Diabetic Kidney Disease: Drug Discovery and Clinical Development Challenges

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Diabetic Kidney Disease: Drug Discovery and Clinical Development Challenges

Tuesday, December 9, 2014

The New York Academy of Sciences

Presented By

 

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in the United States, and is associated with elevated cardiovascular morbidity and mortality. The progression of kidney disease in patients with diabetes occurs over many years, and interventions such as glycemic control and blood pressure lowering with inhibitors of the renin-angiotensin-aldosterone system have been shown to slow this progression. Despite the standard of care, the prevalence of patients with ESRD secondary to diabetic nephropathy continues to rise. Recently, several drugs in late clinical development have failed due to lack of efficacy and/or safety concerns. Finding and validating new targets to treat this condition has proven challenging due to lack of a deep understanding of the pathogenesis of diabetic nephropathy and biomarkers that can reliably define the rate of kidney function loss. This symposium reviews recent experimental approaches that may lead to the identification of targets for preventive or therapeutic interventions, and discusses the current challenges in the clinical development of therapeutic agents to treat diabetic kidney disease.

*Networking reception to follow.

This symposium includes a dedicated Professional Development Workshop for Early Career Investigators:

Editor's Guide to Writing and Publishing Your Paper
8:00 AM - 9:00 AM

In this workshop participants will gain an inside look into the editorial review process and how to best present the results of their work for publication.

Presented by Brooke Grindlinger, PhD, The New York Academy of Sciences
Former Editor, The Journal of Clinical Investigation

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Registration and Webinar Pricing

Member$30
Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

 


The Biochemical Pharmacology Discussion Group is proudly supported by

 

  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


Tuesday, December 9, 2014

8:00 AM

Registration and Continental Breakfast

8:00 AM

Professional Development Workshop for Early Career Investigators:
For Graduate Students, Post-doctoral Fellows, and Junior Faculty

Editor's Guide to Writing and Publishing Your Paper
Brooke Grindlinger, PhD, The New York Academy of Sciences
In this workshop participants will gain an inside look into the editorial review process and how to best present the results of their work for publication.

9:00 AM

Welcome and Introductory Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Frank C. Brosius, MD, University of Michigan

Session I. Target Identification through Novel Experimental Approaches

9:10 AM

New Targets for the Treatment of Diabetic Nephropathy: What we have Learned from Animal Models
Frank C. Brosius, MD, University of Michigan

9:50 AM *

Understanding Glomerular and Tubule Epithelial Cell Biology for Targeting in Diabetic Kidney Disease
Katalin Susztak, MD, PhD, University of Pennsylvania

* The 9:50 am talk will not be broadcast as part of the live webinar.

10:30 AM

Networking Coffee Break

11:00 AM

Targeting Pericyte Differentiation as a Strategy to Modulate Kidney Fibrosis in Diabetic
Nephropathy

Benjamin D. Humphreys, MD, PhD, Brigham and Women's Hospital

Session II. Challenges in Drug Development for Diabetic Kidney Disease

11:40 AM

Drug Discovery for Diabetic Nephropathy: Trying to Leap from Mouse to Man
Matthew D. Breyer, MD, Eli Lilly and Company

12:20 PM

Networking Lunch Break and Poster Viewing

Session II. Challenges in Drug Development for Diabetic Kidney Disease

1:20 PM

Current Drug Development Challenges in Diabetic Kidney Disease (DKD)
Matthias Meier, MD, F. Hoffmann-La Roche Ltd

2:00 PM

Promising Agents in Clinical Development for the Treatment of Diabetic Kidney Disease
Shahnaz Shahinfar, MD, FASN, S. Shahinfar Consulting, Inc. and The Children's Hospital of Philadelphia

2:40 PM

Networking Coffee Break

3:10 PM

The Path to Regulatory Approval: Discussion on New Surrogate Endpoints
Aliza Thompson, MD, Food and Drug Administration (FDA)

Session III. Early Career Investigator Presentations

3:50 PM

Awarding of Early Career Investigator Travel Fellowships
Sonya Dougal, PhD, The New York Academy of Sciences

3:55 PM

Overactive Cannabinoid 1 Receptor in Podocytes Drives Type-2 Diabetic Nephropathy
Tony Jourdan, PhD, NIH/NIAAA

4:15 PM *

A Soluble Guanylate Cyclase Activator Protects from Diabetic Nephropathy beyond the Standard of Care in the ZSF1 Rat
Kathleen Lincoln, Boehringer-Ingelheim Pharmaceuticals

* The 4:15 pm talk will not be broadcast as part of the live webinar.

4:35 PM

Closing Remarks
Frank C. Brosius, MD, University of Michigan

5:00 PM

Poster Session and Networking Reception

6:00 PM

Adjourn

Speakers

Organizers

Magdalena Alonso-Galicia, PhD

MAG Pharma Consulting LLC

Magdalena Alonso-Galicia, PhD, is a cardiorenal physiologist with 20 years of experience in academic research, drug discovery, licensing – search & evaluation, and preclinical / early clinical development. As the sole owner of MAG Pharma Consulting LLC, she provides a wide range of consulting services to Pharmaceutical, Biotech, and Medical Device companies. In her previous role at Forest Research Institute, Inc., she led scientific reviews of licensing opportunities in the areas of renal, cardiometabolic and respiratory. She also served on multiple respiratory and cardiovascular clinical development teams as preclinical pharmacologist, overseeing inflammation-related biomarker and pharmacology studies. Prior to joining Forest in 2010, she worked in drug discovery at Boehringer Ingelheim and Merck & Co., Inc. in the areas of hypertension, heart failure and chronic kidney diseases. She holds a PhD in Physiology & Biophysics from the University of Mississippi and underwent post-doctoral training at the Medical College of Wisconsin.

Ken Jones, PhD

Allergan

Ken is currently a Principal Medical Writer with Allergan in Bridgewater, NJ, where he is preparing regulatory submission documents for novel biological and chemical entities for their neurology portfolio. He has over 20 years of preclinical drug discovery and clinical development experience in the area of CNS disorders. Ken received his PhD in Physiology at Rutgers University and postdoctoral training at the Harvard Medical School Department of Neurobiology where he developed mammalian primary cell culture techniques to map NMDA and AMPA receptors at synaptic and extrasynaptic sites. His subsequent contributions to research include the deorphanization of several G-protein-coupled receptors, including the elucidation of the dimeric nature of GABAB receptors, and the co-discovery of a non-visual photoreceptor that regulates circadian rhythms. Prior to joining Allergan, Ken was a Senior Clinical Scientist within the Department of Psychiatry at Forest Research Institute.

Scott MacDonnell, PhD

Boehringer-Ingelheim Pharmaceuticals

Dr. Scott MacDonnell obtained his undergraduate and master’s degrees in exercise physiology from the University of Delaware and completed his doctoral work in cardiovascular physiology at Temple University in Philadelphia, PA. He completed a post-doctoral fellowship at Temple University Medical School in the lab of Dr. Steve Houser. His fellowship research focused on identifying mechanisms responsible for the pathogenesis of heart failure. Specifically, his work examined the role of CaMKII in altered contractility, myocytes apoptosis, and transcriptional regulation associated with heart failure progression. This work has been published in Circulation Research and recognized as a best manuscript by the editorial board in 2010. Additionally, Scott was recognized by the International Society for Heart Research and awarded the young investigator of the year in 2008. Scott currently works as a principal scientist at Boehringer Ingelheim within the department of CardioMetabolic Disease Research. His research is focused on identifying novel therapeutic treatment options for chronic kidney disease, heart failure, and fibrosis.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Matthew D. Breyer, MD

Eli Lilly and Company

Matthew D. Breyer received his MD from Harvard and training in Nephrology at Parkland UTHSCD. From 1985–2007 he was Professor of Medicine in the division of Nephrology at Vanderbilt University Medical Center where his work focused on the study of prostaglandin receptor transgenic mouse models to study diabetic kidney disease and hypertension. Dr. Breyer held numerous NIH and VA grants and from 2001–2006 headed the nephropathy sub-group of the NIH Animal Models of Diabetic Complications Consortium (AMDCC). As a result of his interest in developing treatments for diabetic nephropathy he moved to Eli Lilly in 2007 to oversee a program to develop bio-therapeutics for diabetic kidney disease. In 2009 he was appointed to his current position at Eli Lilly as Chief Scientific Officer Lead Generation Biotechnology Discovery Research, where he oversees preclinical target identification and validation of biologics for metabolic, neurologic, oncologic and chronic kidney diseases.

Frank C. Brosius, MD

University of Michigan

Frank C. Brosius' laboratory focuses on molecular and translational kidney research with the goal of developing effective new treatments for diabetic complications. He has studied diabetic kidney disease mechanisms for over 20 years and for the past 12 years has been at the center of animal models research in diabetic nephropathy as one of the principal investigators in the NIH Animal Models of the Diabetic Complications Consortium. More recently, as part of a large team-science approach they have worked to uncover the transcriptomic, proteomic and metabolite profiles of diabetic complications in both humans and mouse models. He is the corresponding PI for 2 large multi-investigator grants in this area and is Director of the NIDDK funded O'Brien Kidney Core Center at the University of Michigan. As part of this process, they discovered that the gene expression of a large number of JAK/STAT genes were increased markedly in kidney tissues of patients with diabetic kidney disease, and that these expression changes correlated with the degree of kidney dysfunction. These findings led to development of a phase 2 clinical trial sponsored by Eli Lilly and Co for which he is a principal investigator. He has been sought out by other pharmaceutical companies for unbiased recommendations about the best animal models to use for preclinical studies of diabetic nephropathy as well as for identification of potential targets in humans.

Benjamin D. Humphreys, MD, PhD

Brigham and Women's Hospital

Dr. Humphreys is Director of the Harvard Stem Cell Institute Kidney Program where he is a Principal Faculty member. He is an Associate Professor of Medicine at Harvard Medical School and directs the Laboratory of Translational Research in Kidney Repair. He received a bachelor's degree from Harvard College and MD and PhD degrees from Case Western Reserve University. He completed a residency in Internal Medicine at Massachusetts General Hospital and a fellowship in Nephrology at Brigham and Women's Hospital in Boston. He is an Established Investigator of the American Heart Association and a member of the American Society of Clinical Investigation. He has published 43 peer-reviewed original publications and 42 review articles or book chapters. A specialist in kidney injury, his laboratory utilizes mouse models to identify new treatments for patients suffering from acute and chronic kidney disease.

Tony Jourdan, PhD

NIH / NIAAA

Dr. Tony Jourdan obtained his master's degree and completed his doctoral work in nutrition and physiology at the INSERM U866 "lipids, Nutrition Cancer" in Dijon, France. He focused on the involvement of the peripheral endocannabinoid system in the pathogenesis of obesity and ore particularly on liver metabolism. He is currently holding a visiting Fellow position within the laboratory of physiologic studies under Dr. George Kunos mentorship (National Institute on Alcohol Abuse and Alcoholism, NIH). His current research focuses on studying the impact of peripheral endocannabinoid system on obesity/diabetes, theirs consequences and the development of an effective drug therapy. His work has resulted in numerous publications in peer review journals such as Diabetes, Nature Medicine or PNAS.

Kathleen Lincoln

Boehringer-Ingelheim Pharmaceuticals

Kathleen Lincoln is a researcher within the department of CardioMetabolic Disease Research at Boehringer-Ingelheim Pharmaceuticals, Ridgefield CT. She received a bachelor’s degree from Mercy College and is currently in the final stages of submission of her master’s thesis final project in Integrative Pharmacology from Michigan State University. Kathleen previously worked as a research associate in the VelociGene program at Regeneron Pharmaceuticals creating transgenic mouse models to study specific gene functions. Her current research focuses on developing and characterizing disease relevant animal models of diabetic nephropathy and designing and executing in vivo studies to evaluate new renal therapeutic drug candidates.

Matthias Meier, MD

F. Hoffmann-La Roche Ltd

Dr. Matthias Meier is a board-certified physician in Germany and Switzerland qualified in Internal Medicine with subspeciality in Diabetology and Nephrology currently serving as Senior Medical Director at F.Hoffmann-La Roche Ltd in Basel/Switzerland. He formerly received medical and scientific training at the Diabetes Research Institute in Munich/Germany, the University of Leicester/UK, the Joslin Diabetes Center/Harvard Medical School in Boston/USA as well as the Hannover Medical School/Germany where today he is an associate professor and faculty member. Furthermore, he has specialized in Pharmaceutical Medicine with outstanding experience in preclinical and clinical drug development in cardiovascular and metabolic disease areas. Dr. Meier is member of various scientific associations including 'Fellow of the American Society of Nephrology (FASN)' and acts as a reviewer of renowned scientific journals in his field of key expertise, mainly diabetes mellitus as well as kidney and associated diseases such as renal anemia.

Shahnaz Shahinfar, MD, FASN

S. Shahinfar Consulting, Inc. and The Children's Hospital of Philadelphia

Dr. Shahnaz Shahinfar received her medical degree from Ferdowsi University School of Medicine in Iran. She completed her Residency in Pediatrics and Fellowship in Pediatric Nephrology at Georgetown University Hospital in Washington, D.C. In 1981, she joined Merck & Co., Inc. and was involved with many clinical trials in the areas of diabetes, hypertension, and kidney disease, including outcome trials. Her primary focus and interest has been progression of chronic kidney disease. While at Merck, she initiated and implemented the RENAAL trial, a landmark outcome study in type II diabetic patients with kidney disease. She also has been involved with clinical trials of cardiovascular and renal outcomes in diabetic nephropathy and cardiovascular morbidity and mortality in hemodialysis patients. She conducted some of the first double-blind, placebo-controlled, clinical trials in hypertensive children with enalapril, lisinopril, and losartan. Shahnaz is an Adjunct Associate Professor of Pediatrics in the Associated Faculty of the School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia. Currently, she is a research consultant to the pharmaceutical industry on the design and implementation of clinical trials. Her work has resulted in numerous publications in peer review journals.

Katalin Susztak, MD, PhD

University of Pennsylvania

Katalin Susztak MD, PhD is currently an Associate Professor of Medicine at the Renal Electrolyte and Hypertension Division of the University of Pennsylvania Perelman School of Medicine. Dr. Susztak earned her doctorate (MD, PhD) degrees at Semmelweis University School Medicine, Budapest, Hungary in 1997 and she completed residency in Internal Medicine and clinical fellowship in nephrology at the Albert Einstein College of Medicine. She completed her post-doctoral work with Dr. Erwin Bottinger, where she initially worked on genomic studies of diabetic kidney disease and also defined the role of podocytes in diabetic nephropathy development. Dr Susztak is a nephrologist and physician-scientist. Work in her laboratory is aimed towards the understanding of renal fibrosis and chronic kidney disease development. She has performed translational research work to identify novel, genetic, genomic and epigenomic biomarkers of chronic renal disease. She has shown that an integrative analysis of epigenetic and genetic settings in diseased cells can provide a rational basis for more accurately modeling the critical biological pathways involved in mediating the progressive phenotype in individual patients. Her laboratory uses genetic approaches and mice as a model organism to test the role of candidate signaling molecules directly in vivo. Specifically, her work highlighted the role of the Notch and Wnt/beta-catenin pathway in chronic kidney disease development, renal epithelial cell homeostasis, renal stem or progenitor cell function and differentiation. Her recent results have revealed the role of embryonic programs in adult disease development causing alterations in renal epithelial cells and causing kidney fibrosis development. These studies have broad impact and clinical significance, since novel pharmaceuticals can be created around these principles. The work in the laboratory of Dr. Susztak is supported by the National Institute of Health, the American Diabetes Association and Juvenile Diabetes Association. Dr. Susztak is an elected member of the American Society of Clinical Investigation. She was the recipient of the 2011 Young Investigator Award of the American Society of Nephrology and American Heart Association for her groundbreaking research on chronic kidney disease development.

Aliza Thompson, MD

Food and Drug Administration (FDA)

Aliza Thompson is a Medical Officer and Clinical Team Leader in the Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, at the US Food and Drug Administration. Dr. Thompson joined the Division of Cardiovascular and Renal Products in 2007. She received her medical degree from Johns Hopkins and completed her Internal Medicine and Nephrology training at Columbia University/New York-Presbyterian Hospital. She holds a Master of Science in Biostatistics/Patient Oriented Research Track from the Columbia University Mailman School of Public Health.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Grant Support

This program is supported in part by a grant from Merck and Co., Inc.

Funding for this conference was made possible (in part) by 1 R13 DK103523-01 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the US Government.

Promotional Partners

Kidney & Urology Foundation of America

Nature


The Biochemical Pharmacology Discussion Group is proudly supported by



  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts


Session I. Target Identification through Novel Experimental Approaches

New Targets for the Treatment of Diabetic Nephropathy: What We Have Learned from Animal Models
Frank C. Brosius, MD, University of Michigan

While animal models of diabetic nephropathy have significant shortcomings in their ability to reproduce human DN both phenotypically and mechanistically, they can both suggest and validate potential targets for treatment of human DN through a variety of strategies. One strategy is to humanize expression patterns in diabetic animals (generally mice) by altering expression of genes or pathways that are dysregulated in human DN but not altered in diabetic mice. The replication of human-like disease validates such genes and pathways as potential targets. Conversely, finding common signaling pathways in human diabetic kidneys and those from the best animal models can identify new potential targets, especially those that are likely to be important early in the disease process. This presentation will focus on examples of each of these strategies.
 

Understanding Glomerular and Tubule Epithelial Cell Biology for Targeting in Diabetic Kidney Disease
Katalin Susztak, MD, PhD, University of Pennsylvania

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. DKD is a prototypical disease of gene and environmental interactions. Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. Blood pressure control, especially with medications that inhibit the angiotensin system, is the only effective way to slow disease progression. While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. Concerted clinical and basic research efforts will be needed to understand DKD pathogenesis and to identify novel drug targets.
 

Targeting Pericyte Differentiation as a Strategy to Modulate Kidney Fibrosis in Diabetic Nephropathy
Benjamin D. Humphreys MD, PhD, Brigham and Women’s Hospital and Harvard Stem Cell Institute

Diabetic nephropathy is characterized by tubulointerstitial fibrosis with myofibroblast proliferation and activation. Although there is general agreement that myofibroblasts are a logical therapeutic target in diabetic nephropathy, the origin of these cells is controversial. We have defined pericytes and perivascular fibroblasts as the predominant cellular origin of myofibroblasts in fibrotic disease. Pericytes are a heterogeneous group of extensively branched cells located in microvessels where they stabilize blood vessels, regulate vascular tone, synthesize matrix, participate in repair and serve as progenitor cells, among other functions. A major limitation in this field has been the absence of specific markers to identify the myofibroblast progenitor population from cells located in the pericyte niche. We have recently identified the transcription factor Gli1 as a specific marker for pericyte mesenchymal stem cell-like cells that substantially contribute to organ fibrosis. In vitro, Gli1+ cells express typical MSC markers, exhibit tri-lineage differentiation capacity, and possess colony-forming capacity, despite constituting a small fraction of the platelet-derived growth factor-β (PDGFRβ)+ cell population. Genetic lineage tracing analysis demonstrates that tissue-resident, but not circulating, Gli1+ cells proliferate following kidney, lung, liver, or heart injury to generate myofibroblasts. Genetic ablation of these cells substantially ameliorates kidney and heart fibrosis, and preserves ejection fraction in a model of induced heart failure. These findings implicate perivascular Gli1+ MSC-like cells as a major cellular origin of organ fibrosis and demonstrate these cells are a relevant therapeutic target to prevent solid organ dysfunction in chronic fibrotic disease such as diabetic nephropathy.
 

Session II. Challenges in Drug Development for Diabetic Kidney Disease

Drug Discovery for Diabetic Nephropathy: Trying to Leap from Mouse to Man
Matthew D. Breyer, MD, Eli Lilly and Company

Diabetic Nephropathy (DN) manifests as a clinical syndrome of hypertension, proteinuria, and progressive loss of kidney function. Treatment of hypertension has been a therapeutic mainstay to slow progression of DN to renal failure, however little progress has been made since the introduction of ACEi and ARBs to further slow this disease. Recent clinical failures of Bardoxolone, Aliskerin and combinations of ACEi+ARB underscore the need for a more robust scientific understanding of DN progression, prior to clinical testing of a therapeutic. Most animal models of diabetes lack hypertension and do not develop progressive kidney failure. Development of novel mouse models of DN that exhibit progressive renal failure require hypertension. We report the characterization of two novel hypertensive mouse models of DN: the eNOSko;db/db mouse and ReninAAV Akita diabetic mice. Molecular profiling of kidneys from these animal models versus human diabetic nephropathy identifies novel molecular pathways associated with disease of progression. Defining the molecular mechanisms associated with progressive renal failure in these mice should help identify those novel therapeutic approaches most likely to slow progressive renal failure in the clinic.
 

Current Drug Development Challenges in Diabetic Kidney Disease (DKD)
Matthias Meier, MD, F. Hoffmann-La Roche Ltd, Basel, Switzerland

Diabetic kidney disease (DKD) is the single most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the western world and is also regarded as a clinical model of accelerated cardiovascular disease (CVD) and ageing. Despite improvements in glycemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction DKD is still considered as major health burden globally. During the last decades, however, pharmaceutical drug development attempts to slow down the progression of DKD and reduce its related CVD risk have largely failed due to several possible reasons including the lack of profound understanding of the pathophysiology of chronic renal damage and its associated CVD, an inadequate characterization of molecular mechanisms of currently approved therapies such as RAS blockade, the unclear biochemical property needs required for novel therapeutic approaches, the missing quantity and quality of clinical trials in the nephrology field; and, most importantly, the absence of prognostic renal biomarkers that reflect the severity of the structural organ damage and predict ESRD as well as CVD mortality. There is clearly an insufficient understanding of the heterogeneity in DKD population pinpointing the pivotal relevance of biomarkers and the use of surrogate rare disease indications as Proof-of-Mechanism (PoM) and Proof-of-Concept (PoC) for faster and/or smaller clinical development. Identification of individualized determinants of DKD progression and/or premature CVD will enable personalized medicine in these high-risk patients.
 

Promising Agents in Clinical Development for the Treatment of Diabetic Kidney Disease
Shahnaz Shahinfar, MD, FASN, S. Shahinfar Consulting, Inc. and The Children’s Hospital of Philadelphia

Diabetes and its complications are a growing public health issue. There are 347 million patients with diabetes worldwide. Twenty to forty percent of people with diabetes develop kidney disease. Patients with diabetic kidney disease are at increased risk of cardiovascular diseases (CV) and death. The goal of therapy is to slow down, arrest, or reverse the decline in renal function. There are challenges to drug development for diabetic nephropathy. Three drugs have indications for diabetic kidney disease: captopril (1993), losartan (2001), and irbesartan (2001). Renin angiotensin aldosterone system (RAAS) blockade is considered the standard of care for diabetic kidney disease. RAAS blockade slows the progression, but it does not halt the disease. Current treatment is focused on optimizing kidney and CV risk factors, i.e. blood pressure control, glycemic control and lipid control. There are many promising compounds at different stages of development that target hemodynamic, metabolic, oxidative stress, inflammation, or growth factors. There are several potential targets that need to be evaluated in the future.
 

The Path to Regulatory Approval: Discussion on New Surrogate Endpoints
Aliza Thompson, MD, Center for Drug Evaluation and Research, FDA

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) in the U.S., and therapies are needed to improve clinical outcomes in patients. Over the years, the FDA came to accept a doubling of serum creatinine as a surrogate endpoint and basis for approval of therapies intended to treat DKD. However, the development programs for therapies approved to treat DKD (captopril, irbesartan, and losartan) also showed a reliable linkage between creatinine doubling and ESRD. Because a doubling of serum creatinine is a relatively late event in the course of DKD, there has been interest in lesser changes in renal function as endpoints to decrease the cost, size and duration of clinical trials and possibly extend their conduct to patients at early phases of the disease. But at what cost to the reliability of the surrogate to predict ESRD? In 2012, the National Kidney Foundation and FDA convened a scientific workshop on GFR decline as an endpoint in trials of chronic kidney disease (CKD). Based on analyses of data from observational studies, randomized controlled trials and simulation studies, the planning committee, analytic group and workshop participants concluded that a confirmed decline in eGFR of 40% could be used as an endpoint in clinical trials of CKD. The group also concluded that a confirmed decline of 30% might be acceptable in some settings. During this talk, I will provide an overview of the workshop findings and share my perspective, a regulatory perspective, on eGFR decline as an endpoint in trials of DKD.
 

Session III. Early Career Investigator Presentations

Overactive Cannabinoid 1 Receptor in Podocytes Drives Type-2 Diabetic Nephropathy
Tony Jourdan, PhD, NIH/NIAAA

Diabetic nephropathy is a major cause of end-stage kidney disease, and over-activity of the endocannabinoid/cannabinoid 1 receptor (CB1R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type-2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the renin-angiotensin system (RAS), oxidative/nitrative stress, podocyte loss and increased CB1R expression in glomeruli. Peripheral CB1R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and downregulated renal cortical CB1R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB1R and desmin gene expression were increased while podocin and nephrin content were decreased by either the CB1R agonist arachydonoyl-2′-chloroethylamide, angiotensin II or high glucose, and the effects of all three were antagonized by CB1R blockade or siRNA-mediated knockdown of CNR1. We conclude that increased CB1R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB1R blockade.
 

A Soluble Guanylate Cyclase Activator Protects from Diabetic Nephropathy beyond the Standard of Care in the ZSF1 Rat
Kathleen Lincoln, Boehringer-Ingelheim Pharmaceuticals

The pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide generation and signaling. We evaluated the effect of BI684067, a soluble guanylate cyclase (sGC) activator, in combination with the current standard of care (SOC) on the progression of diabetic nephropathy. Male ZSF-1 rats were administered enalapril (3mg/kg in drinking water) for 10 days, following which they were randomized to either continue to receive enalapril alone, or the combination of enalapril and one of three doses of BI684067 (20, 40 and 80 mg/kg) in chow for 10 weeks. Weekly urinary protein to creatinine ratio (UPCR), daily mean arterial pressure (MAP) and heart rate (HR) were measured. At study end, kidneys were assessed for glomerular lesions and α-SMA expression, a marker of myofibroblast activation. The combination of BI684067 and enalapril resulted in significant dose-dependent decreases of the following when compared to enalapril alone: UPCR (BI684067 at 20, 40, and 80 mg/kg : 27; 39; 48% reductions respectively), incidence of glomerulosclerosis (BI684067 at 20, 40, and 80 mg/kg: 29; 32; 44% reductions, respectively) and α-SMA expression (BI684067at 20, 40, and 80 mg/kg : 26; 40; 42% reductions, respectively). The MAP was significantly reduced by BI684067 in combination with enalapril (−3mmHg vs enalapril alone at the doses of 40 and 80 mg/kg), however there was no significant effect on HR. These results support the efficacy of a sGC activator in preventing the progression of diabetic nephropathy when combined with the SOC.

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