KHI Current Project
Surrogate Endpoints in FSGS
The goals of this project are to identify surrogate endpoint(s) for use in clinical trials in FSGS patients. Despite being associated with a relatively rapid decline in kidney function, there are no approved drugs and no accepted endpoints for registration of investigational products for FSGS. We propose the following goals: review published literature and analyze data from cohorts/completed trials to identify candidate surrogates for endpoints, identify risk factors for progression, critically assess the candidate measures, and identify gaps in the data. The completion of this project should guide future trials and ultimately result in new drugs approved for FSGS.
Publications addressing surrogate endpoints and clinical trial design
Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which may result in extreme proteinuria and rapid progression to end-stage renal-disease. FSGS can present in a variety of ways varying from proteinuria to arterial hypertension, edema and nephrotic syndrome and can progress to ESRD over the course of 5-10 years1. FSGS is a leading and growing cause of nephrotic syndrome worldwide 2 and accounts for 3-4% of prevalent ESRD in the United States 3.
At present, there are no FDA-approved treatments for FSGS. Potential predictors of more rapidly progressive disease have included demographics, genetics, higher baseline proteinuria, histopathologic type, and response to treatment (remission status). Reduction in proteinuria is regarded as beneficial and is the primary goal of treatment to slow the progressive course of FSGS. Current treatment is inhibition of the renin-angiotensin-aldosterone system followed by steroids and potentially immunosuppressives.
Despite the relatively rapid decline in renal function among patients with FSGS, few randomized, controlled trials have been conducted, and guidelines for the treatment of FSGS remain based on generally low-level evidence 4. This is in part due to fact that the disease is rare and requirement of demonstrating a treatment effect on the "hard endpoints" of ESRD or a halving of eGFR or death would require too large and too long of a trial to be feasible. Thus, there is a recognized need to identify an earlier surrogate endpoint that could be used in clinical trials to establish the efficacy of therapies for patients with FSGS who are at high risk of progressing to ESRD 5.
The working group will seek to identify potential short-term and intermediate candidate surrogate outcome measures by: 1) performing a critical review of the literature in FSGS, focused on prospective cohort studies and prospective interventional clinical trials; and 2) analyzing data from available FSGS databases.
|Co-Chair||Keisha Gibson, MD, MPH, FASN||University of North Carolina Kidney Center|
|Co-Chair||Laura Mariani, MD, MS||University of Michigan|
|Member||Michelle Denburg, MD||The Children's Hospital of Philadelphia|
|Member||Lisa Cimino||Boston, MA|
|Member||Ulysses Diva, PhD||Retrophin, Inc.|
|Member||Jürgen Floege, MD||University of Aachen, Germany|
|Member||Duvuru Geetha, MD, FASN||John Hopkins Bayview Medical Center|
|Member||Debbie Gipson, MD, MS||University of Michigan Children's Hospital|
|Member||Peter Greasley, PhD||Astrazeneca|
|Member||Michelle Hladunewich, MD, MS, FASN||University of Toronto|
|Member||Robert Huizinga, RN, PhD, CNeph(C)||Aurinia Pharmaceuticals|
|Member||Jula Inrig, MD, MS, FASN||IQVIA|
|Member||Mona Khurana, MD||US Food and Drug Administration|
|Member||Radko Komers, MD, PhD||Retrophin, Inc.|
|Member||Louis-Philippe Laurin, MD||Hospital Maisonneuve-Rosemont|
|Member||Dustin Little, MD||AstraZeneca|
|Member||Patrick Nachman, MD, FASN||University of Minnesota|
|Member||Kimberly Smith, MD, MS||US Food and Drug Administration|
|Member||Aliza Thompson, MD, MS||US Food and Drug Administration|
|Member||Liron Walsh||Goldfinch Bio|
|Member||Dine Watson||Washington, DC|
|NephCure Kidney International Liaison||Rick Winneker||NephCure Kidney International|
|Additional Support||Judith Schimpf||University of Aachen, Germany|
|Board of Directors Liaison||Barbara Gillespie, MD, FASN||Covance CRO|
|Staff Liaison||Meaghan Allain||Kidney Health Initiative|
|Staff Liaison||Melissa West||Kidney Health Initiative|