EWGGD 2012 1882

Phenotype Spectrum of Hematological and Visceral Disease in Type 3 Gaucher Disease – Genotype Correlations and Response to Imiglucerase Therapy in 325 Patients from the ICGG Registry Pramod Mistry Department of Pediatrics and Medicine. Yale University School of Medicine, New Haven, CT, USA On behalf of : Edwin H. Kolodny1, Anna Tylki-Szymanska2, Nadia Belmatoug3, Juan F. Cabello4, Ashok Vellodi5, J. Alexander Cole6, Amal El-Beshlawy7, Gregory Grabowski8 1New York University School of Medicine, New York, USA; 2Children’s Memorial Health Institute, Warsaw, Poland; 3Centre de Référence des Maladies Lysosomales Assistance Publique-Hôpitaux de Paris Service de Médecine Interne Hôpital, Beaujon, France; 4Laboratorio de Genetica y Enfermedades Metabolicas. INTA, Universidad,de Chile, Santiago, Chile; 5Great Ormond Street Childrens' Hospital NHS Trust, London, UK; 6Biostatistics/Epidemiology, Genzyme, a Sanofi company, Cambridge, MA, USA; 7Pediatric Hospital of Cairo University, Cairo, Egypt; 8Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Background In Gaucher disease, the phenotype spectrum and response to imiglucerase therapy have been characterized in detail for the non- neuronopathic Type 1 Gaucher disease in many large studies. Fewer analyses have focused on long-term outcomes in Type 3 Gaucher disease.

Type 3 Gaucher disease Onset Typical neurological manifestations Before 2 years or later Types 3a, 3b and 3c Typical neurological manifestations Oculomotor apraxia Supranuclear ophthalmoplegia Extrapyramidal features Myoclonic or generalized seizures Cerebellar ataxia Developmental delay

Neuronopathic L444P GBA Mutation – Likely the most common disease mutation world-wide * *

International Collaborative Gaucher Group (ICGG) Gaucher Registry An observational database of phenotype, genotype and treatment status of patients with Gaucher disease Supported by Genzyme Sanofi, governed by international physician experts in Gaucher disease. The largest database of GD with >6,000 GD patients from 60 countries.

Objectives and Analysis Plan What are the correlates of baseline hematological, growth, and visceral organ status in GD3? Set of multivariate regressions to characterize baseline status as a function of covariates What are the predictors of hematological, growth, and visceral organ outcomes in GD3? Second set of multivariate regressions to characterize outcomes as a function of covariates

Methods: Study Population All patients <18 years of age at the start of therapy Enrolled in the ICGG Gaucher Registry as of July 2010 Diagnosis of type 3 Gaucher disease Subsets of patients with baseline data Anemia Thrombocytopenia Splenomegaly Hepatomegaly Height z-score ≤-1

Statistical Analysis Statistical Analysis Non-linear mixed effects models Alpha-level of 0.05 for statistical significance SAS 9.1 (SAS Institute, Cary, NC) 9

Results

Patient Characteristics (N=344) ‡Diagnosed prenatally. 11

Patient Characteristics *13 patients are D409H/D409H 70% of disease alleles are L444P and 2.5% D409H 12

After 4 years of imiglucerase L444P Homozygous GD3 Effects of ERT This is the same individual. This is what we have to think about when we think someone cannot be treated. At Diagnosis After 4 years of imiglucerase Courtesy of Dr Amal El-Beshlawy, University of Cairo

Age at first infusion (n=366)

Scatter plot of age at first infusion x baseline hemoglobin (g/dl) (n=283)

Scatter plot of age at first infusion x baseline platelet count (x103/mm3) (n=287)

Baseline Hemoglobin: Linear Regression, n=247 Estimate (Standard error) p-value Intercept 9.74( 0.52) <.0001 Covariates Ever splenectomized 0.10( 0.38) 0.802 Age categories at first infusion >0 - < 2 referent >2 - < 10 0.25( 0.38) 0.5056 >10 - < 18 1.45( 0.58) 0.0136 Age categories at diagnosis >2 0.02( 0.37) 0.9604 Genotype categories L444P/L444P L444P/OTHER 0.52( 0.38) 0.1741 OTHER/OTHER 0.68( 0.35) 0.0548

Estimate (Standard error) Baseline Platelet Count: Linear Regression (non-splenectomized patients), n=213 Estimate (Standard error) p-value Intercept 151.4(33.55) <.0001 Covariates Age categories at first infusion >0 - < 2 referent >2 - < 10 -39.3(21.75) 0.0725 >10 - < 18 -40.5(36.88) 0.2739 Age categories at diagnosis >2 -13.5(22.51) 0.5492 Genotype categories L444P/L444P L444P/OTHER 15.14(21.85) 0.4894 OTHER/OTHER 24.95(19.71) 0.2076

Baseline Liver Volume (MN): Linear Regression, n=101 Estimate (Standard error) p-value Intercept 2.95( 0.40) <.0001 Covariates Ever splenectomized -0.13( 0.29) 0.6689 Age categories at first infusion >0 - < 2 referent >2 - < 10 -0.07( 0.26) 0.8048 >10 - < 18 -0.48( 0.48) 0.3217 Age categories at diagnosis >2 -0.14( 0.25) 0.577 Genotype categories L444P/L444P L444P/OTHER -0.09( 0.31) 0.7684 OTHER/OTHER -0.61( 0.28) 0.0339

Estimate (Standard error) Baseline Spleen Volume (MN): Linear Regression (non-splenectomized patients), n=101 Estimate (Standard error) p-value Intercept 69.81( 7.42) <.0001 Covariates Age categories at first infusion >0 - < 2 referent >2 - < 10 -1.84( 4.36) 0.6743 >10 - < 18 -3.77(10.51) 0.7213 Age categories at diagnosis >2 -0.62( 4.33) 0.887 Genotype categories L444P/L444P L444P/OTHER -14.1( 5.05) 0.0068 OTHER/OTHER -14.4( 4.51) 0.0022

Baseline Height Z-Score: Linear Regression, n=215 Estimate (Standard error) p-value Intercept -1.39( 0.48) 0.0045 Covariates Ever splenectomized -0.56( 0.34) 0.1023 Age categories at first infusion >0 - < 2 referent >2 - < 10 -0.76( 0.36) 0.0363 >10 - < 18 -1.27( 0.57) 0.0266 Age categories at diagnosis >2 0.23( 0.35) 0.5209 Genotype categories L444P/L444P L444P/OTHER 0.83( 0.38) 0.0285 OTHER/OTHER 0.79( 0.32) 0.0155

Hemoglobin During Follow-Up 20.00 15.00 10.00 Hemoglobin (g/dL) 5.00 0.00 1 2 3 4 5 Years Following Initiation of Therapy N 235 209 180 159 141 130 Median 9.40 10.40 11.40 11.60 11.80 11.90 Mean 10.35 11.33 11.44 11.66 11.75

Platelet Count During Follow-Up 1000.00 800.00 600.00 Platelet Count (X103/mm3) 400.00 200.00 0.00 1 2 3 4 5 Years Following Initiation of Therapy N 203 181 154 133 115 107 Median 101.0 137.0 195.0 208.0 212.0 203.0 Mean 128.3 159.4 228.8 228.1 218.1 210.6

Liver Volume During Follow-Up 8 6 4 Liver Volume in Multiples of Normal 2 1 2 3 4 5 Years Following Initiation of Therapy N 85 69 63 54 42 36 Median 2.19 1.72 1.54 1.39 1.28 1.18 Mean 2.35 1.86 1.57 1.43 1.32 1.26

Spleen Volume During Follow-Up Among Non-Splenectomized Patients 100 75 50 Spleen Volume in Multiples of Normal 25 1 2 3 4 5 Years Following Initiation of Therapy N 87 70 65 55 45 42 Median 37.49 31.60 24.01 20.73 16.78 14.33 Mean 38.17 29.16 24.46 19.04 16.06 14.46

Height Z-Score During Follow-Up 2.5 -2.5 Height Z-Score -5.0 -7.5 -10.0 1 2 3 4 5 Years Following Initiation of Therapy N 197 174 148 135 120 114 Median -2.04 -2.40 -2.02 -1.63 -1.60 -1.45 Mean -2.22 -2.26 -2.01 -1.50 -1.41

Cause of Death 54 out of 325 (17%) patients died and had reported causes of death. The most frequently cited causes of death were: Progressive neurological disease Infections Cardiac complications Malignancy

Kaplan-Meier Analysis 100 Upper 95% CL 80 Survival 60 Lower 95% CL Proportion of Patients Alive 40 20 Number of Patients: 325: Number of Deaths: 54 (17%) 5 10 15 20 Years Following Initiation of Therapy Patients at Risk n = 325 n = 195 n = 90 n = 35 n = 0

Conclusions There is early onset of prominent visceral and hematologic disease in patients with GD3 before the age of 6 years. Moreover, these patients exhibit striking growth failure. These effects are rapidly reversed by alglucerase/ imiglucerase treatment, with improvement within 5 years of treatment. This cohort represents the largest cohort of children with type 3 Gaucher disease ever described to delineate the phenotypic spectrum and its response to alglucerase/ imiglucerase therapy.