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Gregory M. Pastores 1 ; Jeffrey Szer 2 ; Milan Petakov 3 ; Tim Cox 4 ; Pilar Giraldo 5 ; Hanna Rosenbaum 6 ; Dominick Amato 7 ; Eugen Mengel 8 ; Raul Chertkoff.

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Presentation on theme: "Gregory M. Pastores 1 ; Jeffrey Szer 2 ; Milan Petakov 3 ; Tim Cox 4 ; Pilar Giraldo 5 ; Hanna Rosenbaum 6 ; Dominick Amato 7 ; Eugen Mengel 8 ; Raul Chertkoff."— Presentation transcript:

1 Gregory M. Pastores 1 ; Jeffrey Szer 2 ; Milan Petakov 3 ; Tim Cox 4 ; Pilar Giraldo 5 ; Hanna Rosenbaum 6 ; Dominick Amato 7 ; Eugen Mengel 8 ; Raul Chertkoff 9 ; Einat Almon-Brill 9 ; Ari Zimran th EWGGD Meeting Paris June 2012

2 Disclosure GM Pastores\NYU Neurogenetics is the recipient of research grants\support from Actelion, Amicus\GSK, Biomarin, Genzyme\Sanofi, Protalix\Pfizer, Shire HGT, Synegeva and Ultragenics; pharmaceutical\biotechnology companies engaged in drug development programs for the Lysosomal storage disorders

3 Taliglucerase alfa* Plant cell expressed human recombinant Glucocerebrosidase Produced in disposable bioreactors Expression process is free of any mammalian components As of May 1,2012, approved by the US Food and Drug Administration as an ERT for Gaucher disease * Y. Shaaltiel el al;, Plant Biotechnology J., September 2007, volume 5, Issue5 * D. Aviezer et al;,1 March 2009 Volume 4, Issue 3

4 A Phase 3 Multicenter, Open-label, Switchover Trial to Assess the Safety and Efficacy of taliglucerase alfa in Patients with Gaucher Disease Treated with Imiglucerase (Cerezyme®) Enzyme Replacement Therapy PB

5  Assess the safety and efficacy of taliglucerase alfa in patients with Gaucher disease who are currently being treated with imiglucerase enzyme replacement therapy (ERT). Objective

6 Sites InvestigatorInstitution Ari ZimranShaare Zedek Medical Center, Jerusalem, Israel Dominick AmatoMount Sinai Hospital, Toronto, Canada Eugen MengelUniversity Mainz, Mainz, Germany Gregory PastoresNYU School of Medicine, New York USA Hanna RosenbaumRambam Medical center, Haifa, Israel Jeffrey SzerRoyal Melbourne Hospital, Australia Milan PetakovClinical Center of Serbia, Belgrade, Serbia Paul FernhoffEmory University School of Medicine, GA USA Pilar GiraldoHospital Universitario Miguel Servet, Zaragoza, Spain Tim CoxAddenbrooke’s Hospital, Cambridge, UK

7 Design and Patient Population PB Switch Over Screening Clinical stable disease: ≥ 2 years on imiglucerase ≥ 6 months same regimen Stability Evaluation Period Based on 6 evaluations of platelets & hemoglobin 9 Months Treatment Extension Follow Up PB Dec First patient enrolled Dec protocol amended to include children per EMA May 1st 2011 Last adult patient last visit (n=25) May 1st 2011 Last adult patient last visit (n=25) Jul. 2009, due to imiglucerase shortage protocol was amended; -to recruit 30 patients -allow the use of 6 historical hematological parameters for stability evaluation Jul. 2009, due to imiglucerase shortage protocol was amended; -to recruit 30 patients -allow the use of 6 historical hematological parameters for stability evaluation Pediatric cohort (n=5) ongoing 2 completed Pediatric cohort (n=5) ongoing 2 completed 26 adult patients recruited 1 patient dropped out (AE) 26 adult patients recruited 1 patient dropped out (AE)

8 Disease Stability Evaluation“Clinically Relevant Deterioration” Criteria  Hematological Stability Evaluation Parameters:  12 weeks while on imiglucerase or  6 historical values for those patients impacted by ERT shortage  No major surgery in the last year  No blood transfusion or major bleeding episode in the last year  No acute avascular necrosis event in the last year  No evidence of spleen or liver increasing enlargement  Hematological Stability Evaluation Parameters:  12 weeks while on imiglucerase or  6 historical values for those patients impacted by ERT shortage  No major surgery in the last year  No blood transfusion or major bleeding episode in the last year  No acute avascular necrosis event in the last year  No evidence of spleen or liver increasing enlargement  Protocol Defined Criteria  Sustained reduction of platelet count:  A decrease of >20% from the mean value of the Stability Evaluation Period values of ≤120,000 or a decrease of >40% from the mean value of the Stability Evaluation Period values of >120,000  Sustained reduction of hemoglobin:  A decrease of >20% from the mean value of the Stability Evaluation Period  Increase in spleen volume:  A 20% increase in spleen volume by MRI from Baseline to Month 9  Increase in liver volume:  A10% increase in liver volume by MRI from Baseline to Month 9  Protocol Defined Criteria  Sustained reduction of platelet count:  A decrease of >20% from the mean value of the Stability Evaluation Period values of ≤120,000 or a decrease of >40% from the mean value of the Stability Evaluation Period values of >120,000  Sustained reduction of hemoglobin:  A decrease of >20% from the mean value of the Stability Evaluation Period  Increase in spleen volume:  A 20% increase in spleen volume by MRI from Baseline to Month 9  Increase in liver volume:  A10% increase in liver volume by MRI from Baseline to Month 9

9 Platelet Count Stability Hemoglobin Stability A decrease of >20% from the mean value of the Stability Evaluation Period values of ≤120,000 or A decrease of >40% from the mean value of the Stability Evaluation Period values of >120, A decrease of >20% from the mean value of the Stability Evaluation Period

10 Demographic and Baseline Characteristics (n=26) Disease Parameter Mean ± SD (range) Spleen volume* (MN), (n=20) 6 ± 4.8 (0.1 – 20.5) Liver volume* (MN) (n=23) 1 ± 0.2 (0.7 – 1.6) Hemoglobin (g/dL)13.4 ± 1.68 (10.0 – 16.0) Platelets (/mm 3 )154,120 ± 86,550 (39,000 – 328,000) Chitotriosidase (nmol/mL.h) ± ( ,528) MN – Multiple of Normal † DNA sequencing pending on 9 patients *Organ volumes by MRI, except in 2 patients by US, patient choice, not included in analytic set Patient Characteristic Mean ± SD (range) Age47.6 ± 12.9 (18 – 66) Male Female 14 (53.2%) 12 (46.2%) Ashkenazi Jewish non-Jewish 14 (53.8%) 12 (46.2%) Splenectomized3 N370S homozygous other genotype † 8 11

11 Dose Distribution ≥ 30U/kg (n=9) >15U/kg & < 30U/kg (n=8) ≤ 15U/kg (n=8) Taliglucerase dose = prior Imiglucerase dose

12 Hematological Measurements (n=25): Platelet Count (mean)Hemoglobin (mean) Platelet Count (by dose) Hemoglobin (by dose)

13 Organ Volumes Spleen Volume (by dose) Liver Volume (by dose) Spleen Volume (n=20) Liver Volume (n=23)

14 Chitotriosidase Activity (n=25) Mean Value Mean Value by Dose

15 Disease Stability Outcome  Protocol defined stability and deterioration based on hematological, organ volume measurements and clinical presentation  Overall, disease parameters remained stable following switch to taliglucerase alfa  Three patients each had a change in only 1of 4 outcome measures per protocol; all continue to receive taliglucerase alfa Patient ID Dose Spleen volume change (MN) Liver volume change (MN) Platelets count change Hb changeChitotrio sidase change U/kg5.3 to to 1.076,000 to 68, to % U/kg 4.5 to to ,000 to 107, to % U/kg splenectomized0.8 to ,000, 113,800* 14.7 to % *Patient ‘s dose was doubled (week 24 visit onwards), platelet count 170,000 (week 38)

16 Safety: Adverse Events Relatedness # of AEs (# of patients) AEs % of total Non-treatment related115 (23)82.4% Treatment related24 (10)17.6 % Severity # of AEs (# of patients) AEs % of total Adverse events139 (25) Mild or moderate136 (25)97.8% Severe or very severe* 3 (2)2.2% * All 3 severe AEs (hematuria and renal stone; prolapsed rectum, bladder and cervix) reported as not treatment related  Serious Adverse Events  3 SAEs not related to treatment, resolved after intervention (epistaxis; hematuria and renal stone; prolapsed rectum, bladder and cervix - all of which required hospitalization)

17 Safety: Treatment Related Adverse Events  17.6 % of the AEs were reported as related (definitely or possibly)  All AEs were mild or moderate in severity  * One patient withdraw after experiencing hypersensitivity (urticaria, rash) during the first infusion  Negative for IgG and IgE antibodies  Premedication with subsequent infusions refused  No emergent safety concerns from last report at WORLD 2011 AEs # Patients (%)# events Headache2 (7.7%)2 Infusion-related reaction (headache, fatigue, weakness after infusion) 2 (7.7%)3 Hypersensitivity*1 (3.8%)1 Flushing1 (3.8%)3 Weight increase1 (3.8%)1 Asthenia1 (3.8%)1 ALT increase1 (3.8%)1 GGT increase1 (3.8%)1 Pruritus1 (3.8%)9 Lethargy1 (3.8%)1 Diarrhea1 (3.8%)1

18 Neutralizing Antibodies & Clinical Outcome Patient ID Neutralizing activity IgG antibodies IgESpleen volume change Liver volume change Platelets count change Hb change Chitotriosidase change in vitro assayCell-based assay posneg -21% MN -1% MN 3% 117K-121K 0% % 4374*-6909  One patient (20-220) receiving 28 U/kg was positive for neutralizing activity in an in vitro assay, but negative in a cell based assay  At 9 months time point, hemoglobin, platelet, liver and spleen were stable or improved except for the increase in chitotriosidase; the patient continues to receive treatment  3 unrelated AEs:  Facial discomfort and facial flushing  Upper respiratory infection

19 Summary – Switched Patients Efficacy  Overall, patients remained stable with regards to the main disease parameters (hemoglobin, platelet count, spleen and liver volume and chitotriosidase) after switching from imiglucerase to taliglucerase alfa Safety  All AEs were mild or moderate and transient in nature, none of the patients are receiving premedication  All patients continue to receive taliglucerase except the one patient with hypersensitivity who declined to continue infusions with premedication This study demonstrates that taliglucerase alfa has the potential to be an alternative treatment for Gaucher disease

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