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SB-509 is a zinc finger DNA-binding protein transcription factor (ZFP-TF) activator that upregulates the expression of vascular endothelial growth factor A (VEGF-A). VEGF-A plays an important role in both angiogenesis and neurological development. Independent research studies show that VEGF-A has direct neurotrophic activity on axonal outgrowth in in vitro culture conditions. The dual angiogenic and regenerative effects of VEGF-A on nerves suggest a potential therapeutic effect in neuropathic disorders. SB-509 stimulates endogenous VEGF-A expression, of all natural isoforms in their proper ratios. In the streptozotocin-induced diabetes model of neuropathy, SB-509 prevented the typical reduction in motor and sensory nerve conduction velocities. This favorable result led to human trials in diabetic neuropathy. A phase I trial showing trends for meaningful clinical improvement in SB-509-treated subjects led to a phase II trial. In the phase II trial, SB-509-treated subjects showed an increase of 55% in intraepidermal nerve fiber density (IENFD) compared to a decrease of 16% in placebo-treated subjects. Although there was no overall difference in clinical outcome measures between SB-509- and placebotreated subjects, subjects who started out with low IENFD showed clinical improvements correlating with increases in nerve fiber density. Additional clinical studies are in progress in diabetic neuropathy and amyotrophic lateral sclerosis (ALS). These studies have shown that plasmid-mediated delivery of the engineered zinc finger transcription factor is safe and may be a therapeutic option in a variety of diseases. Source


Sands A.T.,Lexicon Pharmaceuticals Inc. | Zambrowicz B.P.,Lexicon Pharmaceuticals Inc. | Rosenstock J.,Dallas Diabetes and Endocrine Center | Lapuerta P.,Lexicon Pharmaceuticals Inc. | And 8 more authors.
Diabetes Care | Year: 2015

OBJECTIVE: To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS: In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002),for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes. © 2015 by the American Diabetes Association. Source


Rigby M.R.,Indiana University | Rigby M.R.,Janssen Pharmaceutical | Harris K.M.,ITN | Pinckney A.,Biostatistics Rho Inc. | And 27 more authors.
Journal of Clinical Investigation | Year: 2015

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458. © 2015, American Society for Clinical Investigation. All rights reserved. Source


Rendell M.,Creighton Diabetes Center
Expert Opinion on Drug Safety | Year: 2013

Introduction: The evaluation of agents to treat elevated blood glucose is straightforward and is accomplished with short duration studies, but it is more difficult to demonstrate safety of these agents over long periods of clinical use. Numerous large studies have raised questions as to the cardiovascular risks of certain drugs such as the thiazolidinediones and even challenged the wisdom of aggressive attempts to normalize plasma glucose. As a result of this uncertainty, the FDA issued new Guidance to Industry to assess cardiovascular risk. This new approach has markedly increased the burden to achieve approval of new diabetes drugs. Areas covered: The author has reviewed the recent history of drug approvals for diabetes drugs, using MEDLINE searches and freedom of information requests to the FDA. The thiazolidinedione saga illustrates that certain risks do not clearly manifest in the relatively short duration studies needed to evaluate control of blood sugar levels. Furthermore, the UKPDS and DCCT-EDIC studies show us that the lowering of plasma glucose has a beneficial effect which can only be reliably assessed over a very long time period. Expert opinion: The present day approval process is flawed in the conception that regulatory agencies can guarantee absolute safety. It is important to acknowledge that the risk-benefit relationship for new agents can only be determined by ongoing long-term clinical experience and prolonged longitudinal controlled studies. The increased costs of thorough safety evaluations must be defrayed by early initial approval and marketing of new therapeutic agents. Patent lifetimes and marketing exclusivity should be prolonged until results of long-term studies are finalized. © 2013 Informa UK, Ltd. Source


Rendell M.,Creighton Diabetes Center | Drincic A.,University of Nebraska Medical Center | Andukuri R.,Creighton Diabetes Center
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: Alogliptin is a highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). It is one of several agents of this class now available for treatment of type 2 diabetes. Areas covered: This review is based upon a PubMed search and personal experience with alogliptin. The pharmacokinetics and pharmacodynamics of alogliptin are reviewed. The glucose-lowering effect of this agent is discussed as monotherapy and in combination with metformin, sulfonylurea, piogilitazone and insulin. The potential adverse effects of alogliptin are summarized. Alogliptin is compared with the other available DPP-4 inhibitors. Expert opinion: Alogliptin is an additional choice in the group of DPP-4 inhibitors. As a group, these agents have a relatively modest glucose-lowering effect, inferior to that of metformin, sulfonylureas, and insulin. They do not have the benefit of weight loss offered by the glucagon-like polypeptide (GLP)-1 agonists. The primary use of DPP-4 inhibitors is in combination with other hypoglycemic agents, mainly metformin. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. A greater use of alogliptin and other DPP-4 inhibitors will occur if long-term studies show reduced cardiac events or long-term retention of insulin secretory capacity. The Examine Trial, a large study of alogliptin in coronary disease patients, is now underway and could provide important supportive data. © 2012 Informa UK, Ltd. Source

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