DIVISION OF NEPHROLOGY
Physician’s Brief clinical and research highlights for our colleagues in nephrology Ye a r- E n d 2014
FDA Approves U-M-invented Drug for Gaucher Disease Cerdelga, a treatment for Gaucher disease Type 1, has been approved by the U.S. Food and Drug Administration. Cerdelga was developed at the University of Michigan Medical School and is licensed to Genzyme Corp. Cerdelga represents the first class of chemical entities conceived and developed at U-M to achieve FDA approval. An oral medication, Cerdelga offers an alternative to intravenous enzyme replacement – the other approved treatment for Gaucher disease, a rare inherited disorder that affects many of the body’s organs and tissues. The strategy of treating Gaucher disease by inhibition of glycolipid synthesis was proposed by the late Norman Radin, Ph.D., a U-M neurochemist, more than 40 years ago. The work directly leading to Cerdelga began 25 years ago when James Shayman, M.D., a nephrologist trained in lipid biology and pharmacology, sat down with Radin and began
inventions were licensed to Genzyme, a Sanofi company, in 2000 for clinical development. “On a personal level, the success of this research program has been tremendously gratifying,” Shayman said. “The FDA approval of Cerdelga provides further motivation for me and my collaborators to bring other drugs through the pipeline.”
James Shayman, M.D.
their collaboration. Their shared work continued at least until 1995 after which Radin retired, but research continued by the Shayman group to design, synthesize and test glycolipid synthesis inhibitors. That included a series of “proof of concept studies” in experimental models of lysosomal storage diseases. Patents covering these compounds and related
The safety and effectiveness of Cerdelga were evaluated in two clinical trials with 199 participants with Type 1 Gaucher disease. “The approval by the FDA is an important milestone for Genzyme, our inventors and the university,” said Ken Nisbet, associate vice president for research, U-M Tech Transfer. “Cerdelga promises to be a landmark therapy for patients afflicted with Gaucher disease, and we congratulate all who helped bring this innovation to market.”
Clinical Trial Highlights NEPTUNE The Nephrotic Syndrome Study Network (NEPTUNE) trial is a multicenter research network for Idiopathic Nephrotic Syndrome (NS), a rare syndrome responsible for approximately 12% of all causes of end-stage renal disease (ESRD) and up to 20% of ESRD in children. The major causes of NS are Focal and Segmental Glomerulosclerosis (FSGS),
Minimal Change Disease (MCD) and Membranous Nephropathy (MN), all rare but serious conditions that can eventually lead to kidney failure. Current treatment strategies include high dose prolonged steroid therapy and the use of immunosuppressive agents including cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil and others. All of these options carry significant side effects, and patients who do not achieve remission with them often progress to ESRD. The goals of the NEPTUNE study are to better understand the underlying mechanism of MCD, FSGS and MN, to identify and test novel treatments targeting the specific disease mechanism and develop matching blood or urine tests to identify the right treatment for the right patient at the right time.
The network was launched in 2010 at 15 centers in the U.S. and Canada, with U-M functioning as the main operational center, and has enrolled more than 600 patients in a prospective cohort study. It also has established a patient registry containing information from more than 1,800 patients. The network has since grown to include physicianscientists from 22 academic medical centers across North America. In October 2014, the National Institutes of Health announced its continued commitment to NEPTUNE, renewing a second five-year funding cycle. U-M is also making a significant contribution to funding the consortium. NEPTUNE is supporting more than 40 ancillary studies using the research networks for a wide spectrum of efforts, including whole genome sequencing, proteomics, digital histopathology, patient self-reported outcomes and multiple interventional trials. “With the expanding clinical, pathological and genomic data that have already been collected in NEPTUNE, the network is now using this comprehensive information to initiate molecular, targeted treatments to improve health outcomes for patients with nephrotic syndrome,” says U-M nephrologist Matthias Kretzler, M.D., NEPTUNE’s principal investigator.
To learn more about NEPTUNE, visit www.NEPTUNE-Study.org.
CureGN Glomerulonephropathy, also known as Primary glomerular disease (GDPrime), is a group of diseases that lead to progressive loss of kidney function over many years and contribute to a significant percentage of new ESRD cases diagnosed annually. Four different diseases comprise GDPrime: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), immunoglobulin A nephropathy (IGAN), and idiopathic membranous nephropathy (IMN). The Cure Glomerulonephropathy Network (formerly the GDPrime consortium) was established in 2013 to support ongoing multidisciplinary, collaborative research into disease mechanisms
and therapeutic pathways, identification and validation of outcomes, early phase testing of novel therapies and effective public-private-patient advocate partnerships. The network’s primary focus is CureGN, a multicenter five-year cohort study of 2,400 pediatric and adult glomerular disease patients funded by the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) at the National Institutes of Health (NIH). Participants are being followed longitudinally to better understand the causes of disease, response to therapy, and disease progression, with the ultimate objective of curing glomerulonephropathy. The patient information and specimens generated by this study, along with the requisite scientific and analytic capacity, will be managed through the consortium’s data coordinating center (DCC). CureGN is extending the NEPTUNE study approach to a wide spectrum of patients and diseases with the goal of a lifelong follow-up. It is housed at U-M and the Arbor Research Collaborative for Health in Ann Arbor, MI and led by Matthias Kretzler, M.D., Debbie Gipson, M.D., Bruce Robinson, M.D. and Brenda Gillespie, Ph.D.
To find out more about enrolling a patient in the CureGN trial, visit https://curegn.org/ JoinOurStudy.asp.
Baricitinib for Diabetic Nephropathy The breakthrough work of U-M nephrology investigators isn’t limited to rare kidney ailments – some of the same advances hold promise for more common conditions, too – notably diabetic kidney disease, a threat to about 30% of the nearly 2 million patients diagnosed with diabetes each year.
Frank C. Brosius III, M.D.
Matthias Kretzler, M.D.
U-M nephrology researchers led by Frank Brosius, M.D., Chief of the U-M Division of Nephrology, and Matthias Kretzler, M.D., are partnering with Eli Lilly and Company in an ongoing phase 2 clinical study with patients that have mild to moderate diabetic kidney disease. The trial will evaluate whether the drug baricitinib, a JAK1/JAK2 inhibitor developed to treat arthritis and skin diseases, might be repurposed to help prevent the progression of diabetic nephropathy.
consortium,” noted Brosius, who, along with Kretzler, led the U-M group that participated in the NIH-sponsored Animal Models of Diabetic Complications Consortium, which concluded in 2011. “Then my group provided the animal model studies and the in-depth understanding of diabetic complications that allowed us to focus on the pathway. This highly collaborative approach makes U-M one of the only places in the world with the combined expertise to move this project forward.”
“Dr. Kretzler put together a network of research teams to establish a worldwide human genome-wide renal gene expression
To find out more about the trial, visit www.clinicaltrials.gov (identifier: NCT01683409)
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