P.K. Tandon, PhD J. Alexander Cole, DSc. Use of Registries for Clinical Evaluation of Rare Diseases

Transcription

1 Disclaimer: Presentation slides from the Rare Disease Workshop Series are posted by the Kakkis EveryLife Foundation, for educational purposes only. They are for use by drug development professionals and statisticians, and are not to be used to guide the prescribing or use of any of the drugs mentioned in the slides. To obtain information on a particular drug, refer to the drug labeling. Do not reproduce or distribute the slides (full set or any portion of) without the permission of the author.

2 P.K. Tandon, PhD J. Alexander Cole, DSc Use of Registries for Clinical Evaluation of Rare Diseases

3 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

4 Gaucher Disease: Disease Mechanism Deficiency of the enzyme acid ß-glucosidase Storage of glucosylceramide Progressive, multisystemic, multiorgan dysfunction

5 Pompe Disease: A Spectrum of Clinical Disease

6 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

7 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

8 Research Databases Disease Management LSD Registry Launch Date Patients Enrolled Physician Participants Countries Represented Gaucher , Fabry , MPS I Pompe Our Model Scientific direction from independent Board of Advisors Operational and financial support

9 Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Disease - Natural History 9

10 Life Expectancy in Type 1 Gaucher Disease Research Question: What is the life expectancy among patients with Type 1 Gaucher disease? 10

11 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

12 Life Expectancy in Type 1 Gaucher Disease Age Normal Type 1 GD Difference Remaining years of expected life Patients with Type 1 Gaucher Disease US Reference Popuation Current age (years) 12

13 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 , Spleen status Partial/total splenectomy Non-splenectomized Gender Male US Reference population 74.3 Type 1 Gaucher disease 52 6, Female US Reference population 79.9 Type 1 Gaucher disease 50 7,

14 Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Stroke Natural History MPS1 Disease - Natural History 14

15 Fabry Disease - Stroke Natural History Research Question: What is the natural history of stroke among patients with Fabry disease? 15

16 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

17 Fabry Disease - Stroke Natural History Strokes per 1000 person years of follow up 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 Fabry Females US Males US Females Fabry patients exhibited a markedly higher incidence of stroke than the general US population. * # 17

18 Fabry Disease - Stroke Natural History Percentage of Patients wtih History of TIA A. TIA B. Arrhythmia 37% 35% 6% 5% Stroke male No Stroke Stroke female No Stroke Percentage of Patietns with History of Arrythmias % % 10 0 Stroke No Stroke 27% Stroke 11% No Stroke Percentage of Patietns with History of Hypertension 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

19 Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Natural History 19

20 Examples of Understanding Natural Histories Life Expectancy in Type 1 Gaucher Disease Fabry Disease - Stroke Natural History MPS1 Disease - Natural History 20

21 MPS-1 Disease - Natural History Research Question: What are the baseline clinical characteristics of patients who enrolled in the MPS-1 Registry? 21

22 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

23 MPS-1 Disease - Natural History Proportion and mean ages of patients enrolled in the Registry by phenotype 23

24 MPS-1 Disease - Natural History Proportion of patients with MPS-1 disease manifestations by age at onset 24

25 Examples of Understanding Natural Histories Cerezyme (Gaucher) Dose-Response Cerezyme (Gaucher) Bone Density Outcome 25

26 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

27 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

28 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)

29 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

30 Examples of Understanding Natural Histories Cerezyme (Gaucher) Dose-Response Cerezyme (Gaucher) Bone Density Outcome 30

31 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

32 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

33 Cerezyme (Gaucher) Bone Mineral Density Bone mineral density z-scores were significantly lower than the reference population at baseline (yintercept = Z-score units, p<0.001) There were significant improvements over time (slope = 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 , , and Z- score units per year, respectively. The BMD of patients treated with ERT at 60 U/kg/2wk increased to within standard deviations of the mean of the reference population after ~8 yr. 33

34 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 Jan;22(1):119-26

35 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

36 Back-up Slides 36

37 Gaucher Timing of Treatment Initiation and Risk of AVN 37

38 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

39 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

40 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, <.0001 >2 years 172 1,653 10, (0.35, 0.68) Incidence rate difference between the two groups was 8.5 per 1,000 person years (95% CI 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?

41 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 , <.0001 No 117 2,106 11, (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

42 Multivariate Poisson Regression Model: Effects of all variables on AVN Incidence Rate Ratio <2 Years vs. >=2 Years Age < 20 vs. Age >= 20 Female vs. Male Before 1991 vs or Later Yes vs. No Before 1995 vs or Later 1995 to 1999 vs 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

43 Fabry Quality of Life Following Treatment Initiation 43

44 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

45 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

46 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 months of Fabrazyme treatment.

47 Where Clinical Trials are Most Feasible Common Homogeneous Heterogeneous Rare Acute Chronic

48 Where Patient Registries May Add Value Common Homogeneous Heterogeneous Chronic Diseases Diseases Heterogeneous Rare Acute Rare Diseases Chronic

49 Fabry Renal Natural History Research Question: What is the natural history of renal progression among patients with Fabry disease? 49

50 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

51 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

52 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)* < < Baseline egfr < Age at baseline egfr Averaged systolic blood pressure Averaged diastolic blood pressure 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.

53 Effect of Proteinuria on egfr Over Time in Patients with Longitudinal Renal Data Males Females egfr (ml/min/1.73m2) 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) 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 UP/Cr 0.8 to 1.5 (n=31) slope UP/Cr 1.5 to 7.3 (n=30) slope Time from Baseline (years) 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.

54 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