Profil Institute for Clinical Research Inc.

San Diego, CA, United States

Profil Institute for Clinical Research Inc.

San Diego, CA, United States
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Krentz A.J.,Profil Institute for Clinical Research Inc. | Fujioka K.,Center for Weight Management | Hompesch M.,Profil Institute for Clinical Research Inc.
Diabetes, Obesity and Metabolism | Year: 2016

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk–benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs. © 2016 John Wiley & Sons Ltd

Mudaliar S.,University of California at San Diego | Henry R.R.,University of California at San Diego | Sanyal A.J.,Virginia Commonwealth University | Morrow L.,Profil Institute for Clinical Research Inc. | And 9 more authors.
Gastroenterology | Year: 2013

Background & Aims Obeticholic acid (OCA; INT-747, 6α-ethyl- chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. Methods We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7α-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. Results When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P =.019) and 20.1% from baseline in the group treated with 50 mg OCA (P =.060). Insulin sensitivity increased by 24.5% (P =.011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. Conclusions In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted., Number: NCT00501592. © 2013 by the AGA Institute.

Rosenstock J.,Dallas Diabetes and Endocrine Center | Bergenstal R.M.,International Diabetes Center at Park Nicollet | Blevins T.C.,Texas Diabetes and Endocrinology | Morrow L.A.,Profil Institute for Clinical Research Inc. | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVEdTo compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGNANDMETHODSdIn this randomized, Phase 2, open-label, 232 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTSdLY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = 29.9 mg/dL [90% CI 214.6 to 25.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P,0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONSdIn type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reducedweight and lowered mealtime insulin doses. Copyright © 2013 by the American Diabetes Association.

Devineni D.,Janssen Research and Development LLC | Morrow L.,Profil Institute for Clinical Research Inc. | Hompesch M.,Profil Institute for Clinical Research Inc. | Skee D.,Janssen Research and Development LLC | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Aim: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. Results: Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. Conclusion: In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control. © 2012 Blackwell Publishing Ltd.

Krentz A.J.,University of Bedfordshire | Krentz A.J.,Profil Institute for Clinical Research Inc. | Viljoen A.,University of Bedfordshire | Viljoen A.,Lister Hospital | Sinclair A.,University of Bedfordshire
Diabetic Medicine | Year: 2013

Clinical metabolic studies have demonstrated that insulin action declines progressively with age in humans. In addition to its close association with Type 2 diabetes, which reduces life expectancy in older people, age-related insulin resistance is implicated in pathogenesis of several highly prevalent disorders for which ageing is a major risk factor. These include atherosclerotic cardiovascular disease, dementia, frailty and cancer. Accordingly, insulin resistance may be viewed as biomarker of age-related ill health and reduced lifespan. The rapidly rising number of older people, coupled with a high prevalence of insulin resistance resulting from obesity and sedentary lifestyles, presents unprecedented public health and societal challenges. Studies of centenarians have shown that preserved whole-body sensitivity to insulin is associated with longevity. The mechanisms through which insulin action is associated with age-related diseases remain unclear. Changes in body composition, i.e. sarcopenia and excess adiposity, may be more potent than age per se. Moreover, the impact of insulin resistance has been difficult to disentangle from the clustering of vascular risk factors that co-segregate with the insulin resistance-hyperinsulinaemia complex. Potentially modifiable mediators of age-related changes in insulin sensitivity include alterations in adipocytokines, impaired skeletal myocyte mitochondrial function and brown fat activity. The hypothesis that improving or maintaining insulin sensitivity preserves health and extends lifespan merits further evaluation. Practical non-pharmacological interventions directed against age-related insulin resistance remain underdeveloped. Novel metabolically active pharmacological agents with theoretical implications for some age-related disorders are entering clinical trials. However, recent adverse experiences with the thiazolidinediones suggest the need for a cautious approach to the use of insulin sensitizing drugs in older people. This could be particularly important in the absence of diabetes where the risk to benefit analysis may be less favourable. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Morrow L.,Profil Institute for Clinical Research Inc. | Muchmore D.B.,Halozyme Therapeutics | Hompesch M.,Profil Institute for Clinical Research Inc. | Ludington E.A.,Halozyme Therapeutics | Vaughn D.E.,Halozyme Therapeutics
Diabetes Care | Year: 2013

OBJECTIVE-To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS-This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcu-taneously (0.15 units/kg) with or without rHuPH20. RESULTS-The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123-131 min and 50% total glucose infused at 183- 186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71-79 min and 50% glucose infused at 127-140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13-to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action. CONCLUSIONS- Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.© 2013 by the American Diabetes Association.

Hompesch M.,Profil Institute for Clinical Research Inc. | Muchmore D.B.,Halozyme Therapeutics | Morrow L.,Profil Institute for Clinical Research Inc. | Vaughn D.E.,Halozyme Therapeutics
Diabetes Care | Year: 2011

OBJECTIVE - To compare the pharmacokinetics, pharmacodynamics, and safety of insulin lispro or regular human insulin (RHI) with or without recombinant human hyaluronidase (rHuPH20) administered before a standardized meal. RESEARCH DESIGN AND METHODS - In this four-way, crossover study, 22 patients with type 1 diabetes received injections of individually optimized doses of lispro or RHI with and without rHuPH20 before a liquid meal. RESULTS - With rHuPH20 coadministration, early insulin exposure (0-60 min) increased by 54% (P = 0.0011) for lispro and 206% (P < 0.0001) for RHI compared with the respective insulin alone. Peak blood glucose decreased 26 mg/dL for lispro (P = 0.002) and 24 mg/dL for RHI (P = 0.017), reducing hyperglycemic excursions (area under the curve for blood glucose > 140 mg/dL) by 79% (P = 0.09) and 85% (P = 0.049), respectively. Rates of hypoglycemia were comparable for lisprowith or without rHuPH20, whereas coadministration of RHI and rHuPH20 reduced hypoglycemia. CONCLUSIONS - Lispro or RHI with rHuPH20 produced earlier and greater peak insulin concentrations and improved postprandial glycemic control. © 2011 by the American Diabetes Association.

Heinemann L.,Profil Institute fur Stoffwechselforschung GmbH | Heinemann L.,Profil Institute for Clinical Research Inc. | Hompesch M.,Profil Institute for Clinical Research Inc.
Journal of Diabetes Science and Technology | Year: 2011

Biosimilar insulins (BIs) are viewed as commercially attractive products by a number of companies. In order to obtain approval in the European Union or the United States, where there is not a single BI currently on the market, a manufacturer needs to demonstrate that a given BI has a safety and efficacy profile that is similar to that of the "original" insulin formulation that is already on the market. As trivial as this may appear at first glance, it is not trivial at all for a good number of reasons that will be discussed in this commentary. As with protein manufacturing, modifications in the structure of the insulin molecule can take place (which can have serious consequences for the biological effects induced), so a rigid and careful assessment is absolutely necessary. The example of Marvel's failed application with the European Medicines Agency provides insights into the regulatory and clinical challenges surrounding the matter of BI. Although a challenging BI approval process might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant and do warrant a careful and evidence-driven approval process. © Diabetes Technology Society.

Heinemann L.,Profil Institute fur Stoffwechselforschung GmbH | Heinemann L.,Profil Institute for Clinical Research Inc.
Diabetes Technology and Therapeutics | Year: 2010

Aim: A good understanding of the relevance of interfering factors having an impact on blood glucose (BG) measurement is needed to obtain the required quality. This depends on the application in which meters designed for self-monitoring of BG (SMBG) are used. Methods: By means of a literature search all publications (from January 1, 1980 to August 10, 2009) were identified that report about the influence of potentially interfering substances/factors on the measurement quality of BG meters. Results: Certain substances (e.g., maltose) can have a profound and misleading impact on the BG measurement result when the enzymatic reaction embedded on the given test strips cross-reacts. Also, a number of other drugs (e.g., acetaminophen) and factors (like temperature and altitude) affect the reliability of BG measurement massively. However, the susceptibility of the BG meter (depending on the enzyme technology of the test strips) differs significantly. Conclusions: In daily practice the factors that have a relevant impact on the reliability of BG measurements with modern BG meters are rarely met. Clearly this also depends on the intended use (SMBG in patient hands vs. point-of-care testing in hospitals). To avoid misleading measurement results requires adequate training of all people involved. © Copyright 2010, Mary Ann Liebert, Inc.

Heinemann L.,Science and Co | Home P.D.,Northumbria University | Hompesch M.,Profil Institute for Clinical Research Inc.
Diabetes, Obesity and Metabolism | Year: 2015

Biosimilar insulins are approved copies of insulins outside patent protection. Advantages may include greater market competition and potential cost reduction, but clinicians and users lack a clear perspective on 'biosimilarity' for insulins. The manufacturing processes for biosimilar insulins are manufacturer-specific and, although these are reviewed by regulators there are few public data available to allow independent assessment or review of issues such as intrinsic quality or batch-to-batch variation. Preclinical measures used to assess biosimilarity, such as tissue and cellular studies of metabolic activity, physico-chemical stability and animal studies of pharmacodynamics, pharmacokinetics and immunogenicity may be insufficiently sensitive to differences, and are often not formally published. Pharmacokinetic and pharmacodynamic studies (glucose clamps) with humans, although core assessments, have problems of precision which are relevant for accurate insulin dosing. Studies that assess clinical efficacy and safety and device compatibility are limited by current outcome measures, such as glycated haemoblobin levels and hypoglycaemia, which are insensitive to differences between insulins. To address these issues, we suggest that all comparative data are put in the public domain, and that systematic clinical studies are performed to address batch-to-batch variability, delivery devices, interchangeability in practice and long-term efficacy and safety. Despite these challenges biosimilar insulins are a welcome addition to diabetes therapy and, with a transparent approach, should provide useful benefit to insulin users. © 2015 John Wiley & Sons Ltd.

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