New Developments of Anti-Diabetic Medications in 2013

UMDNJ New Developments of Anti-Diabetic Medications in 2013 Xiangbing Wang, MD., Ph.D. Division of Endocrinology & metabolism Robert Wood Johnson Medical School-UMDNJ (Rutgers), NJ, USA 1

Development and Progression of Type 2 Diabetes* (Conceptual Presentation) NGT Insulin IGT/ IFG Type 2 Diabetes Resistance Glucose Postprandial glucose Fasting glucose -10-5 0 5 10 15 20 25 30 Relative Activity Insulin level Insulin resistance hepatic and peripheral Beta-cell function 10 5 0 5 10 15 20 25 30 Years from Diabetes Diagnosis 2

TARGETS FOR HGBA1c individualization ADA/EASD Organization Target (%) ADA <7.0 IDF <6.5 ACE <6.5 EASD <6.5 3

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Pharmacologic Therapy C β-cells Sulfonylureas & meglitinides GKAs and GPR40 α cells glucagon receptor blocker β and α-cells GLP-1 analogs (3) DPP4 inhibitors (4) Liver: Metformin Adrenal gland: GI: a-glucosidase inhibitors colesevelam HCl and Orlistate TZDs: rosiglitazone &Pioglitazone Kidney: SGT-2 inhibitors (New) Brain-Hypothalamus Dopamine receptor agonist 5HT2C receptor blocker Insulin : 6

pioglitazone) fibrates) 7

TZDs 1. Pioglitazone and rosiglitazone are synthetic ligans for PPAR gamma receptor. TZDs Increase insulin sensitivity with average in reduce A1c 1-1.5% in mono-therapy. 2. Edema, weight gain and fracture are bothersome side effects. 3. CVD safety is the major concern. Rosiglitazone has been removed form Europe and restricted in US. However, new analysis of RECORD, which followed patients for five years did not show a statistically significant difference in heart safety between Rosiglitazone and older diabetes drugs. 4. FDA announced on April 12, 2013 that the agency will hold hearing in June/5-6/2013 to reassess the results of a safety study on rosiglitazone. 5. Pioglitazone s patent expired in 2011 and possible risk of bladder cancer. 6. TZDs become third or fourth line medication, We need more selective TZDs 8

Liver-Metformin 1. First line and most commonly used oral agent of treat type 2 DM (ADA/EASD: April, 2012) 2. Reducing hepatic glucose production and increase peripheral glucose uptake. 3. Low A1c 1-1.5%, low incidence of hypoglycemia and no weight gain, in some case weight loss. 4. Caution for pts with Cr 1.4-1.5mg/dl and elder pt. 5. Most common side effects is GI, lactic acidosis is 3-6/100,000. 6. Recent data showed benefits effects on CAD protection and cancer mortality. 7. Possible longevity? 9

Renal -SGLT-2 inhibitors In type 2 diabetes, renal gluconeogenesis is increased and renal glucose reabsorption might be enhanced because of up-regulation of the SGLT2 transport. SGLT-2 inhibitors reduce fasting and postprandial plasma concentrations of glucose and HbA1c, losing body weight with low risk of hypoglycemia. SGLT-2 inhbitors were associated with increased risk of genital and urinary tract infections in most studies.

Renal- SGT-2 inhibitor-dapagliflozen

Renal- SGT-2 inhibitor-dapagliflozen FDA recommended against approval of Dapagliflozen, the first of this class of agent in July 2011 (9-6 vote). FDA stalled the drug again on Jan. 6, 2012 for potential risk of bladder and breast cancer. Nine cases of bladder and breast cancer among dapagliflozine group compared with one case each in control group.

SGLT-2 Inhibitor - Canagliflozin Canagliflozin Once daily dosing before 1 st meal of day, 100mg or 300mg tablets MOA: Inhibition of SGLT2 reduces reabsorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss. Blocks approximately 50-80 grams of glucose per day from being reabsorbed

SGLT-2 inhibitor-canagliflozin FDA approved canagliflozin (Invokana) on March 29, 2013. First in its class to be approved in the United States. Invokana is expected to generate sales in 2016 of around $468 million, according to analysts' estimates compiled by Thomson Reuters.

Effects of SGLT2 inhibitors on clinical measures: Glycemia Endpoints Benefits have been observed for both fasting and postprandial glucose measures, as well as for HbA1c Dapagliflozin (Bristol-Myers Squibb ), refiled for FDA approval Reduction in FBG varied with dose, from 0.8 mmol/l (2.5mg) to 1.2-4.7 mmol/l (10mg) Reductions in BG were achieved when used in combination with other OHA and insulin Reduction in HbA1c 0.6% (2.5mg), and 0.8% - 2.7% (10mg) Canagliflozin (Johnson & Johnson) FDA approval on March 29,2013 Reported to produce reductions in FBG ranging from 0.9 to 2.1mmol/L with daily doses between 50mg and 600mg. The corresponding reduction in HbA1c was 0.9% at a dose of 300mg daily Empagliflozin (Eli Lilly, filed for FDA approval) Significant decreases in FBG when used alone or in combination with metformin, with reductions in blood glucose of 1.7 mmol/l and HbA1c of 0.63% 100mg daily. Significantly greater reductions in HbA1c were achieved in patients with higher starting HbA1c levels

Canagliflozin Side Effects http://www.invokanahcp.com/safety-information/safety-and-tolerabilityprofile?utm_source=google&utm_medium=cpc&utm_campaign=invokana+hcp&utm_term=canagliflozin%20side%20effects&utm_content=side+effe cts+-+exact mkwid suzujen2m pcrid 24016786155

GI-Acarbose delays carbohydrate absorption Without acarbose With acarbose Carbohydrate Carbohydrate absorption Carbohydrate absorption Without acarbose With acarbose Duodenum Jejunum Ileum

GI-SGLT1/SGLT2 inhibitor 18

SGLT1/SGLT2 inhibitor-lx4211 The recently completed study was a four-week, randomized, double-blind, placebocontrolled study in 36 patients with type 2 diabetes. placebo (n=12) or LX4211, 150 mg (n=12) or 300 mg (n=12), once daily for 28 days. There was a marked decrease in fasting plasma glucose in both dose groups, with reductions at week four of 53.4 mg/dl 9150MG) and 65.9 mg/dl (300MG) as compared to 15.1 mg/dl for placebo. (p=0.001 and p<0.001, respectively). Notably, a substantial percentage (42%) of patients in the 300 mg dose group achieved fasting plasma glucose levels of <105 mg/dl at week four of dosing as compared to placebo (p=0.037). Importantly, after only four weeks, HbA1c was significantly reduced by 1.15% in the 150 mg dose group (p=0.036) and by 1.25% in the 300 mg dose group (p=0.017), as compared to 0.49 in the placebo group. patients in both dose groups showed weight reduction, decreased blood pressure and triglycerides relative to placebo. LX4211 demonstrated a favorable safety profile in the study with no dose-limiting toxicities. Adverse events were generally mild and equally distributed across all groups, including the placebo group 19

LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo-Controlled Trial 20

GI-other agents for low glucose levels 1. Welchol (colesevelam HCl) is a bile acid sequestrant indicated as an adjunct to diet and exercise to reduce elevated LDL-C and improve glycemic control in adults with T2DM 2. Orlistate blocks pancreatic lipase in the intestine, weight loss and reduction A1c in T2DM 3. Diet or medications change intestinal environments for bacteria? 21

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β-cells: Sulfonylureas 1. Insulin secretagogues used in DM >60 years. 2. Reliable means to treat type 2 DM, initial response 50-80%, average in reduce A1c 1% in monotherapy. 3. Relative cheaper. 4. Hypoglycemia and weight gain are bothersome side effects. 5. No effect or less effect in later stage type 2 DM, 6. No effect or less effect in acute hyperglycemia 7. possible more selective or glucose/atp-sensitive sulfonylurea? 23

Glucokinase activators increased insulin concentrations and reduced glucose concentrations in animal models of diabetes and patients with type 2 diabetes 24

Glucokinase activators (GKAs) Glucokinase activators can additionally reduce glucose concentrations through effects on hepatic glucose metabolism.

Possible effects of GKA 26

Glucokinase activators (GKAs) GKAs lowered or normalized blood glucose in various animal models of type 2 diabetes. Preliminary clinical activities support their potential More than 100 patents Several compounds are on Phase I & Phase II clinical trials: Piragliatin, AZD6370 (AstraZeneca), TTP-399 (TransTech Pharma, PSN-010 (Astellas/Prosidion/Eli Lilly) and MK0941 (Merck). Projected clinical usage:?

Plasma glucose (left panel), serum C-peptide (middle panel), and serum insulin (right panel) concentrations in the postabsorptive state before (predosing) and after administration per os of placebo (orange), piragliatin 25 mg (green), or piragliatin 100 mg... 1. This was a phase Ib randomized, double-blind, placebo-controlled crossover trial of two (25 and 100 mg) doses of piragliatin. 2. Patients included 15 volunteer ambulatory patients with mild type 2 diabetes 3. Administration of a single dose of placebo or piragliatin 25 mg or piragliatin 100 mg at 120 Bonadonna R C et al. JCEM 2010;95:5028-5036

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FFAR1; also known as G-protein-coupled receptor 40 [GPR40] 1. AB G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic beta cells and mediates free fatty acidinduced insulin secretion. 2. [(3S)-6-({2',6'-dimethyl-4'-[3- (methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)- 2,3-dihydro-1-benzofuran-3-yl]acetic acid hemihydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. 3. Molecular Formula: C28H30O7S 30

FFAR1 agonist TAK-875 A phase II, randomized, double-blind, placeboand active comparator-controlled trial 426 patients with type 2 diabetes 4,8 and 12 weeks TAK-875 (50 200 mg/day) reducing A1c by roughly 1%, same as glimepiride (2 4 mg/day) with minimum risk of hypoglycaemia. Burant et al. The Lancet 379:1403-11, 14 April 2012 31

TAK-875, Between 33% and 48% of patients reached the ADA target of HbA 1c less than 7% by week 12 at doses of TAK-875 25 mg and higher, similar to that reported in patients treated with glimepiride. A significant change in HbA 1c compared with placebo was already apparent at week 4 with all doses of TAK-875, suggesting a rapid onset of action, again similar to that seen with glimepiride. By comparison with placebo, the improvement in HbA 1c on TAK-875 is associated with both a reduction in fasting and post-challenge glucose and a decrease in AUC for glucose during OGTT.

Currently on phase III study. Long way to go for TAK-875

Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease Verified March 28, 2013 by Takeda Global Research & Development Center, Inc 1. A Multicenter, Randomized, Double-Blind, Placebo- Controlled, Phase 3 Study to Evaluate Cardiovascular Outcomes of TAK-875, 50 mg in Addition to Standard of Care in Subjects With Type 2 Diabetes and With Cardiovascular Disease or Multiple Risk Factors for Cardiovascular Events 2. MACE composite, including: Cardiovascular death,nonfatal Myocardial infarction, Nonfatal stroke, Hospitalization for unstable angina (with or without revascularization) 3. Estimated Enrollment: 5000 Study Start Date: June 2012 Estimated Study Completion Date: December 2018 Estimated Primary Completion Date: December 2018

Brain: Bromocriptine: A novel approach to the treatment of DM2 Diabetes Care 2000, 23:1154-1161

Dopamine and glucose metabolism Bromocriptine is an ergot alkaloid dopamine-d2-receptor agonist that has been available since 1978 to treat patients with prolactinomas and Parkinson s disease and its effects on glycaemic variables have been noted since 1980.116. In a randomised trial of 3095 patients, bromocriptine quick release reduced the risk of CAD compared with placebo (hazard ratio 0 60) by 52 weeks U.S. Food and Drug Administration (FDA) approved its firstin-class drug Cycloset for the treatment of Type 2 diabetes in May 2009. After three full years, still very limit usage in USA Bromocriptine is not licensed in Europe/China for treatment of T2DM

Brain-hypothalamus-Lorcaserine Lorcaserine is a selective serotonin/5-hydroxytryptamine (5- HT) 2C receptor, with a functional selectivity of about 15 and 100 times that for 5-HT2A and 5-HT2B, respectively FDA approved lorcaserine for weight loss/maintenance on June 29, 2012. Lorcaserin has been shown to improve glycemic control in addition to weight loss in T2DM patients (A1c 0.9-1% vs 0.4% ± 0.06% with placebo). Lorcaserin is the first approved drug for treating obesity since the approval of orlistat (Xenical) in 1999. The most common adverse events were headache, back pain, nasopharyngitis, and nausea.

Drugs targeting α-cell dysfunction GLP-1R agonists and DPP-4 inhibitors reduce glucagon secretion in a glucose-dependent manner. Another mechanism to counter excess glucagon secretion is to block the glucagon receptor or its signaling after binding with the hormone. Animal models with a null mutation of the glucagon receptor or reduced expression with antisense oligonucleotides show significant reduction in basal glycemia and improved glucose tolerance.

Diabetes Care. 34 Suppl 2:S236-43, 2011 41

Other targets: adrenal 11 β-hydroxysteroid dehydrogenase inhibitors INCB13739 Korlym (mifepristone blocks Progesterone and glucocorticoid receptor) was approved by the U.S. FDA to control hyperglycemia in adults with endogenous Cushing s syndrome Feb, 17, 2012. This drug was approved for use in patients with endogenous Cushing s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery.

Mifepristone blocks Progesterone and glucocorticoid receptor

Mifepristone The mean baseline HbA1c of 7.43± 1.52% decreased to 6.29±0.99% at wk 24/ET (P<0.001) The mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7)

Liver Biguanides TZDs DPP-4 inhibitors Major Targets of Oral Drug Classes Pancreatic Islet Cells Sulfonylureas Meglitinides DPP-4 inhibitors Glucose level Muscle and Fat TZDs Biguanides DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinediones. 1. DeFronzo RA. Ann Intern Med. 1999;131:281 303. 2. Buse JB et al. In: Williams Textbook of Endocrinology. 2003:1427 1483. Gut alpha-glucosidase inhibitors 48

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