ASTORASTOR Alport Syndrome Treatments and Outcomes Registry Alport Syndrome Family Conference Alport Syndrome Registries Clifford E. Kashtan, M.D. University of Minnesota July 22, 2012 Minneapolis, MN

ASTORASTOR Disclosures ASTORASTOR I have received reimbursement of travel expenses and honoraria from Athena Diagnostics, one of several commercial laboratories offering molecular genetic testing for Alport syndrome. I am not a paid consultant for Athena and neither my family nor I has any financial interest in the company. The Alport Syndrome Treatments and Outcomes Registry (ASTOR) is supported by private philanthropy, the Alport Syndrome Foundation, federal funding and is engaged in research supported by the Novartis Institute for Biomedical Research.

ASTORASTOR What is a Patient Registry? ASTORASTOR “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition or exposure” “The registry is designed to fulfill specific purposes, and these purposes are defined before collecting and analyzing the data.” Registries for Evaluating Patient Outcomes: A User’s Guide. 2 nd edition. Gliklich RE, Dreyer NA, editors. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Sep.

ASTORASTOR The Purpose of Alport Syndrome Registries The purpose of Alport syndrome registries is to enable the development of safe, affordable and effective therapies for Alport syndrome by testing treatments that have shown promise in animal studies.

ASTORASTOR Why are clinical trials in Alport Syndrome needed? Alport syndrome leads to kidney failure in all affected males and many affected females. Besides kidney transplantation, there is no proven treatment for Alport kidney disease. Several therapies have shown promise in animal studies. These possible therapies are associated with very different potential adverse effects and costs. ACE inhibition has shown promise in studies of animals with Alport syndrome. This therapy is widely used in human Alport syndrome but its efficacy has not been tested in humans. Conventional timing of therapy may prevent maximal benefit.

ASTORASTOR What are the major barriers to clinical trials in Alport syndrome? Alport syndrome is a rare disorder that causes gradual loss of kidney function, creating challenges for -Recruitment of subjects -Funding to initiate and sustain trials Mechanisms of rapidly identifying potential trial participants have been lacking, until recently.

ASTORASTOR How can registries support clinical trials? Feasibility Is the pool of potential participants large enough? Stored biological samples can be used to evaluate a potential therapeutic pathway Recruitment – Rapid identification of eligible individuals Stored contact information Information about new trials can be widely distributed at low cost

ASTORASTOR What else can registries do? Provide better data about a known aspect of the disease Corneal erosions Aortic disease Discover previously unknown problems Publicize new findings

ASTORASTOR Sustaining a Registry Costs Database set-up and maintenance Interviews and data entry Statistical support Personnel: coordinators, programmer, biostatistician Sources of financing Individual donors Foundations Federal government Industry -- pharmaceutical, diagnostic services

ASTORASTOR Alport Syndrome Treatments and Outcomes Registry (ASTOR) ASTOR is a cooperative effort of the U. of Minnesota and the U. of Utah to create an electronic database of all Alport families in North America ASTOR’s goals are to perform studies of early markers of disease progression and to work with registries in Europe and elsewhere to test promising therapies for Alport syndrome –Study 1: A Prospective Study of Microalbuminuria in Untreated Boys with Alport Syndrome ( ) –Study 2: Urinary Biomarkers of Alport Kidney Disease Progression ( ) Over 400 families have enrolled since ASTOR went live in September, 2007 ASTORASTOR

ASTORASTOR ASTOR Enrollment ASTORASTOR

ASTORASTOR A Prospective Study of Microalbuminuria in Untreated Boys with Alport Syndrome Objectives –To determine mean ages of onset of microalbuminuria and overt proteinuria –To determine mean duration of microalbuminuria before transition to overt proteinuria Inclusion criteria –Diagnosis of Alport syndrome –Male gender –Absence of overt proteinuria (urine protein:creatinine ratio < 0.2 mg/mg) –No past or current treatment with angiotensin antagonists ASTORASTOR

ASTORASTORASTORASTOR Affected males (120) Eligible (58) (< 18, no meds, no h/o proteinuria) Ineligible (62) > 18 (N = 14; mean age 35 yrs) on meds (N = 33; mean age 9.2 yrs) > 18 + meds (N = 15; mean age 32 yrs) Urine kits returned (47) (3 heme-negative) Normal urine albumin (24) Mean age 8 yrs Microalbuminuria (13) Mean age 7 yrs Proteinuria (7) Mean age 10 yrs Normal urine albumin (20) Microalbuminuria (2) Proteinuria (2) Microalbuminuria (10) Proteinuria (5) Proteinuria (14) ASTOR Microalbuminuria Study,

ASTORASTOR Stages of Alport Kidney Disease ASTORASTOR TIME O I II III IV hematuria microalbuminuria proteinuria reduced function ESRD

ASTORASTOR Biomarker Studies and Alport Syndrome The ultimate goal of treatment of Alport syndrome is to prevent scarring of the kidneys (renal fibrosis) “Hard” markers of renal fibrosis: –Quantitative measurement of renal fibrosis– requires kidney biopsies –Reduced kidney function – takes too long to develop We need “surrogate” markers of renal fibrosis that are reliable and easily measured ASTORASTOR

ASTORASTOR Biomarker Studies and Alport Syndrome ASTORASTOR

ASTORASTOR Copyright restrictions may apply. Vinge, L. et al. Nephrol. Dial. Transplant : ; doi: /ndt/gfq044 Urine Proteins in Dogs with Alport Syndrome Alport Normal

ASTORASTOR Urinary Biomarkers of Alport Kidney Disease Progression Objective –To identify biomarkers of renal tubular injury and renal fibrosis in urine of people with Alport syndrome Inclusion criteria –Diagnosis of Alport syndrome –Glomerular filtration rate above 60 ml/min/1.73m2 Enrollment target: 100 ASTORASTOR

ASTORASTOR Multicenter Controlled Clinical Trials in Alport Syndrome: A Feasibility Study Goal: to demonstrate that five Alport syndrome research centers have access to sufficient numbers of children and adolescents with Alport syndrome to populate a clinical trial aimed at delaying development of microalbuminuria and proteinuria by very early intervention Supported by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) ASTORASTOR

ASTORASTOR Can Early Intervention Delay ESRD in Alport Syndrome? AGE (years) % ESRD No intervention Intervention at onset of proteinuria Intervention at onset of microalbuminuria Intervention before onset of microalbuminuria

ASTORASTOR Rationale for Targeting Microalbuminuria and Proteinuria ASTORASTOR TIME hematuria microalbuminuria proteinuria No intervention Intervention? hematuria microalbuminuria proteinuria reduced function ESRD

ASTORASTOR Protect Alport Kidneys (PAK) Trial (proposed) ASTORASTOR Male > 12 mos of age Confirmed diagnosis of Alport syndrome Estimated GFR > 60 ml/min/1.73m 2 No past or current treatment with ACEi or ARB Alb/Cr mg/g Microalbuminuria Alb/Cr < 30 mg/g Normalbuminuria Prot/Cr > 0.2 mg/mg Proteinuria ramipril (2.5 mg/m 2 /day) placebo ramipril ( mg/m 2 /day) placebo ramipril ( mg/m 2 /day) placebo ramipril ( mg/m 2 /day) spironolactone (25 mg/day)

ASTORASTOR Alport Research Collaborative (ARC) Alport Syndrome Treatments and Outcomes Registry (ASTOR) U. of MinnesotaClifford Kashtan U. of UtahMartin Gregory European Alport Registry U. of GoettingenOliver Gross Centre de References des Malades Renales Hereditaires de l’Enfant et de l’Adult (MARHEA) Hopital Necker - Enfants Malades (Paris)Laurence Heidet Bertrand Knebelmann The Hospital for Sick Children U. of TorontoChristoph Licht Peking University First Hospital Beijing, ChinaJie Ding

ASTORASTOR ARC: Population Resources Families (approx.) ASTOR500 European Alport Registry400 MARHEA196 The Hospital for Sick Children42 Peking University First Hospital216

ASTORASTOR Early Pro-Tect Trial ASTORASTOR

ASTORASTOR ASTORASTOR Eligibility: Hematuria only or Hematuria + Microalbuminuria Endpoints: Time to progression to next disease level Albuminuria

ASTORASTOR Optimal treatment for Alport kidney disease Effective -- treatment would delay ESRD by years Safe -- low incidence of side effects that are predictable, mild and reversible Inexpensive and available beyond patent protection market is larger than Alport population easy to manufacture easy to ship May involve combination therapy – angiotensin antagonist + anti-fibrotic agent