Fabry RADAR 2007 The Fabry Registry Aggregate Data Annual Report

Transcription

1 Fabry RADAR 2007 The Fabry Registry Aggregate Data Annual Report A program supported by Genzyme Fabr/GL/P341/05/ Genzyme Corporation. All rights reserved.

2 Table of Contents I. II. III. IV. V. VI. VII. VIII. Foreword... 1 Introduction... 2 Publication of Guidelines for Evaluating and Managing Patients with Fabry Disease... 2 Comparison between the Fabry Registry and a Clinical Trial... 2 Progress Towards 2006 Goals... 3 Improve Collection of Cardiac Assessment Data... 3 Identify Clinically Defined Subpopulations within the Fabry Registry to Characterize and Report Longitudinal Outcomes... 3 Publish the Natural Course of Disease in Fabry Registry Patients... 4 Current Data... 4 Demographics... 4 Disease Onset and Progression... 6 Early Symptoms of Fabry Disease in Male and Female Pediatric Patients... 7 Late Symptoms of Fabry Disease and Event Rates in All Patients... 7 Onset of Renal Disease Progression in Male and Female Fabry Patients... 8 Onset of Cardiac Disease in Male and Female Fabry Patients... 9 Quality of Life Patterns of Care Resources Disease Severity Scoring System (DS-3) Summary Goals for Longitudinal Data Collection Describe the Longitudinal Course of Disease Progression in Fabry Disease in Adult Males and Females Focus on Renal Data Focus on Cardiac Data Focus on Neurological Data Advance the Research Priorities of the Registry Boards of Advisors Further explore the natural course of Fabry disease through analyses of Registry data Adverse Event Reporting Appendix Boards of Advisors Appendix 2 Latin American Fabry Registry Coordinators Appendix 3 - Minimum Recommended Schedule of Assessments Appendix Key Presentations of Fabry Registry Data Appendix 5 - Fabry Data Request Form Appendix 6 Abbreviated Sample Patient Case Report... 23

3 Foreword On behalf of the Boards of Advisors for the Fabry Registry, we are pleased to introduce the 2007 Registry Aggregate Data and Annual Report (RADAR). A growing body of longitudinal data has enabled the Fabry Registry to focus on specific subpopulations, including female and pediatric patients. Characterization of Fabry disease within these subpopulations is critical, as increasing evidence indicates that females and children suffer from the symptoms of Fabry disease, but much less is known about the course of disease progression in these patients. By continuing to focus on robust, longitudinal data collection, the Fabry Registry will allow us to investigate these populations and other important aspects of Fabry disease. We hope that you find this edition of RADAR to be a concise and useful summary of the data and activities of the Fabry Registry in Your energy and commitment will continue to strengthen the Fabry Registry as a global research platform for Fabry disease to be used far into the future. Please do not hesitate to contact any one of us through the Fabry Registry helpline at help@fabryregistry.com with your insights and research proposals so that we may support you and collaborate where appropriate in advancing our understanding of Fabry disease. Finally, it is with sadness that we acknowledge the passing of our colleague, Dr. Laura Pinderski, who served as a member of the Fabry Registry North American Board of Advisors in She worked assiduously on behalf of patients with Fabry disease and she shall be missed. William Wilcox, MD, PhD Fabry Registry North American Board of Advisors Prof. Christoph Wanner Fabry Registry European Board of Advisors Christine Eng, MD Fabry Registry International Board of Advisors Dr. D.P. Germain Fabry Registry International Board of Advisors Prof. Ana Maria Martins, MD, PhD Fabry Registry International Board of Advisors 1

4 Introduction Fabry disease is a rare lysosomal storage disease caused by deficient activity of the lysosomal hydrolase, a-galactosidase A. Mutations in the X-linked gene that encodes the a-galactosidase A protein cause progressive accumulation of globotriaosylceramide (GL-3) and related glycolipids in various tissues. Patients with Fabry disease initially experience severe pain crises, exercise intolerance, and gastrointestinal distress. As the disease progresses, more serious complications typically develop, including renal insufficiency, cardiac disease, and stroke. The Fabry Registry is a global, observational, and voluntary program designed to collect clinical data related to the onset, progression, and treated course of Fabry disease. All patients with Fabry disease are eligible to participate in the Fabry Registry, regardless of whether they are receiving enzyme replacement therapy (ERT) and irrespective of the commercial products with which they are being treated. Three Advisory Boards provide scientific oversight and direction to the Fabry Registry, including a North American Board, a European Board, and an International Board. Board members are independent physicians with expertise in Fabry disease who serve as independent links between the Fabry Registry and the Fabry medical community within their respective geographic regions (Appendix 1). In addition, the Latin America Registry Coordinators oversee Registry programs, including outcomes analyses and data entry for the Latin American region (Appendix 2). The Boards of Advisors developed the Fabry Registry s Minimum Recommended Schedule of Assessments (Appendix 3) in conjunction with Genzyme. This schedule recommends key clinical and laboratory parameters for monitoring patients with Fabry disease, and forms the basis of the clinical data and the frequency at which they are collected for the Fabry Registry. Because the Registry is voluntary, assessments and their frequency for individual patients are determined by their treating physicians. The infrastructure of the Fabry Registry is sponsored by Genzyme Corporation, which underwrites a third party to maintain the electronic data capture application and clinical database. Genzyme also provides financial support for data collection at some participating sites. Personnel to manage and administer the Fabry Registry programs operate within the Biomedical Research Division and Global Registry Programs at Genzyme. This year s Fabry Registry aggregate data annual report is entitled RADAR 2007, because it is being published during the 2007 calendar year, though it summarizes data collected in Previous reports have been titled according to the year in which the data were collected. To date, the Fabry Registry is the largest registry that tracks clinical data for patients with Fabry disease. Since its introduction in April 2001, a total of 2,235 patients and 191 physicians worldwide have enrolled in the Fabry Registry. Enrollment is continuously increasing, as shown in Figure 1. Figure 1 Cumulative enrollment of patients and physicians in the Fabry Registry from 2001 to 2006 Publication of Guidelines for Evaluating and Managing Patients with Fabry Disease In 2006, an international group of physicians participating in the Fabry Registry published an article describing guidelines for the evaluation and management of patients with Fabry disease (Eng et al, 2006, Genet Med, Appendix 4). A uniform practice standard would simplify the reporting of clinical data on the natural course of disease progression and treatment outcomes. Furthermore, there is a clear need for such disease management guidelines; due to the rarity of Fabry disease, many medical practices may have as few as one patient. As Fabry disease involves multiple organ systems, its therapeutic management requires participation and communication between various medical specialists, including geneticists, nephrologists, cardiologists, neurologists, and others. The article by Eng et al. proposes specific guidelines for comprehensive monitoring of various organ systems in Fabry patients at regular intervals, regardless of age, gender, or ERT status. Comparison between the Fabry Registry and a Clinical Trial Although clinical trials and Registry programs both compile clinical data from patients, it is important to recognize that there are key differences between these entities. Clinical trials, which are designed to determine within a specified period of time whether a certain intervention is safe and effective, enroll subjects based on specific inclusion and exclusion criteria. Clinical trials also perform source data verification, which is not generally performed within registries. Enrollment in disease registries, such as the Fabry Registry, may continue for extended periods of time, which may not be feasible for clinical trials. In addition, the Fabry Registry is open to all patients with Fabry disease, regardless of whether they are receiving any enzyme replacement treatment. Because the objectives of the Fabry 2

5 Registry are intended to explore and define the natural course and clinical characteristics of Fabry disease, data collection is ongoing with the goal of assembling data over time that will help clarify the presentation, prognosis, and long-term outcomes related to available treatment options. Since the Fabry Registry involves voluntary, observational data collection, it can provide long-term trend data that reflect current clinical practice in a non-selected patient population. Patients who have previously participated in clinical trials are encouraged to enroll in the Fabry Registry and, whenever possible, clinical data from the trial is rolled over into the Registry. This allows the Registry to obtain high-quality longitudinal data from these unique cohorts of patients, and to continue to monitor their clinical status beyond the clinical trial period. Additionally, like a clinical trial, the Fabry Registry employs data checks on key submitted patient data using a combination of electronic edit checks and manual review. Data managers routinely review patient data submitted for accuracy and consistency. Genzyme Registry Associates are in contact with participating physicians to help communicate and resolve any data that has come into question. Progress Towards 2006 Goals The second edition of the Fabry Registry Aggregate Data Annual Report was issued last year. In that report, the following goals were established for the Fabry Registry in 2006: Improve Collection of Cardiac Assessment Data Identify Clinically Defined Subpopulations within the Fabry Registry to Characterize and Report Longitudinal Outcomes Publish the Natural Course of Disease in Fabry Registry Patients The following sections summarize the progress that has been made towards these goals. Improve Collection of Cardiac Assessment Data Cardiac involvement, particularly left ventricular hypertrophy, is a prominent manifestation in patients with Fabry disease. Cardiac manifestations can include left ventricular hypertrophy, congestive heart failure, myocardial ischemia, and life-threatening arrhythmia all contributors to mortality in Fabry disease. It is critical to identify the early stages of cardiac involvement, so that patients may receive appropriate intervention before the onset of cardiac complications. Figure 2 shows the number of patients for whom left posterior wall thickness data are currently available. It can be seen that substantial numbers of patients have left posterior wall thickness data available for up to 48 months after their enrollment in the Fabry Registry. Figure 2 Number of Patients with Left Posterior Wall Thickness Observations by Time Period For patients ever on ERT, baseline refers to the date of first ERT. For patients never on ERT, baseline refers to the earliest echocardiographic data point submitted to the Fabry Registry. Time periods indicate the number of months from baseline where additional data have been submitted. Data shown reflect echocardiographic data collected as of October 6, Identify Clinically Defined Subpopulations within the Fabry Registry to Characterize and Report Longitudinal Outcomes Over the past 6 years, the Fabry Registry has collected an extensive amount of data on 2,235 patients. Because the overall population that participates in the Fabry Registry is highly diverse in terms of age, gender, and state of disease progression, it is useful to segregate patients into specific cohorts. This will enable the Fabry Registry to more accurately characterize disease severity and to perform more meaningful cross-sectional and longitudinal data analyses. To address this issue, two groups of physicians who participate in the Fabry Registry formed a female workgroup and a pediatric workgroup. These groups are focusing on understanding the progression of Fabry disease in the female and pediatric patient subpopulations. Until recently, many female patients were not being enrolled in the Fabry Registry because they had not yet exhibited clinical symptoms. Because formal assessments often reveal abnormalities that are not apparent by medical history alone, the female workgroup encouraged participating physicians to enroll their female patients. The enrollment of females in the Fabry Registry increased from 878 to 1,077 in Similarly, there was a relative paucity of data on pediatric patients in the Fabry Registry until the pediatric workgroup advised physicians to add specific assessments to their standard monitoring of pediatric patients and to ask parents to enroll these patients in the Fabry Registry. The enrollment of children in the Fabry Registry increased from 225 to 250 in 2006, including 14 of 16 pediatric patients 3

6 who participated in a 12-month clinical trial of ERT with agalsidase beta and enrolled in the Fabry Registry after completing the clinical trial program. Publish the Natural Course of Disease in Fabry Registry Patients Analyses of data from the Fabry Registry are being developed into various manuscripts that will be published in the near future. A manuscript describing the demographic and baseline clinical characteristics of patients enrolled in the Fabry Registry will be published in the Journal of Inherited Metabolic Diseases in This publication provides important information regarding the early course of Fabry disease and demonstrates that there is an early burden of disease in both genders and a substantial delay in disease recognition and diagnosis. Two manuscripts based on Fabry Registry data characterizing Fabry disease in female and in pediatric patients are currently in preparation. Publication of these analyses will provide physicians with a more accurate estimate of the frequency of various complications and the ages of onset in these subpopulations of patients. This, in turn, may facilitate the development of treatment guidelines for female and pediatric patients with Fabry disease. A fourth manuscript focusing on renal disease in male and female Fabry patients is also currently in preparation. Renal insufficiency is the most common feature of Fabry disease. A better understanding of how renal disease progresses in male and female patients will enable physicians to provide the most appropriate interventions. Finally, a number of important analyses based on data from the Fabry Registry were presented in 2006 at international meetings. Abstracts from these presentations are included in Appendix 4. Current Data Table 1 Demographic Profile of Fabry Registry patients Statistics Males Females Number Enrolled n (%) 1,158 (52%) 1,077 (48%) Current Age (years) n 1,158 1,076 Age Distribution Mean (SD) 37.3 (14.92) 40.5 (17.40) Median Min, Max 1, 84 0, 86 Age > 18 years n (%) 1,035 (89.4) 949 (88.1) Age < 18 years n (%) 123 (10.6) 127 (11.8) Unknown/Missing* n (%) 0 1 (0.1) ERT Status Not on ERT n (%) 205 (17.7) 698 (64.8) On ERT n (%) 926 (80.0) 357 (33.1) Unknown n (%) 27 ( 2.3) 22 ( 2.0) Ethnicity Caucasian n (%) 871 (75.2) 830 (77.1) Black n (%) 20 ( 1.7) 13 ( 1.2) Hispanic n (%) 82 ( 7.1) 69 ( 6.4) Asian n (%) 37 ( 3.2) 13 ( 1.2) Other n (%) 46 ( 4.0) 26 ( 2.4) Unknown/ Not Reported Fabry in Family? n (%) 102 ( 8.8) 126 (11.7) Yes n (%) 888 (76.7) 906 (84.1) No n (%) 126 (10.9) 32 ( 3.0) Demographics Unknown/ Not Reported n (%) 144 (12.4) 139 (12.9) Of the 2,235 patients enrolled in the Fabry Registry at the end of 2006, 52% were male and 48% were female, as shown in Table 1. The percentages of patients classified as adults (18 years of age or older) were also similar among males and females; 89% and 88%, respectively. As observed previously, the majority of patients within both genders were Caucasian and most patients reported having a family member diagnosed with Fabry disease. As of December 31, 2006, patients from 37 countries had enrolled in the Fabry Registry, as shown in Table 2. Overall, the largest numbers of patients are enrolled in Europe, the United States, and Latin America, as shown in Figure 3. Note: Percentages may not total to 100% due to rounding. *Note that one patient was reported to have died, but the date of death had not yet been reported to the Registry as of December 31, For this reason, this patient s age is designated as unknown. Among the 2,235 patients enrolled in the Fabry Registry, 1,283 (57%) have received ERT. However, there is a striking difference in the percentages of male and female patients who have received ERT. While 80% of males have received ERT, only 33% of females have been treated with ERT, as shown in Figure 4. There is an even greater gender difference within the pediatric subpopulation of patients. Among the 250 pediatric patients enrolled, 57% of males have received ERT, as compared to only 10% of females. These gender differences in ERT status are due, at least in part, to the fact that Fabry disease is an X-linked 1 Eng CM, Fletcher J, Wilcox WR, Waldek S, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007; 30:

7 Argentina 30 Table 2 Countries of origin of Fabry Registry Patients Finland 12 Netherlands 77 Sweden 33 Figure 4 ERT status for Patients in the Fabry Registry 4a. All Males 4b. All Females Australia 73 France 155 Norway 34 Switzerland 42 Austria 1 Germany 101 P. R. China 10 Taiwan 10 Belgium 6 Greece 2 Poland 14 Turkey 1 4c. Pediatric Males 4d. Pediatric Females Brazil 73 Hungary 37 Portugal 15 United Kingdom 207 Canada 134 India 1 Romania 7 United States 843 Chile 21 Israel 4 Saudi Arabia 9 Venezuela 2 Columbia 12 Italy 49 Singapore 1 Pediatric patients are defined as those <18 years of age as of December 31, Czech Republic 97 Denmark 39 Korea 11 Mexico 13 Slovenia 25 Spain 34 The number of patients enrolled is shown for each country. Figure 3 Global Enrollment Distribution Individual countries that have >100 patients enrolled are shown. Countries with <100 patients enrolled are grouped together by geographical region. genetic disorder and male patients are expected to be more profoundly affected than female patients. However, increasing evidence suggests heterozygous female patients may exhibit significant complications of Fabry disease and that they should be monitored and treated accordingly. 2,3,4,5 The study population within the Fabry Registry continues to mature. A total of 1,863 patients in the Fabry Registry (83%) have been participating in the Registry for one year or more and 470 patients (21%) have now been participating for 3 years or more, as shown in Figure 5. This includes patients who enrolled in the Registry after completing various clinical trials. Thus, over time, the Registry has the potential to provide longitudinal data, which may be used to more effectively evaluate disease progression as well as the longterm effects of treatment. One example of how longitudinal data from the Registry has been used to evaluate disease progression is to compare the age at symptom onset, diagnosis, clinical events, and the initiation of ERT in adult male and female patients who received ERT. Clinical events included cardiac, cerebrovascular, and renal events. Cardiac events were defined as arrhythmia, myocardial infarction, angina pectoris, congestive heart failure, or a significant cardiac procedure. Cerebrovascular events included stroke and renal events included dialysis or kidney transplantation. There was a 4-year difference in the median ages at onset of symptoms in males and females (10 years in male patients and 14 years 2 Gupta, S, Ries, M., Kotsopoulos, S., Schiffmann, R. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine 2005, 84: Deegan P., Baehner, A.F., Barba-Romero, M.A., Hughes, D., Kampmann, C., Beck, M. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2005; 43: Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007; 9: Eng CM, Fletcher J, Wilcox WR, Waldek S, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007; 30:

8 Figure 5 Length of time patients have been enrolled in the Fabry Registry in female patients), as shown in Figure 6. However, there was an 11-year difference in the median ages at diagnosis (27 years in males and 38 years in females). This highlights the importance of better characterizing the natural course of Fabry disease in adult females to facilitate earlier diagnosis in these patients. Among patients who experienced renal, cardiac, and cerebrovascular events, the ages at first onset of events were similar in males and females, although males tended to experience their first cardiac event at an earlier median age than females (42 years in males versus 48 years in females). Females began ERT at a much later age than males (median 37 years in males versus 46 years in females). Disease Onset and Progression 6a. Adult males Figure 6 Age at First Event in Adult Male and Female Patients One of the primary goals of the Registry is to delineate the natural progression of Fabry disease. Data from the Fabry Registry were used to develop a model of disease progression, as shown in Figure 7. Fabry disease becomes progressively more severe and affects multiple organ systems over time. The lack of a-galactosidase A causes GL-3 to accumulate at abnormally high levels. This accumulation of GL-3 initially causes cellular dysfunction and sub-clinical disease. Early symptoms reflect disease progression in the peripheral and autonomic nervous systems and include neuropathic pain, gastrointestinal symptoms, and hypohidrosis. Over time, as the disease progresses, secondary disease processes such as tissue responses to cellular signals, dysfunction, or damage occur. Clinical manifestations of disease progression in the kidney, the heart, and the cerebrovascular system usually occur later in a Fabry patient s life, although in severely affected patients these may occur in the second and third decades of life. These late complications are associated with much of the morbidity and mortality associated with Fabry disease. This model highlights the importance of assessing and monitoring each organ compartment before irreversible organ damage has occurred. Figure 7 Schematic model of the progression of Fabry disease 6b. Adult Females Data shown represent natural history data (i.e., prior to the start of ERT) in adult male and female patients current age >18 years) who eventually received ERT. Note that dates of symptom onset and diagnosis were not available for all patients. Black dots within each bar indicate the median. 6

9 Early Symptoms of Fabry Disease in Male and Female Pediatric Patients The increased number of pediatric patients enrolled in the Fabry Registry, as well as the increased amount of longitudinal data available for individual patients enables a more detailed characterization of the early symptoms of Fabry disease. As shown in Table 3 below, male patients typically experienced their first Fabry symptoms at an earlier age than females (6.0 years in males versus 8.1 years in females). However, among pediatric patients, there was much less of a gender gap in the average age at diagnosis (7.2 years in males versus 7.8 years in females), compared to adult patients; the median age at diagnosis was 27 years in adult males and 38 years in adult females (see Figure 6). On average, male pediatric patients began ERT at the age of 10.5 years, as compared to 12.2 years in female pediatric patients. The availability of a more complete set of data for pediatric Fabry patients has also enabled an evaluation of the age at onset of specific symptoms in childhood. As shown in Figure 8, pediatric patients exhibit an array of symptoms at a surprisingly early age. On average, male pediatric patients experienced the onset of all symptoms at an earlier age than female patients. However, the ages of onset of some symptoms exhibited more pronounced gender differences than others. For example, the average age at onset of neuropathic pain is not markedly different, at 6.4 years in males and 7.9 years in females. Gastrointestinal symptoms, in contrast, began at an average age of 5.7 years in males and 9.5 years in females. Figure 8 Age at Symptom Onset in Pediatric Patients Data shown represent natural history data. Pediatric patients are defined as those <18 years of age as of December 31, Note that 2 pediatric patients of each gender exhibited cerebrovascular, cardiovascular, or renal symptoms; thus, the mean ages for these symptoms must be interpreted cautiously. A zero-value indicates that no patients reported experiencing this symptom. Neuro, other corresponds to neurological symptoms that are not neurological pain or cerebrovascular symptoms. Other corresponds to Other, specify on the case report form. Figure 9 Mean Age at Symptom Onset in All Fabry Registry Patients Table 3 Average Ages for Symptom Onset, Diagnosis, and ERT in Fabry Registry Pediatric Patients Males (N=123) Females (N=127) N Average Age in years (SD) N Average Age in years (SD) Registry Enrollment First Fabry Symptom Fabry Diagnosis First ERT Infusion ( 4.46) ( 4.22) ( 2.96) ( 3.92) ( 4.33) ( 4.55) ( 3.92) ( 2.38) Pediatric patients are defined as those <18 years of age as of December 31, SD=standard deviation Late Symptoms of Fabry Disease and Event Rates in All Patients Figure 9 shows the mean age at symptom onset among all patients (i.e., all ages) in the Fabry Registry. Similar to what was observed in pediatric patients, males consistently reported exhibiting all symptoms at an earlier age than females. However, as with pediatric patients, some symptoms exhibit more marked gender differences in age at onset. For Data shown represent natural history data. The number of patients (N) from each gender and the various symptom categories ranged from 13 to 641. All Fabry Registry patients (all ages) with data available as of December 31, 2006, were included in these analyses, with the exception of the cerebrovascular symptoms category, which includes only patients age 18 years. Analysis of cerebrovascular symptom data across all patients revealed that many adult males reported a history of experiencing cerebrovascular symptoms during early childhood (mean = 16.4 years, N=37). Reports of cerebrovascular symptoms that occurred during childhood (age <18 years, n=24) are omitted from this analysis and are being verified where possible at the sites. Neuro, other corresponds to neurological symptoms that are not neurological pain or cerebrovascular symptoms. Other corresponds to Other, specify on the case report form. example, among all patients, neuropathic pain began at an average age of 10.4 years in males and at 14.3 years in females. In contrast, cardiovascular symptoms began at an average age 7

10 of 21.1 years in males, as compared to 33.3 years in females. The Fabry Registry also tracks the number of clinical events reported by patients. Figure 10 shows that a higher percentage of male patients reported experiencing renal, cardiac, or cerebrovascular events, as compared to female patients. Renal events were defined as dialysis or kidney transplantation, cardiac events were defined as arrhythmia, myocardial infarction, angina pectoris, congestive heart failure, or a significant cardiac procedure, and cerebrovascular events were defined as stroke. The largest gender difference was in renal events, which were experienced by 18.1% of male patients and by 6.6% of female patients. The percentages of patients experiencing cardiac events, stroke events, or any event, were approximately 50% higher in male patients versus female patients overall, as shown in Figure 10. Figure 10 Percentage of Patients in Fabry Registry Experiencing 1 or More Natural History Events Table 4 Classification of Chronic Kidney Disease Stages CKD Stage* GFR (ml/min/1.73m 2 ) Normal (no kidney disease) GFR 90 without proteinuria Stage 1 GFR 90 with proteinuria Stage 2 GFR >60 and 89 Stage 3 GFR >30 and 59 Stage 4 GFR >15 and 29 Stage 5 GFR < 15 (or dialysis) CKD = chronic kidney disease; GFR = glomerular filtration rate *As described in the National Kidney Foundation clinical practice guidelines for chronic kidney disease. Am J Kid Dis 2002; 39:S1 S266. All Males Table 5 Estimated GFR and Age by CKD Stage and Gender Variable Stage 1 Stage 2 Stage 3 Stage 4/5 % (N) 51% (221) 25% (107) 11% (46) 13% (56) Estimated GFR (ml/min/1.73m 2 Mean (SD) 117 (24.5) 77 (9.2) 45 (8.4) 18 (7.2) Males >40 years % (N) 22% (35) 37% (60) 20% (33) 21% (34) All Females % (N) 47% (237) 40% (202) 10% (51) 3% (17) Estimated GFR (ml/min/1.73m 2 Mean (SD) 108 (16.8) 76 (8.3) 52 (7.7) 14 (6.9) Females >40 years % (N) 33% (98) 48% (143) 16% (47) 4% (12) Data shown represent natural history data. The percentages of patients with clinical events are calculated as a percentage of all patients with a known ERT status, including those who did not report to the Registry whether they experienced any clinical events. Patients experiencing more than one event type will appear in each relevant event category. Cerebro = cerebrovascular. Onset of Renal Disease Progression in Male and Female Fabry Patients Renal insufficiency is a prominent aspect of Fabry disease. The growing body of data from female patients in the Fabry Registry has made it possible to analyze various aspects of renal disease in male and female patients. The presence of proteinuria and reduced glomerular filtration rate (GFR) values reflect impaired renal function, as indicated by the guidelines established by the National Kidney Foundation (see Table 4). According to these guidelines, 937 adult patients (430 males and 507 females) within the Fabry Registry exhibited some level of chronic kidney disease (CKD) as shown by natural history data summarized in Table 5. Further analyses Data shown represent a cross-sectional analysis of natural history data (i.e., prior to the start of ERT) for 430 male and 507 female adult patients ( 18 years of age) who had renal function data and who had not received dialysis or a kidney transplant as of June 2, Presented by A. Ortiz at the 2006 European Renal Association-European Dialysis and Transplant Association meeting in Glasgow (see Appendix 4). indicated that 24% of males and 13% of females had an estimated GFR <60 ml/min/1.73m 2, which corresponds to CKD stages 3-5. Among patients 40 years of age, 41% of males and 20% of females were in Stage 3-5 CKD. Note that these values represent only Fabry Registry patients for whom renal function data were available and who had not received dialysis or a kidney transplant. Proteinuria levels were also evaluated among adult patients within the Fabry Registry who were characterized as having CKD Stages 1, 2, 3, or 4/5. Figure 11 shows that proteinuria levels progressively increased with advancing renal disease in these patients. A higher percentage of male patients exhibited proteinuria levels of >0.3 g/day, among patients who were in CKD Stage 1, Stage 2, or Stage 3. Among patients in Stage 4/5 CKD, approximately 90% of both male and female patients exhibited proteinuria levels of >0.3 g/day. The association between proteinuria and advancing CKD stage is an important observation, as baseline proteinuria has been identified as a strong prognostic factor for renal progression. 6,7 6 de Zeeuw D, Remuzzi G, Parving HH, Keane WF, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;6: Zhang Z, Shahinfar S, Keane WF, Ramjit D, et al. Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. J Am Soc Nephrol. 2005;16:

11 In addition, proteinuria itself may become an important therapeutic target for angiotensin-converting enzyme inhibitor or angiotensin-ii type I receptor blocker therapy. 8 Figure 12 Left Ventricular Mean Wall Thickness Grouped by CKD Stage Figure 11 Percentage of Male and Female Adult Patients with Proteinuria > 0.3 g/day by CKD Stage Data shown represent natural history data. Left ventricular mean wall thickness was defined as the mean of the interventricular septal thickness and the left ventricular posterior wall thickness, as determined by echocardiography. Data shown represent a cross-sectional analysis of 317 male and 413 female adult patients ( 18 years of age) who had renal function data and left ventricular mean wall thickness data available and who had not received dialysis or a kidney transplant as of June 2, Data shown represent natural history data. Data shown represent a crosssectional analysis of 430 male and 507 female adult patients ( 18 years of age) who had renal function data and who had not received dialysis or a kidney transplant as of June 2, Presented by A. Ortiz at the 2006 European Renal Association-European Dialysis and Transplant Association meeting in Glasgow (see Appendix 4). Figure 13 Percentage of Patients with Cardiovascular Events Onset of Cardiac Disease in Male and Female Fabry Patients In addition to renal dysfunction, cardiovascular disease is a prominent manifestation of Fabry disease. A number of analyses have been undertaken to determine whether decreased renal function is related to the progression of cardiovascular disease in Fabry patients. As shown in Table 5, adult patients in the Fabry Registry who had renal function data and who had not received dialysis or a kidney transplant were categorized as having CKD Stages 1, 2, 3, or 4/5, based on their estimated GFR. Left ventricular mean wall thickness was then evaluated in these subgroups of patients. As shown in Figure 12, left ventricular mean wall thickness generally increased progressively with decreasing renal function in both male and female patients. Because left ventricular hypertrophy can be asymptomatic initially, these findings suggest that cardiac function should be monitored carefully in Fabry patients in the early stages of renal disease. The types and frequency of cardiac events reported in Fabry Registry patients were also evaluated. A total of 475 male patients and 354 female patients had cardiovascular events and/or echocardiographic or electrocardiographic exam results reported to the Fabry Registry as of June 2, Among these patients, similar percentages of males and females experienced myocardial infarctions and congestive heart failure, as shown in Figure 13. A slightly Data shown represent natural history data. Data shown represent 475 male and 354 female patients who had cardiovascular events and/or echocardiographic or electrocardiographic exam results reported to the Fabry Registry as of June 2, Presented by J. Strotmann at the 2006 World Congress of Cardiology meeting in Barcelona (see Appendix 4). higher percentage of females experienced angina and a slightly higher percentage of males experienced arrhythmia. Furthermore, 12% of males and 10% of females experienced first cardiac events at a mean age of 39 ± 12 years (males) and 46 ± 13 years (females) (Strotmann et al, Appendix 4). These data demonstrate that males and females experienced cardiac involvement in Fabry disease at similar frequencies. 8 Tahir J, Aldridge L, Warnock D. Sustained Antiproteinuric Effect of ACE Inhibitors and Angiotension Receptor Blockers (ACEi/ARBs) in Fabry Disease. Abstract, presented at the American Society of Nephrology Meeting, Nov. 18,

12 Quality of Life Patients with Fabry disease frequently experience debilitating pain symptoms, including recurrent episodes of severe neuropathic pain in the extremities, beginning in childhood and adolescence, as well as pain crises in response to changes in temperature and physical exercise. Fabry disease is also associated with gastrointestinal symptoms, such as diarrhea, abdominal pain, nausea, and vomiting. These and other symptoms of Fabry disease significantly impair patients daily functioning and quality of life. The frequency of various pain-related symptoms was compared in all male and female patients in the Fabry Registry, as well as in the pediatric subpopulation. As shown in Figure 14a, among all patients, a higher percentage of female patients reported experiencing abnormal heat and cold tolerance, abnormal sweating, chronic pain, abdominal pain, and diarrhea. There was no consistent gender difference across these symptoms in the pediatric subpopulation of patients (Figure 14b), where certain symptoms were reported by a higher percentage of males (i.e., angiokeratoma and abnormal sweating), but other symptoms were reported by similar percentages of males and females (i.e., chronic pain, abdominal pain, and diarrhea). The SF-36 Health Survey is a questionnaire that measures patients subjective assessments of quality of life. The SF- 36 measures both physical and mental aspects of quality of life, and is divided into eight subcomponent scores, including physical functioning, role physical, bodily pain, Figure 14 Percentage of Patients with Abnormal Sweating, Heat and Cold Intolerance, Chronic Pain, Angiokeratoma, Abdominal Pain, and Diarrhea 14a. All Patients 15a. Males Figure 15 SF-36 Quality of Life in Fabry Registry Patients Data shown represent natural history data. The percentages of patients with symptoms are calculated as a percentage of all patients with a known ERT status, including those who did not report to the Registry whether they experienced any symptoms. 14b. Pediatric Patients 15b. Females Data shown represent natural history data. The percentages of pediatric patients with symptoms are calculated as a percentage of all pediatric patients regardless of ERT status, including those who did not report to the Registry whether they experienced any symptoms. Pediatric patients are defined as those <18 years of age as of December 31, Data shown represent cross-sectional natural history data from 204 male and 389 female patients who had SF-36 data reported to the Fabry Registry as of December 31,

13 general health, vitality, social functioning, role emotional, and mental health. Cross-sectional SF-36 data were available for 204 males and 389 females in the Fabry Registry of the age 14 years. Although this is not longitudinal data (i.e., different patients are represented in each age group), SF-36 scores among males remained relatively stable, or decreased slightly with increasing age, as shown in Figure 15a. In contrast, female patients exhibited consistent decreases in SF-36 scores across increasing age groups (Figure 15b). Thus, quality of life appears to decrease more markedly in female Fabry patients with increasing age, as compared to male patients. This is consistent with the finding that female patients reported more pain-related symptoms than male patients (Figure 15a). Patterns of Care The data presented in Figures 8-15 consistently indicate that female patients suffer from substantial symptoms of Fabry disease. These findings are supported by several independent studies 9,10,11,12 and contrast sharply with earlier views that females were generally asymptomatic carriers of the disease. 13 Despite the growing body of evidence indicating that females exhibit significant complications of Fabry disease, they are considerably less likely than males to receive ERT, as shown in Figure 4. Furthermore, when females do receive ERT, it is at a considerably later age. Table 6 shows the average age at Registry enrollment, diagnosis, symptom onset, and initiation of ERT in male and female patients in the United States and in Europe. Among all patients in both the United States and in Europe, female patients typically begin ERT 8 years later than male patients. The gender gap in age at initiation of ERT was smaller among pediatric patients, but very few female pediatric patients in the Fabry Registry actually receive ERT (N=7 in the United States and N=6 in Europe) Table 6 Age at Diagnosis, Symptom Onset, and Initiation of ERT in Fabry Registry Patients in the United States and Europe Total Number of Patients N United States All Patients Europe Males Females Males Females N = 452 N = 391 N = 494 N = 507 Age (years) mean (SD) N Age (years) mean (SD) N Age (years) mean (SD) N Age (years) mean (SD) Current Age (15.47) (17.66) (14.77) (17.45) Registry Enrollment (15.63) (17.49) (14.70) (17.28) First Fabry Symptom (11.04) (14.94) (13.29) (16.61) Fabry Diagnosis (15.70) (18.17) (16.08) (17.35) First ERT Infusion (14.59) (14.41) (13.60) (14.43) Total Number of Patients N United States Pediatric Patients Europe Males Females Males Females N = 58 N = 54 N = 43 N = 57 Age (years) mean (SD) N Age (years) mean (SD) N Age (years) mean (SD) N Age (years) mean (SD) Current Age (4.38) (4.21) (3.26) (4.08) Registry Enrollment (4.26) (4.04) (4.61) (4.26) First Fabry Symptom (3.27) (3.98) (2.41) (3.75) Fabry Diagnosis (3.89) (4.33) (4.33) (4.44) First ERT Infusion (3.04) (2.88) (4.54) (1.75) 9 Gupta, S, Ries, M., Kotsopoulos, S., Schiffmann, R. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine 2005, 84: Deegan P., Baehner, A.F., Barba-Romero, M.A., Hughes, D., Kampmann, C., Beck, M. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2005; 43: Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007; 9: Eng CM, Fletcher J, Wilcox WR, Waldek S, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007; 30: Desnick R, Ioannou Y and Eng C. Alpha-galactosidase A deficiency: Fabry disease. In: The metabolic and molecular basis of inherited disease, edited by Scriver C, Sly W, Childs B, Beaudet A, Valle D, Kinzler A and Vogelstein B, New York, McGraw Hill, 2001, pp

14 Resources Through its website, fabryregistry.com, the Fabry Registry provides participating physicians and health care advocates with various resources to obtain updated information from the Registry. Completed Data Request Reports can be found in the secure area of fabryregistry.com by clicking on the Fabry Registry Data Request Reports link on the Fabry Registry Reports, Publications and Communications page. Data requests are a way for Fabry Registry Participants to query the database to answer specific questions. All data requests are completed using de-identified patient data, and the information is frequently used by Registry physicians to help assist in clinical decision-making and/or for publication. A sample Data Request Form is included in Appendix 5. Patient Case Reports are individualized patient clinical outcomes assessment reports that enable patients physicians, nurses, and genetic counselors to monitor changes in patients disease progression. The reports graphically summarize the changes in clinical parameters over time. A sample of the type of data that is reported in a Patient Case Report is included in Appendix 6. Individualized Patient Case Reports can be accessed by physicians only after logging into the secure area of fabryregistry.com. The Fabry Registry e-newsletter can be accessed by clicking the Fabry Registry Newsletter link on the Fabry Registry Reports, Publications and Communications page. These periodic e-newsletters are ed to Fabry Registry participating physicians and health care advocates to communicate key updates and share key findings in the registry. Disease Severity Scoring System (DS-3) The guidelines proposed by Eng et al. (Genet Med, Appendix 4) for the evaluation and management of patients with Fabry disease represent an important step towards developing a practice standard for the management of Fabry disease. In addition, a group of physicians, listed in Table 7 below many of whom already participate in the Fabry Registry is currently developing a detailed diseaseseverity scoring system (DS-3) for Fabry disease. The DS-3 aims to create an evidence-based classification system for Fabry disease which may allow clinicians to form accurate expectations for disease progression and response to therapy in individual patients. In addition, the DS-3 may allow for a more systematic description of disease progression and response to therapy over time. The DS-3 working group met in Berlin in April, This working group, along with an expanded group of international experts, has completed a series of Delphi questionnaires to determine which parameters and methods of assessment are most appropriate to include in the DS-3. In October, 2006, the DS-3 working group held a second meeting at the 7th European Fabry Roundtable in Barcelona to further refine the domains of the draft DS-3. In 2007, the draft will be qualified using a case series technique and then validated using Fabry Registry data. This instrument will be validated and integrated into the Fabry Registry in the latter half of 2007 and into early Table 7 Members of the Fabry Registry DS-3 Working Group Member Affiliation Location Dr. E. Gianinni Cincinnati Children s Hospital Medical Center Cincinnati, Ohio, US Prof. Dr. M. Beck University of Mainz Mainz, Germany Dr. D. Bichet Hôpital du Sacré-Coeur de Montréal Montréal, Canada Dr. R. Brady National Institute of Neurological Disorders and Stroke Bethesda, Maryland, US Dr. J. Clarke Hospital for Sick Children Toronto, Canada Dr. D. P. Germain Hôpital Européen Georges Pompidou Paris, France Prof. Dr. M. Hilz University of Erlangen - Nuremberg Erlangen, Germany Prof. Dr. A. Linhart General Teaching Hospital Prague, Czech Republic Dr. E. Mengel University of Mainz Mainz, Germany Dr. A. Mehta Royal Free Hospital London, United Kingdom Dr. J. Strotmann University Hospital Würzburg, Germany Dr. S. Waldek Hope Hospital Manchester, United Kingdom Prof. Dr. C. Wanner Medizinische Universitätsklinik Würzburg, Germany Dr. D. Warnock University of Alabama at Birmingham Birmingham, Alabama, US Dr. M. West Queen Elizabeth II Hospital Halifax, Canada 12

15 Summary As of December 2006, the Fabry Registry has accrued clinical assessment and outcomes data from 2,235 patients. The major points summarized in RADAR 2007 are: Guidelines for the evaluation and management of Fabry disease were published in A comprehensive strategy for monitoring various organ systems in patients with Fabry disease provides medical specialists with much-needed standards for assessing progression and providing treatment. Data from the Fabry Registry clearly indicate that female patients experience considerable symptoms of Fabry disease, although these generally occur at a later age than in male patients. A substantial proportion of female patients suffer from clinical events, including renal disease and cardiac disease. In addition, more females report pain-related symptoms and a lower quality of life with increasing age. Both male and female pediatric patients exhibit a variety of symptoms of Fabry disease at a surprisingly early age. Female pediatric patients are much less likely to receive ERT than male pediatric patients. After 6 years of collecting data, the Fabry Registry has made significant progress towards reporting longitudinal outcomes. Detailed data describing the early and late complications of Fabry disease, as well as clinical events are now available in males and females. Increased amounts of data from pediatric patients are also becoming available for analysis. Goals for 2007 Longitudinal Data Collection The Fabry Registry will work to define cohorts of patients with longitudinal data in order to better allow for prospective analyses to be performed. This will require a focus on centers with access to patients who have been enrolled in the Fabry Registry for a substantial period of time and patients for whom assessments have been consistently performed and reported to the Registry. Collection of longitudinal data represents a key step towards improving characterization of disease progression and severity. Describe the Longitudinal Course of Disease Progression in Fabry Disease in Adult Males and Females Data describing the progression of Fabry disease will continue to be published in As discussed in this report, key areas that are being focused on include female and pediatric subpopulations of patients. The effect of Fabry disease on the renal, cardiovascular, and neurological systems will also be characterized in future publications. Participating physicians will present findings based on Fabry Registry data at various international meetings in Focus on Renal Data Renal manifestations of Fabry disease include progressive increases in proteinuria, which frequently lead to end stage renal disease. Evaluation of urinary protein and creatinine levels represent the mainstay for monitoring kidney function. With longer follow-up periods in sizeable patient cohorts, it may be possible to characterize renal disease progression over time, as well as patients response to ERT. Focus on Cardiac Data Better characterization of the role of cardiac dysfunction in Fabry disease is currently an area of considerable interest. The prevalence of cardiomyopathy in patients with Fabry disease has not been well established. A comprehensive cardiac medical history and continuous cardiac assessments, including the regular echocardiogram and electrocardiogram data submitted to the Fabry Registry, will help to identify critical cardiac risk factors for disease progression. Cardiac outcomes against major disease manifestations, such as left ventricular hypertrophy and arrhythmia, in patients who have or have not received ERT will be a primary area of focus for the Fabry Registry in Focus on Neurological Data Patients with Fabry disease frequently experience cerebrovascular complications, such as transient ischemic attack and stroke. Neurological manifestations also underlie many of the pain-related symptoms of Fabry disease, including acroparesthesia, heat and cold tolerance, and joint pain. Collection of higher quality neurological data in the Fabry Registry will enable physicians to better understand the progression of the neurological and cerebrovascular symptoms of Fabry disease. Advance the Research Priorities of the Registry Boards of Advisors In 2006, the Fabry Registry s Boards of Advisors proposed a research agenda for the Fabry Registry in 2007, including the following points: Identify disease progression rates and risk factors in major organ areas and patient cohorts Explore risk factors for CNS and cardiac disease progression Characterize ERT response in major organ areas and patient cohorts Determine if genotype can predict disease progression Identify early clinical events in children The Fabry Registry has started to advance each of these priorities by focusing on increasing the amount of longitudinal patient data, according to the recommended schedule of assessments. 13