Gaucher Clinic 2007: Clinical trials

Transcription

1 Gaucher Clinic 2007: Clinical trials ERT: TKT032 (Shire) ERT: TKT034 (Shire) ERT: PB (Protalix) SRT: GENZ (Genzyme) Chaperones: AT2101 (Amicus)

2 Conventional Recombinant DNA Approach Evolution of Protein Production Human Cell Gene-Activation Approach Hamster Cell Human Cell Human Cell Gene-Activated human Glucocerebrosidase (GA-GCB) GA-GCB is produced by proprietary Gene-Activation technology in a human cell line GA-GCB has terminal mannose residues which target the enzyme to the macrophage, the primary target cell in Gaucher disease Primary amino acid sequence of GA-GCB is identical to natural human enzyme commercial C recombinant enzyme product differs from natural human enzyme (GA-GCB) by one amino acid; AA495 GA-GCB has specific activity of approximately 40 U/mg protein

3 Phase I/II + Extension Study : Design and bjectives An open-label study in 12 patients with type 1 Gaucher disease: Escalating dose to 60 U/kg in first three patients 60 U/kg starting dose for remaining 9 patients Every other week dosing regimen for 9 months Study objectives: Evaluate safety of GA-GCB Evaluate pharmacokinetics Evaluate effects on selected clinical parameters An pen-label Extension study was available to all patients who had completed the Phase I/II study After Month 12 (9 months Phase I/II and 3 months on Extension), each patient was eligible for a step-wise dose reduction if they met 2 out of 4 criteria based on 1 year therapeutic goals for ERT (Based on Seminars in Hematology, Pastores, et al, 2004) From 60U/kg to 45U/kg for 3 months Then from 45 U/kg to 30U/kg after ~3 months Patients continue to receive 30U/kg of GA-GCB Conclusions Safety GA-GCB was well tolerated at a 60U/kg, 45U/kg, and 30U/kg dose every other week No drug related serious adverse events No patient developed antibodies to GA-GCB up to 24 months Clinical Activity 24 months from baseline Hemoglobin: Mean increase of 2.44g/dL; Mean percent increase of 21.5% Platelet: Mean increase of 69.9x10 3 /mm 3 ; Mean percent increase of 119.8% Spleen volume: Mean percent reduction as measured by MRI of 70.9% Liver volume: Mean percent reduction as measured by MRI of 26.9% Biomarkers: Chitotriosidase: Mean percent reduction of 79.7% CCL18: Mean percent reduction of 51.2% Phase III program has begun (2007)

4 ERT: TKT032 (Shire) A multi-center, randomized, double-blind, two-dose study of GA-GCB enzyme replacement therapy in patients with type I Gaucher Disease IV, every other week, 60 or 45 un/kgbw End point: improvement in hemoglobin Ethical issue: children age > 2 years ERT: TKT034 (Shire) Multi center, switch-over trial IV once every 2 weeks Dose as administered in the past 6 months (15 to 60 u/kgbw) End points: reduction in liver volume and improvement in blood counts Unique ethical issue: switch Ethical issue: switch from an approved drug to a biosimilar ; lack of deterioration

5 of Phase I SUMMARY F FASE I prgcd (Protalix) prgcd administered up to the highest dosage planned for Phase III clinical trial dose is: Safe Non immunogenic Dose-related increase in Cmax and AUC prgcd in human serum is active following IV infusion ERT: PB (Protalix) Multi-center Double-blind, parallel group, dose-ranging 9 months Ethical issue: Bio-similar ; plant-derived

6 SRT: Clinical trials with miglustat (Zavesca) 001, 003, 004 & 005 Proof of concept Efficacy Dose response N CH 2 H Side effects (GI, PN, BW) CH 3 Approval by EMEA & FDA Post marketing surveillance EWGGD, Prague 2002 J Inherit Metab Dis, 2003;26: J Inherit Metab Dis, 2004;27:1-10. Clin Ther. 2005;27(8): SRT: GENZ (Genzyme) Phase II Multi center trial Two tablets a day, 12 months Intensive monitoring End points: reduction in spleen volume and improvement in blood counts Unique ethical issue: liver biopsy

7 Lysosomal Storage Diseases ften Result From the Inability of Degrading Enzymes to Fold Properly in the ER HN CH 2 (CH 2 ) n CH 3 CH 2 (CH 2 ) 11 CH 3 glucocerebrosidase glucose H GC HN CH 2 (CH 2 ) n CH 3 glucosylceramide CH 2 (CH 2 ) 11 CH 3 H ceramide Gaucher Disease Results When Lysosomal GC Activity Drops Below a Threshold Value ( 10 %)

8 Farmacological Chaperone Technology Lysosomal Storage Pharmacological Chaperone Endoplasmic Reticulum Golgi Apparatus Lysosome Substrate Reduction Reduced Cellular Stress and Inflammation Enhanced Trafficking Misfolded Protein Substrate Accumulation Protein-Chaperone Complex

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