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 Advances in transplantation
100 • Radiation • Prednisone • 6-MP 80 • Cyclosporine Microemulsion • Cyclosporine • Tacrolimus 60 • OKT3 • Mycophenolate mofetil • Daclizumab • Basiliximab 40 • Azathioprine Percent • ATGAM • Thymoglobulin • Sirolimus • Rituxumab 20 Rejection <12 months • Alemtuzumab 1-Year Survival • Leflunomide • Everolimus 0 • Belatacept ’60 ’65 ’70 ’75 ’80 ’85 ’90 ’95 ’00 ’05 Year
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
5 year survival 5 year survival 90 100 80 90 70 80 60 70 60 50 50 40 40 30 30 20 20 10 10 0 0
SRTR 2012 Annual Data Report National Cancer Institute srtr.transplant.hrsa.gov 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 Immunosuppression Immunosuppression Monitoring Shortage Efficacy Toxicity Diagnostics Warm preservation Anti-CD40 Tolerance Cell-free DNA Ex vivo Anti-IL6 Diagnostics Microarray panels perfusion/reconditi oning Anti-IR injury Complement inhibitors Solid phase (siRNA, CO) antibody detection Protease inhibitors Molecular microscope Anti-B cell therapies Cell therapies Adherence promoting 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…) JAK and Cytokine Signaling
JAK inhibition suppresses the signaling of multiple cytokines
Cytokine Tofacitinib Cytokine Effects on the immune system α β γ blocks phosphorylation Stimulate the proliferation and differentiation of Th, IL-2 of STAT and Tc, B and NK cells downstream Induce the differentiation of Th0 to Th2 JAK JAK activation IL-4 Induce Ig switching P P P Promote the development, proliferation and survival P STAT
STAT IL-7
of T, B and NK cells STAT STAT IL-9 Stimulate intrathymic T cell development P Promote the proliferation, cytotoxicity and cytokine IL-15 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. Tofacitinib in rheumatoid arthritis
Fleischmann R et al. N Engl J Med 2012;367:495-507. 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
Extension, Day 1 to Month 12 (A3921030) A3921050
Tofacitinib Tofacitinib 15 mg BID 10 mg BID Screening Day -30 to Tofacitinib Tofacitinib 0 15 mg BID 10 mg BID
Transplant 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). 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 Novartis 800 Roche Astellas 600 400 200 CsA MMF Tac 0 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 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?