GTCbio's Research Bulletin: Biotech and Pharmaceutical Industry Update

With Aaron I. Vinik, M.D., Ph.D. , Professor of Internal Medicine; Director, Strelitz Diabetes Institute

Pancreas transplantation has provided a cure for many insulin dependent diabetic patients. By the end of 2005 there were about 25,000 done worldwide, 18,000 of these in the . The 3 year survival has now reached 95% for pancreas alone, pancreas and kidney and staged kidney pancreas procedures. That this is really designed to address people with advanced disease who need a kidney is borne out by the high mortality approaching 40% in those on the waiting list. In addition the need for of immunosuppressive therapy on a lifelong basis are not without hazards but graft function for 3 or more years occurs in 75-80% of cases and for some unknown reason is better with a staged procedure. This is highly efficient but major surgery and clearly desirable in patients needing a kidney! Islet transplantation prior to the year 2000 was feasible but the islet survival was dismal, the need for immunosupression great, and the freedom from taking insulin rare. With the introduction of the Edmonton protocol which utilize 2-4 pancreases, avoids the use of steroids and uses a relatively benign immunosuppressive approach the possibility that a cure could be accomplished successfully essentially eliminating surgical risks associated with whole pancreas transplantation loomed loud and clear. The original Shapiro data suggested insulin independence in only 10-20 % of patients despite improved C peptide after 48 months. In a multicenter trial using this protocol there are some centers e.g. Miami that have achieved a greater rate of insulin independence while others have failed dismally. The argument is that even a small amount of insulin may reduce the burden of diabetic complications. Ther are however major needs to improve immunosupression and techniques such as nanoencapsulation and the use of a variety of non toxic immunosuppressant agents is actively being pursued. However the availability of pancreases is seriously limited + 8000/year and it take 2-4 for a successful transplant limiting the procedure to about 1500/y clearly an embarrassingly low number considering the deserving patients who are out there in need of help. Alternative methods are clearly needed to provide functioning islets. Until recently it was considered heretical to even dream of expanding islet mass. It is now evident that there are several ways in which islet mass can be expanded by causing hypertrophy, hyperplasia, and replication of preexisting beta cells or, by inducing neogenesis of new w islets derived form protodifferentiated stem cells resident in the human pancreas for as long as patients have been examined. Balancing these forces are those that cause apoptosis or necrosis of pancreatic beta cells such as autoimmune destruction of islet in type 1 diabetes and programmed cell death probably mediated by hIAPP in type 2 diabetes so that the onset of the disease there is already a 50% loss of islets and there is a progressive decline at the rate of abut n6-10%/y. Recent evidence suggest that a number of growth factors can initiate growth, proliferation, differentiation of these precursor cells in vivo into functioning islets capable of secreting insulin in a regulated manner and of curing diabetes in animals and mitigating its severity in humans. The growth factors include INGAP, gastrin and EGF and each has its own merits and demerits. The need for prevention of destruction by autoimmunity is still present and retardation of the apoptotic process may be achievable with GLP-1 analogues, the TZDs or DPP1V inhibitors. We are at the dawn of an era of regeneration of pancreatic islets from pancreatic acinar tissue. The process requires protodifferentiated stem cells. The first agent shown to promote islet neogenesis was INGAP. It has now bee shown to not only promote islet regeneration but protect the beta cells from destruction. In addition the concern with unbridled cell proliferation may not be as great a concern with this peptide since it had been established that there is a negative feedback loop as a restraint mechanism limiting unbridled growth and proliferation. The mechanisms of this process are being elucidated. There are a number of critical issues that need to be addressed to translate theses observations into clinical care. But conservatively, from a not uninvolved perspective the future promises great advances in the de novo production of islet tissue in diabetic patients as a “cure” for some forms using INGAP alone or in combination with immunosupression or other trophic and antiapototic agents.

Dr. Vinik will be covering this topic in greater detail at GTCbio's 3rd Metabolic Diseases World Summit. November 1,2 2007 in San Diego.

Thyroid hormones in excess elicit effects that could be beneficial, such as induction of lowering of weight and plasma cholesterol levels, but also have deleterious actions on heart, bone and muscle. We have been developing compounds that selectively modulate the thyroid hormone receptor (TR) to elicit beneficial but not deleterious effects. These compounds have selectivity for actions through the β-form of the TR and for uptake into various tissues. The compounds have been studied in rodents, monkeys and humans. Although there are differences in the compounds and in species, overall it appears that they have potent actions to remove cholesterol from the body using both the low density (LDL) and high density (HDL) lipoprotein pathways, reduce plasma and hepatic triglyceride levels, and promote fat but not muscle loss. These actions can be observed at doses of the compounds where deleterious effects on heart, muscle and bone are not observed and [unlike the case with the natural thyroid hormone, triiodothyronine (T3)] where toxic effects are not observed. Whereas diabetes can worsen in hyperthyroidism, these compounds elicit potent actions to reduce blood glucose animals in mice. These compounds show promise to attack the metabolic syndrome.

Dr Baxter will be covering this topic in greater detail at GTCbio's 3rd Metabolic Diseases World Summit. November 1,2 2007 in San Diego.

Insulin sensitizing Thiazolidinediones (TZDS) are generally thought to function as activators of the nuclear transcription factor PPARg? . It is often forgotten that the TZDs were discovered and optimized in animal models long before the PPARg agonism of rosiglitazone was discovered. We were involved in the original optimization of pioglitazone using animal models and found that only specific binding site for radio-labeled pioglitazone was in the mitochondria. This observation gave rise to the discovery of a unique protein (mitoNEET) in the outer mitochondrial membrane that generates reactive oxygen (ROS) and appears to control oxidative metabolism. We have recently synthesized a group of insulin sensitizing molecules with reduced ability to bind to PPARg. This talk will summarize the alternate view that the original TZD insulin sensitizing pharmacology results not from direct activation of PPARg, but rather from the prevention of a metabolic inflammation that originates from ROS generated from excessive oxidative metabolism at the level of the mitochondria. We suggest that the pharmacological superiority of pioglitazone versus rosiglitazone results from the reduced activation of PPARg and moreover that PPARg-sparing insulin sensitizers (i.e., mitochondrial specific compounds that do not bind to PPARg) will provide further improved profiles in correcting the aspects of insulin resistance that contribute to both diabetes and the cardiometabolic syndrome. (msdRx.com)

Dr Colca will be covering this topic in greater detail at GTCbio's 3rd Metabolic Diseases World Summit. November 1,2 2007 in San Diego.

Click here for more information on this meeting.

A series of events in the world of metabolic therapeutic development over the past decade have led to the involvement of the media, Congress, and academic pundits in the evaluation and regulation of drugs for diabetes and other chronic therapies. The results, however well-intended, threaten the development of therapies aimed at meeting unmet clinical need in general—and for people with diabetes in particular. What is needed is not a complete re-invention of the review processes at FDA but a better general understanding among all stakeholders of what is involved in developing needed therapies.

This presentation will outline the sensational story of metabolic drug development and regulation with the emphasis on the pivotal chapters of metformin, troglitazone, muraglitazar, rimonabant, and rosiglitazone. Some of the lessons learned from this experience will be suggested. The possibly scenarios for changes in how diabetes drugs are developed and regulated will be discussed. It is hoped that this presentation will equip the participants for effective participation in the public discussions that will influence how therapies will be developed and evaluated in the future.

Hear this topic in greater detail at GTCbio's 3rd Metabolic Diseases World Summit. November 1,2 2007 in San Diego.

Click here for more information on this meeting.

Next week: Dr. Jerry Colca , President and CSO, Metabolic Solutions Development Co. will be talking about Metabolic Inflammation and New Approach to Insulin sensitizers.

Myocardial ischemia causes rapid depletion of ATP in part due to inefficient hydrolysis of ATP when the mitochondrial F1F0 ATP synthase switches to a hydrolase, which serves no useful work. The amount of ATP hydrolyzed by this enzyme during myocardial ischemia represents a substantial fraction of that used during an ischemic event. Studies with oligomycin (inhibits both F1F0 ATP synthase and hydrolase activities) done previously showed that it conserved ATP during ischemia and its efficacy varied with species. A peptide, IF-1, activated by low pH and conditions similar to those seen during ischemia, inhibits F1F0 ATP hydrolase activity and is highly expressed in “slow heart rate species” (dog, rabbit) and poorly expressed in rat. Upon restoration of normal pH, IF-1 loses its activity, therefore giving it selectivity for inhibiting hydrolase activity and serves as a form of endogenous protection. Development of a peptide mimetic of IF-1 is impossible and a small molecule selective for the hydrolase would be difficult if the switch from synthase to hydrolase is merely a chemical reversal, but it has been suggested that this reversal may be a conformational change. The focus of this review is on BMS-199264 that is a small molecule F1F0 ATP hydrolase selective inhibitor that protects ischemic myocardium by conserving ATP during the ischemic episode. BMS-199264 has no effect on F1F0-ATP synthase activity and not only conserves ischemic ATP, but enhances reperfusion recovery of contractile function and ATP, showing that upon reperfusion, that the enzyme has switched back to synthase mode. The efficacy of BMS-199264 suggests that the switch from synthase to hydrolase activity during ischemia may not merely be a chemical reaction “run in reverse”.

Dr Grover will be covering this topic in greater detail at GTCbio's 3rd Metabolic Diseases World Summit. November 1,2 2007 in San Diego.

Click here for more information on this meeting.