Research platform Diabetes Ilse Weets Diabetes Research Center, Vrije Universiteit Brussel Klinische Chemie & Radio-immunologie, UZ Brussel Belgisch Diabetes Register CMI Center for Medical Innovation 2013 The Global Burden of Type 1 Diabetes • • • • • • Increasing incidence childhood Type 1 DM More adults than children develop Type 1 Life-long insulin therapy Daily home glucose monitoring Type of Diabetes with highest risk of (severe) hypoglycemia Type of Diabetes with highest risk of hyperglycemic complications • Reduced quality of life • Reduced life expectancy* Unmet Needs Translational Clinical Trials * N Engl J Med 2014; November 20 Belgian Diabetes Registry (established 1989) Collaborative platform of > 200 clinicians and researchers from >100 different clinical centers in Belgium. DIABETIC PATIENTS 12000 • Type 1 Diabetic Patients aged 0-39 years at diagnosis  < 15 yrs:  15 - 40 yrs: 10000 n= 3970 n= 7276 • Patient information • Serum - DNA Bank (> 100 000 samples) 8000 11.146 6000 4000 2000 2015 2013 2011 2009 2007 2005 2003 2001 1999 1997 1995 1993 1991 1989 0 DIABETIC PATIENTS 12000 • Type 1 Diabetic Patients aged 0-39 years at diagnosis  < 15 yrs:  15 - 40 yrs: 10000 n= 3970 n= 7276 • Patient information • Serum - DNA Bank (> 100 000 samples) 8000 11.146 6000 At diagnosis and annual follow-up  Autoantibodies  Genetic markers  Metabolic markers  New biomarkers in selected populations 4000 2000 2015 2013 2011 2009 2007 2005 2003 2001 1999 1997 1995 1993 1991 1989 0 Functional Beta Cell Mass in Human Type 1 Diabetes ? Normal 25% (10-40) After Months to Years of Hyperglycemia At Onset of Hyperglycemia Vandemeulebroucke E, et al. Diabetologia 2010 Keymeulen B, et al. NEJM 2005 & Diabetologia 2010 Cadaveric “Islet” Beta-Cell Transplantation Keymeulen B, et al. PNAS 2006 Glycemic variability before and after beta cell transplantation Severe hypoglycemia no +++ C-peptide neg C-peptide pos Fasting glycemia (mg/dl) 600 500 Islet Cell Transplant 400 300 200 100 0 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 Time (months) B. Keymeulen et al. Diabetologia 41: 452-9, 1998 Functional Beta Cell Mass in Human Type 1 Diabetes ? Normal Immunotherapy 25% (10-40) After Months to Years of Hyperglycemia At Onset of Hyperglycemia Vandemeulebroucke E, et al. Diabetologia 2010 Keymeulen B, et al. NEJM 2005 & Diabetologia 2010 Therapies Aimed at Preservation of Beta Cell Function: CMI Center for Medical Innovation Otelixizumab levels 3000 2 2000 1000 1 0 0 0 2 4 7 14 Days iv 8 8 8 8 8 8 mg 21 Otelixizumab levels (µg/ml) CD3+ Cells (n/mm³) Therapies aimed at preservation of beta cell function: Otelixizumab CD3-Ab administered at clinical onset protects against further decline of functional beta cell mass during the following years All patients Insulin Dose IU/kg/day 0.8 Placebo ** 0.4 *** * ** *** Base-line factors associated with CD3-Ab effect on insulin dose: 1 residual beta cell function at start 2 age Otelixizumab 0.0 10 HbA1c % 9 8 7 * 6 0 12 24 36 48 Months Post hoc comparison of subgroups < P50 and ≥ P50 of 80 patients at start CD3-Ab administered at clinical onset protects against further decline of functional beta cell mass during the following four years subgroups according to initial C-peptide 1.5 1.0 1.0 0.5 0.5 0.0 0.0 IU x kg-1 x d-1 0 Insulin Dose Initial C-Peptide ≥ P50 1.5 1 nmol x L-1 x min- AUC C-Peptide Initial C-Peptide < P50 6 12 18 0.8 0.4 0.4 0 6 12 18 Months Otelixizumab Placebo * 0 0.8 0.0 * 0.0 6 12 18 * 0 * * * p<0.001 * p<0.05 6 12 18 Months B. Keymeulen et al. NEJM 352:2598-2608, 2005 Conclusions: Effects of treatment and factors at baseline that are predictive for success at 48 months Patients with higher initial beta cell function and younger age benefit the most from treatment with Otelixizumab 48 mg In this patient group, preservation of beta cell function is associated with lower insulin needs during at least 48 months In this patient group, preservation of beta cell function is associated with lower glycemic variability between 18 and 48 months CMI Center for Medical Innovation Arrest of Disease Process in Recent Onset Type 1 Diabetes with Otelixizumab Study Phase Dose Efficacy Adverse events Academic 2 48 mg yes yes Tolerx 3 3.1 mg no no 1/2 9/18/27/36 mg ? ? GSK CMI Diabetes Platform GSK-BDR Clinical Trial Otelixizumab  Prescreening n=69 Newly diagnosed type 1 DM patients from registry/biobank (febr 2014)  Clinical data, autoantibody positivity, residual beta cell function, EBV serology.  33 different centres actively recruited patients (1-6 patients, with a median of 1 patient/centre). CMI Center for Medical Innovation CMI Diabetes Platform DiabIL-2 Clinical Trial – EU sponsored (FP7)  Interleukin 2  Newly diagnosed type patients aged 7-35 years  Efficacy and optimal regimen  25 centers throughout Europe  Similar strategy as for Otelixizumab CMI Center for Medical Innovation 1 diabetic Acknowledgements The following participants have, on a voluntary basis, recruited new patients or relatives and/or handled blood samples for the Belgian Diabetes Registry Abrams P, Algoet C, Annaert M, Arnouts P, Ayoubi S, Ballaux D, Baltieri D, Bataille G, Beckers V, Beckers D, Becq H, Beirinckx J, Beirinckx A, Bellavia S, Benhalima K, Bex M, Bodson A, Bollaerts K, Bosly F, Bouquegneau MS, Bourguignon JP, Brochier S, Carlier A, Casteels K, Cavatorta E, Chivu O, Claessens A, Claeys L, Cnop M, Coeckelberghs M, Col V, Colson A, Coolens JL, Coremans P, Corvilain B, Crenier L, Daems T, Damoiseaux P, Daoudi N, Daper C, Daubresse C, Daubresse JC, De Block C, De Feyter I, De Grande E, De Paepe L, De Schepper J, De Schynkel K, De Waele K, De Winter P, Decerf JA, Decochez K, Decraene P, Defoer F, Degrande E, Den Brinker, Depoorter S, Derdelinckx L, Deweer S, Dooms L, Dorchy H, Dotremont H, Driessens S, Dumasy V, Duvivier E, Duyck F, Dysseleer A, Eeckhout B, Eenkhoorn V, Emsens L, Engelen W, Ers V, Eykens A, Favere N, Féry F, Fils R, France A, Garmyn K, Gérard J, Gerniers S, Geronooz I, Geyskens L, Ghys C, Gies I, Gillard P, Godon E, Gorus F, Grabczan L, Guiot J, Haemers S, Haumont S, Herbaut C, Heureux M, Heyns E, Hilbrandts R, Huard A, Hubermont G, Huysman F, Jandrain B, Joosen P, Jopart P, Jousten E, Karmali R, Keymeulen K, Kleynen P, Kockaerts Y, Krzentowski G, Laga K, Lamberigts G, Lambrecht E, Lebrethon MC, Lemay P, Lemy C, Leus J, Lienart F, Lim TT, Litvine C, Logghe K, Louis J, Lowyck I, Lysy Ph, Maes M, Marchal M, Maris E, Marcq Ph, Martens M, Massa G, Mathieu C, Maus Y, Mekahli F, Mekeirele K, Mertens A, Messaaoui A, Monballyu J, Moorkens G, Mortelmans K, Mouraux T, Mullens A, Naudts K, Nemery A, Neven I, Neven S, Nicolaij D, Nobels F, Nollet A, Ooms V, Oriot P, Paciorkowski F, Paquot N, Paris I, Paulussen J, Peeters G, Peiffer F, Pelckmans C, Pen J, Philips JC, Picron B, Pieron M, Pipeleers D, Ponchon M, Poschet K, Rademecker R, Ramon I, Remacle B, Remy C, Renneboog B, Righes C, Robbrecht S, Rocour-Brumioul D, Rooman R, Ruige J, Scarniere D, Scheen A, Schils E, Schoemaker I, Selvais P, Seret N, Slap F, Spijker T, Spincemaille K, Stassen-Joly MP, Strivay M, Taelman P, Taes Y, Tenoutasse S, Tits J, Triches K, Tshibuabua G, T'sjoen G, Tuyttens C, Unger J, Unuane D, Van Acker K, Van Aken E, Van Aken S, Vanbesien J, Vanboxelaer I, Van Crombrugge P, Van de Poel G, Van Den Bruel A, Van Den Driessche A, Van Doninck N, Van Doorn J, Van Gaal L, Van Helvoirt M, Van Imschoot S, Van Parys C, Van Pottelbergh I, Van Poucke K, Van Rooy P, Van Winghem C, Vande Mergel X, Vandecauter H, Vandemeulebroucke E, Vandenbon C, Vandenbroeck P, Vandenbroucke M, Vandenbussche E, Vandergheynst A, Vanderijst JF, Vanderijst M, Vanderschueren B, Vanderstappen H, Vandewalle C, Van Durme Y, Vanfleteren E, Vanhaverbeke G, Vanneste S, Vanuytsel J, Verbiest R, Vercammen C, Verhaegen A, Verhaert G, Verjans V, Verniest R, Verschuere J, Vets B, Vieillevoye G, Vinck W, Vinckx J, Vinken S, Warnotte C, Watillon P, Weber E, Weemaes I, Weets I, Winne L, Woestenburg A, Yucel H.