Victims of success: Do we still need clinical trials? Robert S. Gaston, MD CTI Clinical Trials and Consulting University of Alabama at Birmingham

Disclosure Employee: CTI Clinical Trials and Consulting (Medical Director) Consultant: CSL Behring Novartis Vitaeris

Percent Advances in transplantation 100 80 60 40 20 Radiation Prednisone 6-MP Azathioprine ATGAM Year Cyclosporine OKT3 Cyclosporine Microemulsion Tacrolimus Mycophenolate mofetil Daclizumab Basiliximab Thymoglobulin Sirolimus Rituxumab Rejection <12 months Alemtuzumab 1-Year Survival Leflunomide Everolimus 0 Belatacept 60 65 70 75 80 85 90 95 00 05 Adapted from Zand MS. Semin Dial. 2005;18:511-519.

The evolution of transplant therapeutics 2005-17: A Changing Age Belatacept (approved 2011) Fingolimod (FTY720, S-1-P receptor blocker) Sotrastaurin (PKC inhibitor) Tofacitinib (Xeljanz )

The Graveyard of Transplant Drugs From F. Vincenti 5

The evolution of transplant therapeutics 2005-17: A Changing Age Belatacept (approved 2011) Fingolimod (FTY720, S-1-P receptor blocker) Sotrastaurin (PKC inhibitor) Tofacitinib (Xeljanz )

What is required for a clinical trial? Unmet need

We don t need cyclosporine we are doing just fine with Imuran and prednisone

KI 7.4 Immunosuppression use in adult kidney transplant recipients

Transplantation v. Cancer 90 80 70 60 50 40 30 20 10 0 5 year survival 100 90 80 70 60 50 40 30 20 10 0 5 year survival SRTR 2012 Annual Data Report srtr.transplant.hrsa.gov National Cancer Institute seer.cancer.gov Courtesy of K. Newell, Emory University

Deceased donor kidney transplants in US Annual rate of graft loss Lamb et.al. Am J Transplant. 2011;11(3):450-462.

Medical Care

Unmet needs in transplantation Organ shortage Long term outcomes Immunosuppression Efficacy Toxicity Monitoring/diagnostics Stegall MD et al, Am J Transplant 16: 1094, 2016 O Connell PJ et al, Transplantation 101: 1527, 2017

What is required for a clinical trial? Unmet need Investigational product/pathway to development (the science )

Unmet needs in transplantation Investigational products Organ Shortage Immunosuppression Efficacy Immunosuppression Toxicity Monitoring Diagnostics Warm preservation Anti-CD40 Tolerance Cell-free DNA Ex vivo perfusion/reconditi oning Anti-IR injury (sirna, CO) Anti-IL6 Diagnostics Microarray panels Complement inhibitors Protease inhibitors Anti-B cell therapies Cell therapies Adherence promoting Solid phase antibody detection Molecular microscope

Unmet needs in transplantation What we don t have Clean protocols that test intervention Validated surrogate endpoints Affected by treatment True endpoint affected by treatment Consistent association with true endpoint Superiority (vs. non-inferiority) endpoints Appropriately defined patient populations

What is required for a clinical trial? Unmet need Investigational product/pathway to development Sponsor and market (the money )

STAT STAT JAK and Cytokine Signaling JAK inhibition suppresses the signaling of multiple cytokines Cytokine α JAK P P STAT β γ JAK P P Tofacitinib blocks phosphorylation of STAT and downstream activation STAT P Cytokine IL-2 IL-4 IL-7 IL-9 IL-15 Effects on the immune system Stimulate the proliferation and differentiation of Th, Tc, B and NK cells Induce the differentiation of Th0 to Th2 Induce Ig switching Promote the development, proliferation and survival of T, B and NK cells Stimulate intrathymic T cell development Promote the proliferation, cytotoxicity and cytokine production of NK cells mrna IL-21 Enhance T and B cell function Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc, cytotoxic T cell

Tofacitinib in rheumatoid arthritis Fleischmann R et al. N Engl J Med 2012;367:495-507.

Transplant Study Design A Phase 2b, randomized, multicenter, partially blinded, parallel-group study To the subjects and investigators, assignment to the two tofacitinib groups was blinded but assignment to CsA vs tofacitinib was open-label Day 1 to Month 12 (A3921030) Extension, A3921050 Screening Day -30 to 0 Tofacitinib 15 mg BID Tofacitinib 15 mg BID Tofacitinib 10 mg BID Tofacitinib 10 mg BID CsA D1 M3 M6 M9 M12 Concomitant immunosuppressive agents across all arms Basiliximab induction (Days 0 and 4) Cellcept 2 g/day or Myfortic 1.44 g/day (up to 3 g/day in black patients in the CsA group) Corticosteroid taper CsA target 12 hour trough whole blood levels: 125-400 ng/ml (M1-3), 100-300 ng/ml (M4-12) BID, twice daily; CsA, cyclosporine 21

Tofacitinib Phase 2b Trial 12 month results CsA CP1 CP2 N 109 106 107 BPAR (%) 19 17 15 Graft Survival (%) 97 97 97 GFR (ml/min) 54 65* 65* IF/TA - 1 yr biopsy (%) 48 25* 24* NODAT (%) 21 10 9 CMV disease (%) 5 20* 13* BKV nephritis (%) 1 3 4 PTLD (cases) 0 2 (4) 1 BKV = BK virus; CMV = cytomegalovirus. Vincenti et al. American Transplant Congress, 2011 (Abstract 4).

A market in transplantation? 1800 1600 1400 1200 1000 800 600 Novartis Roche Astellas 400 200 0 CsA MMF Tac 2016 Sales ($millions)

What is required for a clinical trial? Unmet need Investigational product/pathway to development Sponsor and market Investigators Includes institutions and patients (the will )

Why are we so reluctant to try new things?

Why are we so reluctant to try new things? Primary commitment is to the patient Does this study offer something to the patient? What risks are involved? What inconveniences are required?

Why are we so reluctant to try new things? Secondary commitments Institution Is research consistent with values? Infrastructure? Cost structure? Career impact Clinical research does not generate wrvus Industry-funded research is inconsistently rewarded Scientific merits variable Advancing the field Role of scorecards and performance metrics

Root causes of barriers to progress (from Randall Morris) Human behavior (Loss aversion, status quo bias) Culture (organizational structures) Time (priorities) Money

How are we to change the dynamic? Worries about our patients this is positive aspect of our roles as physicians and should never change Worries about our center s outcomes CMS/UNOS/other payers must address issues regarding proper interpretation of outcomes for patients in clinical trials We must learn to recognize our own deficiencies Presuppositions regarding optimal therapies/combinations in clinical trials Obsession with short- over long-term outcomes Transplant community must recognize the urgency of what is happening, working towards a collaborative model involving NIH, industry, FDA, other centers to alter basic design of/approach to clinical trials

2018: A new age for clinical trials in transplantation? The need? Different, but still very real The science? Evolving and exciting The money? Substantial but encumbered The will?