Funding NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom - PDF document

Options for β Cell Replacement in Diabetes Michael German MD Division of Endocrinology Department of Medicine UCSF Funding NIH/NIDDK; Beta-Cell Biology Consortium Larry L. Hillblom Foundation The Leona M. and Harry B. Helmsley Charitable Trust Nora Eccles Treadwell Foundation Juvenile Diabetes Research Foundation American Diabetes Association Neuroendocrine Tumor Research Foundation Justine K. Schreyer Endowed Chair in Diabetes Research Iacocca Family Foundation Disclosure Stock in Viacyte, Inc. Patents on Nkx2.2, Nkx6.1, Neurog3, Rfx6 and β cell production 1

Patient History 58yo woman referred for management of Type 1 Diabetes Mellitus. Diabetes history: • Dx at age 13, presented with DKA. • No family history of T1DM. • Treated initially with BID insulin, started multiple injections in her 20’s, pump in her 40’s, back to multiple injections in 50’s. Currently Humalog and Lantus ~22 u/day. >6 FSBG/day. • Last HbA1C 8.0 Patient History Complications: Developed neuropathy, retinopathy, microalbuminuria in 40’s. Over the past decade, increasing blood glucose fluctuations, serious hypoglycemic events, hypoglycemia unawareness. Meds: Insulin, HCTZ, Lisinopril Other: Hypertension, Graves’s disease at age 37 2

Patient History Exam: Ht: 5’ 5” Wt: 122 BMI: 20.4 BP: 117/68 P: 96 HEENT: retina: photocoagulation scars neck: mild thyromegaly Neuro: loss of sensation to 10g monofilament toes and plantar foot bilaterally 3

β Cell Replacement for Type I Diabetes • Insulin Injection: • Multiple injections • Pump • CGM • Closed loop (in trials) • Transplant • Pancreas Transplant • Islet Transplant • Stem Cell Transplant • β Cell Regeneration Pancreas Transplant • Simultaneous Pancreas/Kidney (SPK) • Pancreas after Kidney(PAK) • Pancreas Transplant Alone (PTA) 4

John D. Pirsch, Jon S. Odorico & Hans W. Sollinger 1-Year Pancreas/Kidney Graft Function USA Primary DD Pancreas Transplants, 10/1/1982 – 12/31/2014 2/15 5

5-Year Pancreas/Kidney Graft Function USA DD Primary Pancreas Transplants, 1/1/1984 – 12/31/2014 3/15 UCSF Evolution in Immunosuppression for Pancreas/ Kidney Transplantation 1989-Current (n=462) ERA 1-3 : OKT3 Induction ERA 4 : Thymoglobulin Induction Maintenance Incidence of rejection of either kidney or pancreas ERA 1: CSA/AZA/PRED 80% ERA 2: CSA/MMF/PRED 50% ERA 3: TACROLIMUS/MMF/PRED 15-20% ERA 4: STEROID AVOIDANCE 10-15% Thymoglobulin Induction low dose tacrolimus/ sirolimus/MMF 6

Effect on Secondary Complications ✦ Difficult to demonstrate an impact on disease progression because patients often present with far advanced disease. ✦ Progression of retinopathy halted. ✦ Progression of nephropathy halted; some improvement in pathologic changes. ✦ Some reversal of neuropathy: Peripheral > Autonomic. ✦ Reduced hypoglycemia. Effect on Quality of Life ✦ More positive perception of health. ✦ Less pain. ✦ More flexibility. ✦ Greater ability to function socially. ✦ Patients with failed grafts return for retransplantation. 7

Worldwide Pancreas Transplants Pancreas Transplants 12/16/1966 – 12/31/2014 ■ USA: n = 29,128 ■ Non US n = 19,164 Why Are Transplant Rates Decreasing? ✦ Decreased/delayed nephropathy ✦ Improvements in insulin delivery technologies ✦ Increased BMI of recipients ✦ Increased BMI, age and DM in donors 8

Why Transplant Islets? Are They Replacing Whole Organ Transplants? Safer, Simpler Procedure than Pancreas Transplant Graft Survival (insulin independence) Islet Transplant Registry Edmonton • 87% 9

10

11

Naftanel, M. A. & Harlan, D. M. Pancreatic islet transplantation. PLoS medicine 1 , e58; quiz e75, doi: 10.1371/journal.pmed.0010058 (2004). Illustration by Giovanni Maki 12

Results: HbA1c Ryan EA Diabetes 54:2060-2069, 2005 13

The Islet Transplant Experiment: Time for a Reassessment J. S. Bromberg, B. Kaplan, P. F. Halloran and R. P. Robertson American Journal of Transplantation 2007; 7: 2217–2218 Blackwell Munksgaard Publication of the initial results of the Edmonton protocol in 2000 (1) raised hopes that many of the technical and immunologic hurdles of islet transplantation had finally been solved and that a new era for the treatment and cure of type 1 diabetes had arrived. Unfortunately, while shortterm results utilizing this specific protocol were repeatedby other groups around the globe, long-term follow-up revealed that islet transplantation with this particular protocol is far less successful than originally hoped (2,3). Thus, although 5 years after transplantation 85% of recipients had measurable plasma C-peptide, well-controlled HbA1c levels, significant diminution in amount of daily insulin required, and virtually no clinical hypoglycemia (3), only 10% of patients experienced freedom from exogenous insulin use. While this still may represent partial success in alleviating the debilitating symptoms that brought them to islet transplant in the first place, such a claim needs to ultimately be established in a controlled trial, like other medical advances. Moreover, toxicities from the calcineurin inhibitors combined with sirolimus used for immunosuppression produced worrisome trends in renal function (4). Given continued insulin dependence, the shortage of donor organs, the complications of immunosuppression, and the great expense of this procedure, sober reassessment of the clinical applicability of this protocol and particular experiment is needed. Decay in Islet Function ✦ Rejection? ✦ Autoimmunity? ✦ Drug toxicity? ✦ No precursor cells? 14

Total Pancreatectomy and Islet Autotransplantation (TPIAT) ✦ Used for treatment of chronic pancreatitis, benign pancreatic tumor, trauma. ✦ Low rates of DM immediately post surgery (~50%) and long term, despite low islet yields. ✦ Pancreas transplant post pancreatectomy can also prevent exocrine deficiency, but requires donor pancreas and immunosuppression. ✦ Therefore, allo- and/or autoimmunity are the cause of long term failure of islet transplants for T1DM. 15

Better outcome with more aggressive induction immunosuppression Centers with 5-Yr Insulin Independence ≥ 50% 16

Costimulation/Adhesion Blockade LEA29Y Efalizumab (Belatacept, (Raptiva) CTL4-Ig) -­‑ ¡ Used ¡successfully ¡in ¡kidney ¡(both) ¡and ¡liver ¡transplanta8on ¡(belatacept) ¡ Vincenti, AJT 2002 ¡-­‑ ¡Allow ¡reduc8on ¡of ¡Calcineurin ¡inhibitors ¡w/o ¡increased ¡rejec8on ¡ ¡ Adverse ¡Effects ¡ ¡-­‑ ¡Both ¡increase ¡risk ¡of ¡Post-­‑transplant ¡lymphoprolifera8ve ¡ ¡ ¡ ¡ ¡ ¡ ¡disorder ¡(PTLD) ¡if ¡used ¡at ¡high ¡doses ¡ ¡ ¡-­‑ ¡Both ¡increase ¡risk ¡of ¡Progressive ¡mul8focal ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡leukoencephalopathy ¡(PML, ¡fatal) ¡ ¡ ¡-­‑ ¡Rap8va ¡taken ¡off ¡market ¡5/09 ¡(4 ¡cases ¡PML/40,000pts) ¡ ¡ Immunosuppressive Protocols ¡ SIROLIMUS (Target trough 8-12 ng/L) (substitute mycophenolate if not tolerated) ¡ EFALIZUMAB 1 mg/kg/wk 0.5mg/kg/wk Drug withdrawn in all pts on May, 2009 ATG Efalizumab * Solumedrol -2 0 +2 +4 +7 10 28 90 180 27 365 1yr 1yr 1 yr 2 yr 2yrs 2 yrs 2 yrs 3 yrs 0 +90 +180 +270 +90 +180 +270 Days relative to Transplant Txp SIROLIMUS (Target trough 8-12 ng/L) (substitute mycophenolate if not tolerated) Belatacept (10mg/kg/mo) 5mg/kg/mo 5mg/kg/2mos Belatacept ATG Solumedrol * -2 0 +2 +4 +7 10 28 90 180 27 365 1yr 1yr 1 yr 2 yr 2yrs 2 yrs 2 yrs 3 yrs +90 +270 +180 +90 +180 +270 0 Days relative to Transplant Txp 17

Graft Function in EFA and BELA Treated Patients BELA-1 Insulin Independent BELA-2 Partial Use BELA-3 Full Use Tx # 2 (day 750) BELA-4 Tx # 2 (day 445 ) BELA-5 * EFA d/c’ed Tx # 2 (day 442 ) EFA-1 * EFA-2 * EFA-3 Pancreas Txp * EFA-4 * Tx # 2 (day 40 0) EFA-5 Pancreas Txp * 0 365 730 1095 1460 1825 Time from initial transplant (days) HbA1c Levels after Islet Transplantation Belatacept ¡ Efalizumab ¡ 10.0 10.0 9.0 9.0 EFA-1 BELA-1 8.0 8.0 HbA1c (%) HbA1c (%) EFA-2 BELA-2 7.0 EFA-3 BELA-3 7.0 6.0 BELA-4 EFA-4 6.0 5.0 BELA-5 EFA-5 5.0 4.0 3.0 4.0 0 30 75 120 180 270 365 455 545 730 0 30 75 120 180 270 365 455 545 730 Time from Transplant (d) Time from Transplant (d) 18

C-peptide Responses to a Mixed Meal Tolerance Test 10 9 9 8 8 7 C - Peptide (ng/ml) C - Peptide (ng/ml) BELA 1 EFA 1 7 6 6 BELA 2 EFA 2 5 5 BELA 3 EFA 3 4 4 BELA 4 EFA 4 3 3 EFA 5 BELA 5 2 2 1 1 0 0 -10.0 -5.0 0.0 15.0 30.0 60.0 90.0 120.0 -10.0 -5.0 0.0 15.0 30.0 60.0 90.0 120.0 Time (minutes) Time (minutes) Belatacept ¡ Efalizumab ¡ Glomerular Filtration Rates after Islet Transplantation 140 Belatacept Efalizumab 120 2 ) 100 GFR (ml/min/1.73m 80 60 40 20 0 0 180 365 0 180 365 Time from Transplant (days) 19