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A Survey of Commercial Product Development in T1DM: Reports from along the commercial roads to treatments and cure Randy L. Anderson, Ph.D., VP, Global Product Development (Metabolics) Presentation at JDRF Research Summit, Washington, DC, 9 March 2013 JDRF Pedigree 1963 T1DM Diagnosis at age 6 1983– 1989 PhD, Biostatistics; diabetes consulting 1979 Diabetes management independent study 2 1994 Pharmaceuticals development 1990 Began work as diabetes clinical trialist 1999 2001 First local JDRF Walk to Cure Diabetes Firstborn son T1DM diagnosis; first JDRF work 2003– 2006 JDRF Medical Sci Review Cmte; >45 reviews 2001– 2007 NIH/JDRF Immune Tolerance Network via PPD 2006– Now JDRF ad hoc proposals reviewer; >12 reviews 2004 First local JDRF Hope Gala 2003 Head Metabolics for PPD; 50-years with T1DM Technical or Biological Cure? ● ● 3 Technical innovations − Insulin pumps − Continuous glucose monitors − Artificial pancreas Biological cure − Immune tolerance − Beta cell regeneration Review: JDRF Triumvirate Cure Strategy Immune Tolerance Induction ● 4 To stop original causal autoimmune process Beta Cell Regeneration ● To restore functional beta cell mass Artificial Pancreas ● To bridge gap between treatment initiation and fully functional beta cell mass T1DM Products in Development By Product Class Count Immunomodulator Immunomodulator Insulin analog, analog, injected injected Insulin Other or or unspecified unspecified Other Insulin analog, analog, oral oral Insulin cell regeneration regeneration ββ cell SGLT1/SGLT2 inhibitor inhibitor SGLT1/SGLT2 cell, encapsulated encapsulated β βcells, GLP-1 analog analog GLP-1 Total: 94 iInsulin analog, analog, glucose glucose responsive responsive iInsulin Glucagon receptor receptor agonist agonist Glucagon Glucagon analog analog Glucagon Insulin analog, analog, inhaled inhaled Insulin 0 Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013 5 10 20 30 Immunomodulators (A Sampling) 6 Product/Sponsor Ph Status Gevokizumab, Xoma052 (Xoma) 2 No improvement in BG, but big reduction in CRP, LDL chol α-1 antitrypsin (OmniBio, Kamada) 2 Supresses beta cell apoptosis. Ph 2 results 1H2013 beta cell-specific mTCRs fused to cytokines IL-4 & IL-13 (Immunocore) Pre Clin Naimit Consortium (natural immunomodulators) partner; EU 7th Framework Program funding li key engenders antigen-specific CD4+ T-helper cell stimulation (Antigen Expr) Pre Clin “robust, long lasting antigen-specific immune response” Diabetes vaccine (Selecta Bioscience) Pre Clin Targeted toleragenic antigen-specific vaccine. JDRF industry partner “ We have demonstrated in antea-diabetic mouse model that lifelong recovery of β cells has a strong correlation with normalization of the Treg cell population in pancreatic lymph notes (PLNs). This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in PLNs as a therapeutic approach for type 1 diabetes (T1D). 7 ” Curative Hematopoietic Stem Cell Transplant NOD mouse develops autoimmune diabetes spontaneously ● NOD mouse undergoes immune system ablation Experiment ● Transplanted hematopoietic stem cells from NORMAL mouse ● Transplanted islets placed under kidney capsule temporarily to maintain normoglycemia Results ● New Tregs appear in pancreatic lymph nodes 3 Weeks Later ● New pancreatic islets appear spontaneously in recipient mouse pancreas ● NOD mouse has normal, permanent, functioning autologous pancreatic islets ● NOD mouse has NO islet autoimmunity 16 Weeks Later 8 Immunomodulators T1DM Viability Assessment ● Essential for cure − Immune system complexity lowers prospects − Near certain need for combination therapies − ● Safety: Selective immune tolerance is critical Timing Timing Safety Safety Prevent Prevent Need to verify low cancer risk, low infection risk Treat Treat Best cure prospect appears to be some stem cell transplant Cure Cure − ● Long follow-up times Potential 0 9 50 100 T1DM Products in Development By Product Class Count Immunomodulator Immunomodulator Insulin analog, analog, injected injected Insulin Other or or unspecified unspecified Other Insulin analog, analog, oral oral Insulin β cell cell regeneration ββ cell regeneration regeneration SGLT1/SGLT2 inhibitor inhibitor SGLT1/SGLT2 cell, encapsulated encapsulated β βcells, GLP-1 analog analog GLP-1 Total: 94 iInsulin analog, analog, glucose glucose responsive responsive iInsulin Glucagon receptor receptor agonist agonist Glucagon Glucagon analog analog Glucagon Insulin analog, analog, inhaled inhaled Insulin 0 Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013 10 10 20 30 Beta Cell Regeneration 11 Product/Sponsor Ph Status Human proislet peptide (CureDM/Sanofi) 1 Stabilized form of human proislet peptide (analogous to INGAP). Ph 1 study completed Nov2012 FT-201 (Fate Therapeutics) Pre Clin Rh protein stimulate islet neogenesis EVT-770 (Evotec/AZ) Pre Clin β cell growth factor NGM-282 (NGM Biopharm/ Daiichi Sankyo) 1 β cell regeneration modulators. JDRF industry partner. SAD/MAD design on clinicaltrials.gov 1Feb2013 Beta Cell Regeneration T1DM Viability Assessment ● ● ● Efficacy: Essential for cure Potential − Immune tolerance prerequsite Timing Timing − Concept verified in animal and human T2DM implies high likelihood of efficacy, AFTER immune tolerance Safety Safety Safety: Need to verify low cancer risk Timing: Moderate regulatory hurdles Prevent Prevent Treat Treat Cure Cure 0 12 50 100 Roche Accu-Chec® Diaport New York, 16 August 2011 “ ...JDRF will provide funding to test two new devices aimed at providing mechanical means to achieve faster insulin action. The first will support Dr. Howard Zisser at the University of California, Santa Barbara's Sansum Diabetes Research Institute testing Roche Diabetes Care's Accu-Chek® DiaPort system. The Accu-Chek DiaPort is a percutaneous port system, connected with an external pump, that delivers insulin directly to the liver, the primary site of insulin action.... ” 13 Technical or Biological Cure? 14 ● Dietary carbohydates absorbed as glucose from small intestine ● Pancreas circulation includes glucose-enriched circulation from small intestine ● Pancreas releases insulin in response to glucose-enriched circulation ● Pancreatic insulin and glucose enriched blood flows to liver through hepatic portal vein ● Insulin release inhibits glucagon release from α cells, which stops liver release of stored glucose and initiates liver storage of excess glucose from gut ● Both liver actions are critical to stabilizing blood glucose Optimizing Insulin Action: Intraperitoneal Infusion vs. Subcutaneous Injection Schade DS, et.al. Diabetologia, 1980; 19(1): 35-39 15 Roche Accu-Chec® Diaport 16 Roche Accu-Chec® Diaport® Diaport provides more appropriate timing of insulin, delivered more directly to liver 17 ● Stabilize blood glucose against large post-meal spikes ● Increase liver storage of glucose (as glycogen) ● Increased liver glycogen storage reduces hypoglycemia risk Current Accu-Check Diaport® Studies Phase Protocol Title Completion Date Sample Size 2 Evaluation of Accu-Chek DiaPort, a Port System for Continuous Intraperitoneal Insulin Infusion, in Patients With Type I Diabetes Feb 2013 12 2 Closed Loop Artificial Pancreas Using Intraperitoneal (IP) Insulin Via DiaPort® Dec 2013 10 Source: Clinicaltrials.gov, 5Mar2013 18 T1DM Products in Development By Product Class Count Immunomodulator Immunomodulator Insulin analog, analog, injected injected Insulin Other or or unspecified unspecified Other Insulinanalog, analog, oral oral Insulin Insulin analog, oral cell regeneration regeneration ββ cell SGLT1/SGLT2 inhibitor inhibitor SGLT1/SGLT2 cell, encapsulated encapsulated β βcells, GLP-1 analog analog GLP-1 Total: 94 iInsulin analog, analog, glucose glucose responsive responsive iInsulin Glucagon receptor receptor agonist agonist Glucagon Glucagon analog analog Glucagon Insulin analog, analog, inhaled inhaled Insulin 0 Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013 19 10 20 30 Oral Insulins 20 Product/Sponsor Ph Status Oshadi Drug Admin (Israel) 1-2 Methods/use patent granted 2012; trial start Feb2013 Oramed (Israel) 2 IND filed 12Dec2012; trial start pending IND approval Capsulin, Diabetology (UK) 2 No activity in clinicaltrials.gov Novo Nordisk (Denmark) 1 Oral basal insulin Tamarisk (USA) 1 Nano-encapsulation preclinical white paper Feb 2012 Ora-lyn®, Generex (Canada) 3 Registration trials results expected Mar 2013 TrabiOral, Transgene Biotech (India) Preclin Ongoing preclinical development Potential of Oral Insulins Positives ● ● ● 21 Suppresses postprandial glucagon from pancreatic alpha cells Adequately insulinizes liver for postprandial glucose storage – Great protection against post-meal highs – Much less susceptibility to lows No injection! Negatives ● ● Must prevent insulin (protein) digestion before absorption Requires predictable insulin activity after absorption – Uniformity of absorption? – Dosing accuracy? Oral Insulins T1DM Viability Assessment ● ● ● Promising preclinical data Need evidence of liver insulinization − Moderated BG excursions − Lowered hypoglycemia risk Potential Timing Timing Safety Safety Moderate regulatory hurdles Prevent Prevent Treat Treat Cure Cure 0 22 50 100 T1DM Products in Development By Product Class Count Immunomodulator Immunomodulator Insulin analog, analog, injected injected Insulin Other or or unspecified unspecified Other Insulin analog, analog, oral oral Insulin cell regeneration regeneration ββ cell SGLT1/SGLT2inhibitor inhibitor SGLT1/SGLT2 SGLT1/SGLT2 inhibitor cell, encapsulated encapsulated β βcells, GLP-1 analog analog GLP-1 Total: 94 iInsulin analog, analog, glucose glucose responsive responsive iInsulin Glucagon receptor receptor agonist agonist Glucagon Glucagon analog analog Glucagon Insulin analog, analog, inhaled inhaled Insulin 0 Sources: Citeline Pipeline®, JDRF & Pharma websites, 3-5Mar2013 23 10 20 30 Sodium Glucose Cotransporter (1&2) Inhibitors ● SGLT1 predominant gut glucose transporter − ● SGLT2 predominant kidney glucose transporter − 24 Inhibition reduces postprandial BG spikes Inhibition stops glucose reabsorption from kidney filtrate, leaving excess in urine SGLT1-2 Inhibitors 25 Product/Sponsor Ph Status Canagliflozin (J&J) 3 (SGLT2 only) In T2DM, concerns about increased CV risk; increased LDL cholesterol, UTIs, fungal infections, hypotension, hypoglycemia Dapagliflozin (BMS/AZ) 3 (SGLT2 only) In T2DM, concerns about bladder cancer; increased UTIs, fungal infections, hypotension Empagliflozin (BI/Lilly) 3 (SGLT2 only) In T2DM, increased UTIs, fungal infections LX4211 (Lexicon) 2 (Both) In T2DM, better HbA1c, lower infection rates, better weight loss Luseogliflozin (Taisho/Novartis) 2 (Both) In T2DM, better HbA1c, lower infection rates, better weight loss SGLTx Inhibitors T1DM Viability Assessment ● ● ● Efficacy: High likelihood in T1DM based on Phase 3 studies in T2DM Safety: − Need PK activity limited to daytime hours − Need to verify no hypoglycemia exacerbation in T1DM Timing: Low regulatory hurdles implies short development time Potential Timing Timing Safety Safety Prevent Prevent Treat Treat Cure Cure 0 26 50 100 T1DM Perspectives 1923-2013 1923–1963 Glass syringe, SS 16g needle, beef/pork insulin, Ames Clinitest® tablets for urine BG testing 1965 1970, 1971 JDRF founded; Ames photoreflectance glucometer BD plastic disposable syringes, 23g needle; Ames Dextrostix® colorimetric BG strips 27 1995, 1996 DPT-1 Study; Lilly Humalog R receives FDA approval 1983 Lilly human insulin of recombinant DNA origin; Minimed 502 insulin pump 2003, 2004 NIH/JDRF Trialnet starts; <12 products in development 2000, 2001 FDA approves Novo Novolog R, Aventis Lantus; NIH/JDRF Immune Tolerance Network starts 2004, 1971 >94 drugs/ biologics in development; Highly accurate BG meters; Medtronic Veo pump/CGM; Dexcom G4 CGM; 5 major pumps; >3 artificial pancreas devices in development 2006 NIH/JDRF TEDDY study starts; Medtronic pump/CGM Randy’s Top Prospects 2013-Forward Treat 28 ● SGLT1/2 inhibitors for BG control ● Oral insulin for “natural” insulin action in liver Cure Prevent ● Vaccine to maintain beta cell-specific Tregs in pancreatic lymph nodes ● Hematopoietic stem cell transplant to reconfigure immune system against autoimmunity JDRF works for me; so I work for JDRF! 29