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P.K. Tandon, PhD J. Alexander Cole, DSc Use of Registries for Clinical Evaluation of Rare Diseases
Outline Background on Rare Disease Registries Gaucher Disease Registry Fabry Disease Registry MPS-1 Disease Registry Pompe Disease Registry Examples of Understanding Natural Histories of Rare Diseases Examples of Treatment Outcomes Based on Longitudinal Data Summary
Gaucher Disease: Disease Mechanism Deficiency of the enzyme acid ß-glucosidase Storage of glucosylceramide Progressive, multisystemic, multiorgan dysfunction
Pompe Disease: A Spectrum of Clinical Disease
Why Develop a Rare Disease Patient Registry? Rare Diseases Rare Disease Registry Limited experience and knowledge Aggregated longitudinal data Incomplete characterization of disease Increased understanding of disease Lack of data on long-term outcomes Improved quality of care and patient outcomes
Clinical Trial versus Patient Registry Clinical Trial Registry Purpose Controlled experiment Real-world observations Duration Finite Indefinite Inclusion Criteria Specific General Data Collection Required Voluntary Patient Visits Protocol Practice Analytic Methods Biostatistics Epidemiology Disease Characteristics Per protocol Cross-sectional, longitudinal Treatment Outcomes Efficacy Effectiveness Generalizability Narrow Broad
Research Databases Disease Management LSD Registry Launch Date Patients Enrolled Physician Participants Countries Represented Gaucher 1991 5,900 772 61 Fabry 2002 3,800 238 41 MPS I 2003 900 145 30 Pompe 2005 900 120 26 Our Model Scientific direction from independent Board of Advisors Operational and financial support
Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Disease - Natural History 9
Life Expectancy in Type 1 Gaucher Disease Research Question: What is the life expectancy among patients with Type 1 Gaucher disease? 10
Life Expectancy in Type 1 Gaucher Disease Study population: All Type 1 disease patients enrolled in the ICGG Gaucher Registry (n=2,876) Time period: Follow-up for each patient from Registry enrollment through 1) last reported assessment, or 2) date of death (n=13,509 person-years) Analysis: Life table calculations of mortality rates with comparison to general population estimates 11
Life Expectancy in Type 1 Gaucher Disease Age 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Normal 77.1 72.8 67.9 62.9 58.1 53.3 48.6 44.0 39.5 35.0 30.5 26.2 22.1 18.3 14.8 11.7 9.0 6.8 Type 1 GD 68.2 65.6 62.1 57.6 53.0 49.2 44.2 39.4 35.6 31.3 27.2 23.0 19.1 15.3 11.7 8.7 7.0 2.5 Difference 8.9 7.2 5.8 5.3 5.1 4.1 4.4 4.6 3.9 3.7 3.3 3.2 3.0 3.0 3.1 3.0 2.0 4.3 90 80 Remaining years of expected life 70 60 50 40 30 20 10 Patients with Type 1 Gaucher Disease US Reference Popuation 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Current age (years) 12
Life Expectancy in Type 1 Gaucher Disease Personyears Average Life Expectancy at Type of Population Deaths Birth (years) U.S. Reference population 77.1 Difference from U.S. Population Type 1 Gaucher Disease 102 13,509 68.2-8.9 Spleen status Partial/total splenectomy 49 4195 63.9-13.2 Non-splenectomized 53 9305 72.0-5.1 Gender Male US Reference population 74.3 Type 1 Gaucher disease 52 6,081 66.9-7.4 Female US Reference population 79.9 Type 1 Gaucher disease 50 7,428 70.0-9.9 13
Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Stroke Natural History MPS1 Disease - Natural History 14
Fabry Disease - Stroke Natural History Research Question: What is the natural history of stroke among patients with Fabry disease? 15
Fabry Disease - Stroke Natural History Study population: All natural history patients enrolled in the Fabry Registry (n=2,446) who were either: 1. Untreated patients, or 2. ERT-treated patients with data reported before initiation of therapy Time period: Follow-up for each patient from birth until most recent data available (before initiation of therapy) 16
Fabry Disease - Stroke Natural History Strokes per 1000 person years of follow up 50 40 30 20 10 0 Fabry Males Fabry Females US Males US Females 0 to < 25 yr 25 to < 35 yr 35 to < 45 yr 45 to < 55 yr 55 to < 65 yr 65 to < 75 yr 75 to <85 yr Fabry Males 0.32 3.47 4.89 9.70 22.05 48.58 Fabry Females 0.18 1.09 1.83 3.14 6.30 18.43 US Males 0.00 0.00 0.40 1.79 3.50 8.43 16.17 US Females 0.00 0.00 0.44 0.99 2.60 6.12 13.46 Fabry patients exhibited a markedly higher incidence of stroke than the general US population. * # 17
Fabry Disease - Stroke Natural History Percentage of Patients wtih History of TIA 70 60 50 40 30 20 10 0 A. TIA B. Arrhythmia 37% 35% 6% 5% Stroke male No Stroke Stroke female No Stroke Percentage of Patietns with History of Arrythmias 70 60 50 40 36% 30 20 15% 10 0 Stroke No Stroke 27% Stroke 11% No Stroke Percentage of Patietns with History of Hypertension 70 60 50 40 30 20 10 0 Males C. Hypertension 48% 23% Stroke No Stroke Females 62% 18% Stroke No Stroke Males Females Patients who had strokes (solid bars) were much more likely to have reported a medical history of various risk factors for strokes Males Females 18
Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Natural History 19
Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Disease - Natural History 20
MPS-1 Disease - Natural History Research Question: What are the baseline clinical characteristics of patients who enrolled in the MPS-1 Registry? 21
MPS-1 Disease - Natural History Study population: All patients enrolled in the MPS-1 Registry (n=302) Time period: Data within two years of inception of the Registry Analysis: Prevalence of MPS-1 disease related manifestations at baseline 22
MPS-1 Disease - Natural History Proportion and mean ages of patients enrolled in the Registry by phenotype 23
MPS-1 Disease - Natural History Proportion of patients with MPS-1 disease manifestations by age at onset 24
Examples of Understanding Natural Histories Cerezyme (Gaucher) Dose-Response Cerezyme (Gaucher) Bone Density Outcome 25
Cerezyme (Gaucher) Dose-Response Research Question: Among patients with Gaucher disease, is there a dose-response relation with changes in hematologic and visceral organ measures? 26
Cerezyme (Gaucher) Dose-Response Study population: Matched groups of Type 1 Gaucher disease patients who received ERT enrolled in the ICGG Gaucher Registry Time period: Data following each patient s initiation of ERT Analysis: Non-linear mixed models to characterize changes in measures following initiation of ERT 27
Cerezyme (Gaucher) Dose-Response Results: Baseline characteristics After Matching 15 U/kg/2wk 30 U/kg/2wk 60 U/kg/2wk N=122 N=122 N=122 p-value Age at diagnosis, Mean (SD) 20.5 (20.1) 20.9 (19.7) 21.5 (19.7) 0.92 Age at baseline, Mean (SD) 22.1 (19.9) 22.6 (19.9) 23.1 (19.8) 0.92 Hemoglobin, normalized * (g/dl), Mean (SD) 0.3 (1.0) 0.5 (0.8) 0.3 (1.0) 0.25 Platelet count (x 10 3 /mm 3 ), Mean (SD) 95.2 (34.5) 92.4 (26.7) 94.1 (31.1) 0.78 Splenic volume (Multiples of Normal), Mean (SD) 13.4 (6.9) 13.0 (11.4) 13.1 (8.9) 0.94 Hepatic volume (Multiples of Normal), Mean (SD) 1.5 (0.3) 1.5 (0.5) 1.5 (0.4) 0.65 28
Cerezyme (Gaucher) Dose-Response Results: Dose-response relation with platelet count Dose-response relations with hemoglobin, liver volume, and spleen volume followed a similar pattern 29
Examples of Understanding Natural Histories Cerezyme (Gaucher) Dose-Response Cerezyme (Gaucher) Bone Density Outcome 30
Cerezyme (Gaucher) Bone Mineral Density Research Question: Among patients with Gaucher disease, what are the changes in bone mineral density following initiation of treatment? 31
Cerezyme (Gaucher) Bone Mineral Density Study population: Adults with Type 1 Gaucher disease patients who received ERT and had bone mineral density assessments of the lumbar spine Time period: Data following each patient s initiation of ERT Analysis: Mixed models to assess changes in bone mineral density lumbar spine z-score following initiation of ERT 32
Cerezyme (Gaucher) Bone Mineral Density Bone mineral density z-scores were significantly lower than the reference population at baseline (yintercept = -1.17 Z-score units, p<0.001) There were significant improvements over time (slope = +0.132 Z-score units per year for ERT 60 U/kg/2wk, p<0.001) in a dose-dependent manner, with the slopes for 15, 30 and 60 U/kg/2wk of +0.064, +0.086, and +0.132 Z- score units per year, respectively. The BMD of patients treated with ERT at 60 U/kg/2wk increased to within -0.012 standard deviations of the mean of the reference population after ~8 yr. 33
What are the Outcomes of Treatment? No ERT (n=160) ERT with Imiglucerase (n=340) 60U/kg/2wks 30U/kg/2wks 15U/kg/2wks In the absence of treatment, BMD shows no improvement or worsening over time Patients treated with imiglucerase at 60U/kg/2wks achieve a normal BMD after ~8 years R Wenstrup, K Kacena, P Kaplan, G Pastores, A Prakash-Cheng, A Zimran, T Hangartner. J Bone Miner Res. 2007 Jan;22(1):119-26
Summary Registries are key for further understanding of the natural history and treatment outcomes in rare diseases Natural history Global participation enables characterization of the phenotypic heterogeneity of rare diseases Provides background context to inform studies of treatment outcome Treatment outcomes Long-term follow-up of patients which is not possible through clinical trials Real world patient population and treatment patterns 35
Back-up Slides 36
Gaucher Timing of Treatment Initiation and Risk of AVN 37
Gaucher Timing of Treatment Initiation and Risk of AVN Research Question: Does the timing of therapy initiation impacts the subsequent risk of avascular necrosis among Type 1 Gaucher patients? 38
Gaucher Timing of Treatment Initiation and Risk of AVN Study population: Type 1 Gaucher Patients enrolled in the ICGG Gaucher Registry who received ERT Time period: Data following each patient s initiation of ERT Analysis: Multivariate Poisson regression to estimate rate ratios of AVN according to initiation of therapy < 2 years vs. > 2 years following GD diagnosis, adjusted for potential confounding variables 39
Gaucher Timing of Treatment Initiation and Risk of AVN Years Between Incidence Rate Diagnois and AVN Number Person-Years per 1,000 Rate Ratio Initiation of ERT Cases of Patients of Follow-up Person-Years (95% CI) p-value <2 years 41 1,047 5,084 8.1 0.49 <.0001 >2 years 172 1,653 10,384 16.6 (0.35, 0.68) Incidence rate difference between the two groups was 8.5 per 1,000 person years (95% CI 5.0-12.0 per 1,000 person-years) Crude incidence rate ratio of 0.49 Represents a 51% decrease in the rate of AVN Are there other confounding risk factors for AVN?
Gaucher Timing of Treatment Initiation and Risk of AVN Splenectomy Incidence Rate Before Initiation AVN Number Person-Years per 1,000 Rate Ratio of ERT* Cases of Patients of Follow-up Person-Years (95% CI) p-value Yes 94 587 3,502 26.8 2.74 <.0001 No 117 2,106 11,949 9.8 (2.09, 3.60) *Excludes 7 patients who received a splenectomy but the date of the procedure was unknown. Splenectomy is also a strong risk factor for AVN Crude incidence rate ratio of 2.74 Represents a nearly 3-fold increase in the rate of AVN Does this explain the association with interval between diagnosis and initiation of therapy? Examine all variables together in a regression model
Multivariate Poisson Regression Model: Effects of all variables on AVN 3.50 3.00 Incidence Rate Ratio 2.50 2.00 1.50 1.00 2.35 1.15 0.50 0.58 0.72 0.76 0.75 0.72 0.00 <2 Years vs. >=2 Years Age < 20 vs. Age >= 20 Female vs. Male Before 1991 vs. 1991 or Later Yes vs. No Before 1995 vs. 2000 or Later 1995 to 1999 vs. 2000 or Later Years From Diagnosis to Initiation of ERT Age at Initiation of ERT Gender Year of Gaucher Diagnosis Splenectomy Before Initiation of ERT Year of Initiation of ERT
Fabry Quality of Life Following Treatment Initiation 43
Fabry Quality of Life Following Treatment Initiation Research Question: Among patients with Fabry disease, are changes in quality of life reported following treatment initiation? 44
Fabry Quality of Life Following Treatment Initiation Study population: Fabry Registry enrollees Males had SF-36 assessments reported at baseline and at least 3 posttreatment assessments (n=71) Females had SF-36 assessments reported at baseline and at least 2 post-treatment assessments (n=59) Time period 36 months following initiation of therapy for males 24 months following initiation of therapy for females Analysis: Changes from baseline were analyzed using a repeated measures model, including age at baseline as a covariate 45
Fabry Quality of Life Following Treatment Initiation * p<0.05 by repeated measures model using age at baseline as a covariate; p=0.0614; SEM, standard error of the mean PCS and MCS Scores improved after 24-36 months of Fabrazyme treatment.
Where Clinical Trials are Most Feasible Common Homogeneous Heterogeneous Rare Acute Chronic
Where Patient Registries May Add Value Common Homogeneous Heterogeneous Chronic Diseases Diseases Heterogeneous Rare Acute Rare Diseases Chronic
Fabry Renal Natural History Research Question: What is the natural history of renal progression among patients with Fabry disease? 49
Fabry Renal Natural History Study population (n=462): All natural history patients enrolled in the Fabry Registry who were either: Untreated patients, or ERT-treated patients with data reported before initiation of therapy 2 serum creatinine values for egfr over a span of 12 months before treatment 1 urine protein/creatinine ratio (UP/Cr, g/g) values Time period: Follow-up for each patient from birth until initiation of therapy or before chronic dialysis/kidney transplant 50
Fabry Renal Natural History Analysis Mixed model regression to identify predictors of egfr slope Stratification by quartiles of urine protein/creatinine ratio Analyses were conducted separately for males and females 51
Regression Modeling of egfr Slope Males Females Parameter Estimate Standard Error p-value Parameter Estimate Standard Error p-value Predictor Variables Averaged UP/Cr (transformed)* -6.402 0.502 <0.0001-2.109 0.239 <0.0001 Baseline egfr -0.012 0.006 0.065-0.026 0.004 <0.0001 Age at baseline egfr Averaged systolic blood pressure Averaged diastolic blood pressure -0.017 0.013 0.194-0.025 0.007 0.001 0.009 0.012 0.457 0.002 0.008 0.815-0.041 0.017 0.015-0.004 0.011 0.687 Proteinuria was a predominant factor in predicting renal disease progression rate for both genders, with a greater impact in men than in women. In women, lower baseline egfr and increased age at baseline were also associated with more rapid loss of kidney function.
Effect of Proteinuria on egfr Over Time in Patients with Longitudinal Renal Data Males Females 120 120 110 110 egfr (ml/min/1.73m2) 100 90 80 UP/Cr 0.0 to 0.2 (n=30) slope -0.2 UP/Cr 0.2 to 0.8 (n=30) slope -1.3 egfr (ml/min/1.73m2) 100 90 80 UP/Cr 0.0 to 0.1 (n=85) slope 0.3 UP/Cr 0.1 to 0.3 (n=85) slope -0.3 UP/Cr 0.3 to 1.2 (n=86) slope -0.7 UP/Cr 1.2 to 6.4 (n=85) slope -1.3 70 UP/Cr 0.8 to 1.5 (n=31) slope -3.3 70 60 UP/Cr 1.5 to 7.3 (n=30) slope -5.6 60 50 0 1 2 3 4 Time from Baseline (years) 50 0 1 2 3 4 Time from Baseline (years) The average egfr slope was 0.2 ml/min/1.73 m2/year among the 30 men in the lowest averaged UP/Cr quartile and 5.6 ml/min/1.73 m2/year among the 30 men in the highest UP/Cr quartile. Renal function was more stable for women, but the highest levels of proteinuria were associated with more rapid declines in renal function.
Incidence of Selected Rare Diseases Fabry Disease Males Females Gaucher Disease General Population Ashkenazi Jewish Population MPS 1 Disease Hurler Hurler-Scheie Scheie Pompe Disease Infantile-onset Juvenile-onset Adult-onset Infantile: African-American in the US 1 in 40,000 live births 1 in 30,000 live births 1 in 120,000 live births 1 in 850 live births 1 in 85,500 live births 1 in 131,600 live births 1 in 344,800 live births 1 in 833,300 live births 1 in 40,000 live births 1 in 100,000 live births 1 in 400,000 live births 1 in 80,000 live births 1 in 24,000 live births