials, the first in recipients of prolonged in patients receiving reflecting a disruption in the T standard criteria living or deceased belatacept (Figure 3). effector-T regulatory balance donor organs (BENEFIT), and the resulting from co-stimulation second in recipients of extended Co-stimulation blockade was blockade.23, 24, 28 Renal function criteria deceased donor organs accompanied by an improved remained better in the belatacept (BENEFIT-EXT) have recently been atherogenic lipid profile and better treatment arms among patients published.23, 24 Results at one year blood pressure. Blood glucose was who developed acute rejection. of follow up revealed equivalent not affected by belatacept treatment. The increased incidence of survival in the belatacept treatment Updated results of the trials, presented rejection was not reproduced in the

Time to progression to stage 4/5 chronic kidney disease22, 23 – Figure 3

BENEFIT BENEFIT-EXT Standard Criteria Living and Deceased Donor Organs Extended Criteria Deceased Donor Organs

100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 Belatacept MI Belatacept MI PERCENT REMAINING EVENT FREE PERCENT REMAINING EVENT FREE 20 Belatacept LI 20 Belatacept LI Cyclosporine Cyclosporine 10 10 0 0 0 6 12 18 24 0 6 12 18 24

TIME (MONTHS) TIME (MONTHS) Avoiding the Calcineurin Pathway Christian P. Larsen, MD, Dphil

BENEFIT-EXT study. The incidence emerging, requiring a shift in clinical itemized some of the challenges of PTLD was also higher among surveillance when these agents are to the use of new agents in belatacept-treated patients, and administered long-term. transplant immunosuppression. found to be most prevalent among These include adequate long-term EBV seronegative recipients. Dr. Larsen then turned attention control of rejection, identifying to the potential of adhesion patient subpopulations with Taken together, the results of molecule blockade as a transplant the most favorable benefit- recent clinical trials of agents immunosuppressive strategy. risk profiles, combining newer closest to the clinic suggest that Using as an example, drugs with currently available bypassing the calcineurin activation he described the development immunosuppressants and the pathway may provide effective pathway from approval in psoriasis potential to spare corticosteroids. immunosuppression and improve to voluntary withdrawal as a result These concerns were corroborated the cardiovascular risk profile of the development of progressive by the audience, 42% of whom of kidney transplant recipients. multifocal leukencephalopathy selected the potential for However, new safety signals are (PML) in 2 patients maintained on reactivation of latent viruses and for greater than 3 years.29,30 29% of whom cited an increased Results of a Phase 1/2 clinical risk of severe acute rejection as Summary: Avoiding trial in kidney transplant recipients cause for surveillance following the calcineurin treated for 6 months with two the administration of new pathway different dosing schedules of immunosuppressive agents. Dr. efalizumab in combination with full- Danovitch concluded by pointing Understanding of lymphocyte activation has opened rational or half-dose CsA revealed good out that, with a limited patient pool control of acute rejection and no available for the study of agents development increased risk of post-transplant working through non-calcineurin Agents blocking co-stimulation lymphoproliferative disorder except pathways, heightened surveillance and JAK cytokine response in the higher dose efalizumab- for these and other new adverse pathways are promising new full dose CsA treatment arm.31 Dr. events is warranted and close drug candidates Larsen suggested that adhesion follow up will be required. • Potential to maintain molecule blockade warrants • Evidence of reduced further study in transplantation. At cardiovascular and issue are appropriate concomitant metabolic burden medications, including the potential Surveillance for new adverse to combine adhesion inhibition events is key to successful with co-stimulation blockade, and development of novel attention to the relative risk of PML immunosuppressive agents and PTLD in transplant recipients. • Infection • In his commentary on Dr. Larsen’s • Novel metabolic presentation, Dr. Danovitch complications

9 References

1. Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. Nov 12 2009;69(16):2227-2243.

2. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med. Aug 10 1995;333(6):333-336.

3. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. Jul 2002;62(1):311-318.

4. Kaplan B, Schold J, Meier-Kriesche HU. Poor predictive value of serum creatinine for renal allograft loss. Am J Transplant. Dec 2003;3(12):1560-1565.

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6. Fellstrom B, Jardine AG, Soveri I, et al. Renal dysfunction is a strong and independent risk factor for mortality and cardiovascular complications in renal transplantation. Am J Transplant. Aug 2005;5(8):1986-1991.

7. Gaston RS, Kasiske BL, Fieberg AM, et al. Use of cardioprotective medications in kidney transplant recipients. Am J Transplant. Aug 2009;9(8):1811-1815.

8. de Vries AP, Bakker SJ, van Son WJ, et al. Metabolic syndrome is associated with impaired long- term renal allograft function; not all component criteria contribute equally. Am J Transplant. Oct 2004;4(10):1675-1683.

9. Porrini E, Delgado P, Bigo C, et al. Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis. Jul 2006;48(1):134-142.

10. Courivaud C, Kazory A, Simula-Faivre D, Chalopin JM, Ducloux D. Metabolic syndrome and atherosclerotic events in renal transplant recipients. Transplantation. Jun 27 2007;83(12):1577-1581.

11. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med. Dec 11 2003;349(24):2326-2333.

12. Gaston RS. Chronic calcineurin inhibitor nephrotoxicity: reflections on an evolving paradigm. Clin J Am Soc Nephrol. Dec 2009;4(12):2029-2034.

13. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. Feb 2009;4(2):481-508.

14. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with . N Engl J Med. Dec 22 2005;353(25):2643-2653.

15. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. Sep 27 2007;357(13):1301-1310. 16. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. Jun 27 2005;165(12):1410-1419.

17. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. Jun 12 2008;358(24):2545-2559.

18. George M, Stein B, Muller O, et al. Metabolic activation stimulates acid secretion and expression of matrix degrading proteases in human osteoblasts. Ann Rheum Dis. Jan 2004;63(1):67-70.

19. O’Neill LA. Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov. Jul 2006;5(7):549-563.

20. Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. Oct 31 2003;302(5646):875-878.

21. Busque S, Leventhal J, Brennan DC, et al. Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients. Am J Transplant. Aug 2009;9(8):1936-1945.

22. Vincenti F. Abstract LB08. Am J Transplant. 2010;10 (Suppl 4):211.

23. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. Mar;10(3):535-546.

24. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant. Mar;10(3):547-557.

25. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. Mar 2005;5(3):443-453.

26. Durrbach A. Abstract 143. Am J Transplant. 2010;10 (Suppl 4):83.

27. Larsen C. Abstract 142. Am J Transplant. 2010;10 (Suppl 4):82.

28. Grinyo J. Abstract 144. Am J Transplant. 2010;10 (Suppl 4):83.

29. http://www.medscape.com/viewarticle/590862. Accessed 5/14/10.

30. Raptiva Prescribing Information. San Francisco, CA: Genetech, Inc.; March 2009.

31. Vincenti F, Mendez R, Pescovitz M, et al. A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am J Transplant. Jul 2007;7(7):1770-1777.

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