A Survey of Commercial Product Development in T1DM: Reports from along the commercial roads to treatments and cure Randy L. Anderson, Ph.D.

Transcription

1 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

2 JDRF Pedigree 1963 T1DM Diagnosis at age PhD, Biostatistics; diabetes consulting 1994 Pharmaceuticals development 2001 First local JDRF Walk to Cure Diabetes JDRF Medical Sci Review Cmte; >45 reviews 2006 Now JDRF ad hoc proposals reviewer; >12 reviews 1979 Diabetes management independent study 1990 Began work as diabetes clinical trialist 1999 Firstborn son T1DM diagnosis; first JDRF work NIH/JDRF Immune Tolerance Network via PPD 2004 First local JDRF Hope Gala 2003 Head Metabolics for PPD; 50-years with T1DM 2

3 Technical or Biological Cure? Technical innovations Insulin pumps Continuous glucose monitors Artificial pancreas Biological cure Immune tolerance Beta cell regeneration 3

4 Review: JDRF Triumvirate Cure Strategy Immune Tolerance Induction 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 4

5 T1DM Products in Development By Product Class Count Immunomodulator Insulin analog, injected Other or or unspecified Insulin analog, oral β cell regeneration SGLT1/SGLT2 inhibitor β β cells, cell, encapsulated GLP-1 analog iinsulin analog, glucose responsive Glucagon receptor agonist Glucagon analog Insulin analog, inhaled Total: 94 Sources: Citeline Pipeline, JDRF & Pharma websites, 3-5Mar

6 Immunomodulators (A Sampling) 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) li key engenders antigen-specific CD4+ T-helper cell stimulation (Antigen Expr) Diabetes vaccine (Selecta Bioscience) Pre Clin Pre Clin Pre Clin Naimit Consortium (natural immunomodulators) partner; EU 7 th Framework Program funding robust, long lasting antigen-specific immune response Targeted toleragenic antigen-specific vaccine. JDRF industry partner 6

7 We have demonstrated in antea-diabetic mouse model that lifelong recovery of β cells has a strong correlation with normalization of the T reg cell population in pancreatic lymph notes (PLNs). This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of T reg cells in PLNs as a therapeutic approach for type 1 diabetes (T1D). 7

8 Curative Hematopoietic Stem Cell Transplant NOD mouse develops autoimmune diabetes spontaneously Experiment NOD mouse undergoes immune system ablation 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 16 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 8

9 Immunomodulators T1DM Viability Assessment Essential for cure Immune system complexity lowers prospects Near certain need for combination therapies Long follow-up times Safety: Selective immune tolerance is critical Need to verify low cancer risk, low infection risk Best cure prospect appears to be some stem cell transplant Potential Timing Safety Prevent Treat Cure

10 T1DM Products in Development By Product Class Count Immunomodulator Insulin analog, injected Other or or unspecified Insulin analog, oral β cell β cell regeneration SGLT1/SGLT2 inhibitor β β cells, cell, encapsulated GLP-1 analog iinsulin analog, glucose responsive Glucagon receptor agonist Glucagon analog Insulin analog, inhaled Total: 94 Sources: Citeline Pipeline, JDRF & Pharma websites, 3-5Mar

11 Beta Cell Regeneration Product/Sponsor Ph Status Human proislet peptide (CureDM/Sanofi) FT-201 (Fate Therapeutics) 1 Stabilized form of human proislet peptide (analogous to INGAP). Ph 1 study completed Nov2012 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 1Feb

12 Beta Cell Regeneration T1DM Viability Assessment Efficacy: Essential for cure Immune tolerance prerequsite Concept verified in animal and human T2DM implies high likelihood of efficacy, AFTER immune tolerance Safety: Need to verify low cancer risk Timing: Moderate regulatory hurdles Potential Timing Safety Prevent Treat Cure

13 Roche Accu-Chec Diaport New York, 16 August 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

14 Technical or Biological Cure? 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 14

15 Optimizing Insulin Action: Intraperitoneal Infusion vs. Subcutaneous Injection Schade DS, et.al. Diabetologia, 1980; 19(1):

16 16 Roche Accu-Chec Diaport

17 Roche Accu-Chec Diaport Diaport provides more appropriate timing of insulin, delivered more directly to liver Stabilize blood glucose against large post-meal spikes Increase liver storage of glucose (as glycogen) Increased liver glycogen storage reduces hypoglycemia risk 17

18 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 Closed Loop Artificial Pancreas Using Intraperitoneal (IP) Insulin Dec Via DiaPort Source: Clinicaltrials.gov, 5Mar

19 T1DM Products in Development By Product Class Count Immunomodulator Insulin analog, injected Other or or unspecified Insulin analog, oral β cell regeneration SGLT1/SGLT2 inhibitor β β cells, cell, encapsulated GLP-1 analog iinsulin analog, glucose responsive Glucagon receptor agonist Glucagon analog Insulin analog, inhaled Total: 94 Sources: Citeline Pipeline, JDRF & Pharma websites, 3-5Mar

20 Oral Insulins 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 20

21 Potential of Oral Insulins Positives Negatives 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! Must prevent insulin (protein) digestion before absorption Requires predictable insulin activity after absorption Uniformity of absorption? Dosing accuracy? 21

22 Oral Insulins T1DM Viability Assessment Promising preclinical data Need evidence of liver insulinization Moderated BG excursions Lowered hypoglycemia risk Moderate regulatory hurdles Timing Safety Prevent Potential Treat Cure

23 T1DM Products in Development By Product Class Count Immunomodulator Insulin analog, injected Other or or unspecified Insulin analog, oral β cell regeneration SGLT1/SGLT2 inhibitor β β cells, cell, encapsulated GLP-1 analog iinsulin analog, glucose responsive Glucagon receptor agonist Glucagon analog Insulin analog, inhaled Total: 94 Sources: Citeline Pipeline, JDRF & Pharma websites, 3-5Mar

24 Sodium Glucose Cotransporter (1&2) Inhibitors SGLT1 predominant gut glucose transporter Inhibition reduces postprandial BG spikes SGLT2 predominant kidney glucose transporter Inhibition stops glucose reabsorption from kidney filtrate, leaving excess in urine 24

25 SGLT1-2 Inhibitors 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 HbA 1c, lower infection rates, better weight loss Luseogliflozin (Taisho/Novartis) 2 (Both) In T2DM, better HbA 1c, lower infection rates, better weight loss 25

26 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 Timing Safety Prevent Treat Cure Potential

27 T1DM Perspectives Glass syringe, SS 16g needle, beef/pork insulin, Ames Clinitest tablets for urine BG testing 1970, 1971 JDRF founded; Ames photoreflectance glucometer 1995, 1996 DPT-1 Study; Lilly Humalog R receives FDA approval 2003, 2004 NIH/JDRF Trialnet starts; <12 products in development 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 1965 BD plastic disposable syringes, 23g needle; Ames Dextrostix colorimetric BG strips 1983 Lilly human insulin of recombinant DNA origin; Minimed 502 insulin pump 2000, 2001 FDA approves Novo Novolog R, Aventis Lantus; NIH/JDRF Immune Tolerance Network starts 2006 NIH/JDRF TEDDY study starts; Medtronic pump/cgm 27

28 Randy s Top Prospects 2013-Forward Treat Prevent Cure SGLT1/2 inhibitors for BG control Oral insulin for natural insulin action in liver Vaccine to maintain beta cell-specific Tregs in pancreatic lymph nodes Hematopoietic stem cell transplant to reconfigure immune system against autoimmunity 28

29 JDRF works for me; so I work for JDRF! 29