Fabry.Cong.Balcanic.2009

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Fabry.Cong.Balcanic.2009

  1. 1. Fabry disease: results of the enzyme replacement therapy with agalsidase beta C. SPÂNU, C. DRUGAN, C.NIŢĂ, S.SPÂNU, C. CRĂCIUN, M. RADU,V.TODEA, M. GHERMAN- CĂPRIOARĂ Cluj, Romania
  2. 2. Lysosomal storage disorders and enzyme replacement therapy (ERT) Disease Enzyme deficiency ERT available Producer Gaucher type 1, 3 Acid β-glucosidase Imiglucerase Genzyme Corp. (Cerezyme®) Fabry α-Galactosidase A Agalsidase alfa Shire Pharm. (Replagal®) Agalsidase beta Genzyme Corp. (Fabrazyme®) MPS I α-L Iduronidase Laronidase Genzyme Corp. (Aldurazyme®) Pompe Acid α-glucosidase Alglucosidase alfa Genzyme Corp. (MyozymeTM) MPS VI Arylsulfatase B Galsulfase BioMarin Pharm.
  3. 3. ERT for Fabry Disease: Characteristics of Drugs Agalsidase alfa Agalsidase beta (Replagal®) (Fabrazyme®) Mode of production Gene activated human α-GalA Recombinant human α-GalA expressed in a continuous human expressed in a continuous CHO cell cell line line Structure Homodimer consisting of two Homodimer consisting of two ~50kDa subunits. ~50kDa subunits. Aa sequence is identical to the Aa sequence is identical to the endogenous human enzyme endogenous human enzyme Sialic acid:galactose 0.56 0.88 Mannose-6-phosphate 1.8 ± 0.0 mol/mol protein 3.1 ± 0.1 mol/mol protein Specific activity 3.4 - 3.9 nmol/kg/h 3.8 nmol/kg/h Provided as Sterile isotonic solution Lyophilised powder Recommended dose 0.2 mg/kg bw 1 mg/kg bw
  4. 4. Biosynthesis, secretion and recapture of α-GalA Endoplasmic reticulum Extracellular secretion of-GalA •Α-GalA synthesis & glycosylation •M6PR synthesis Golgi apparatus Α-GalA mannose residues phosphorylation α-GalA + M6PR recapture from Endosome extracellular Cell membrane fluid α-GalA dissociation from M6PR M6PR Lysosome Germain DP, Expert Opin Investig Drug, 2002
  5. 5. ERT for Fabry disease : main clinical trials • Agalsidase α (Replagal) Schiffmann et al, JAMA, 2001 (randomized placebo-controlled ): * reduction of neuropathic pain * stabilization of renal function and improvement of renal histology after 24 weeks; • Agalsidase β (Fabrazyme ) Eng et al, N Engl J Med, 2001 (randomized placebo-controlled ): * resolution of the microvascular endothelial deposits of GL-3 from kidney, heart and skin after 20 weeks; * persistence of deposits in podocytes and distal tubular epithelium; Wilcox et al, Am J Hum Genet, 2004 (open-label extension trial): *stable renal function at 36 mo in pts with baseline normal GFR; *progression to renal insufficiency in pts with baseline impaired GFR and glomerulosclerosis≥ 50% Benikazemi et al, Ann Intern Med, 2007 (randomized placebo-controlled ): * slowed progression to renal, cardiac, and cerebrovascular complications and death in pts with advanced Fabry disease
  6. 6. Current Guidelines for ERT in Fabry Disease Patients ( Eng CM et al, Genet Med, 2006) Fabry population Guideline for instituting ERT Adult males (>16y) At time of diagnosis of Fabry disease Pediatric males At time of development of significant symptoms or, if asymptomatic, consider at 10- 13 yr Females (all ages) Monitor; institute if significant symptoms or evidence of progression of organ involvement
  7. 7. Patients and methods • 15 pts, 7 M ( 25 -46 yr) and 8 F ( 8-69 yr), from 3 different families - 3 pts - index cases, all males - 12 pts - dx by active family screening • Routine clinical, laboratory and imagistic exam • Clinical pedigree analysis • Plasma and leukocytes α-Gal activity (14 pts) • DNA analysis ( 11 pts from 2 families) • Renal biopsy (4 pts, TEM in 2 pts) • Enzyme replacement therapy ( 7 pts): agalsidase β ( Fabrazyme® ) 1 mg/Kg biweekly
  8. 8. Clinical and biochemical findings in 7 males and 8 females with Fabry disease Males Females Age (yrs) 25-47 8-69 α-Gal activity plasma ↓↓↓ 7/7 ↓ 4/8 leukocytes ↓↓↓ 7/7 ↓ 3/8 Proteinuria >0.15g/24hr 5/7 (0.8-3.8) 2/6 (0.17-1.3) ↓GFR (ml/min) 7/7 (22.2-89.8) 3/6 (34.3-66.5) Acroparesthesia 6/7 1/8 Angiokeratomas 4/7 0/8 Edema 3/7 0/8 Hypertension 3/7 3/8 LV hypertrophy 5/7 3/6 Hearing loss 4/7 1/8 Cornea verticillata 4/7 1/6
  9. 9. Results of ERT in 7 Fabry disease patients • Patients: 5 males (25, 40, 43, 46 and 47 yrs of age) 2 females (45 and 69 yrs of age) (1 pair donor-recipient of renal transplantation) • Treatment protocol: agalsidase β (FABRAZYME®) 1 mg/kg biweekly • Follow-up: > 36 mo - 3 pts > 24 mo - 2 pts < 6 mo - 2 pt (stop, adverse effects- 1pt)
  10. 10. Evaluation: baseline and after every 6 months or any event 1. General clinical exam 2. Ophtalmology, neurology, electro and echocardiography 3. Biochemistry: proteinuria / 24 hr, s.creatinine, GFR 4. Questionaries that evaluated general health: - brief inventory pain - mos-36 short-form health survey
  11. 11. Baseline and follow-up serum creatinine in 5 Fabry pts treated with agalsidase β 7 6 creatinina serica (mg/dl) 5 MP 4 MI BA 3 CO 2 CM 1 0 0 luni 6 luni 12 luni 18 luni 24 luni 30 luni 36 luni
  12. 12. Baseline and follow-up GFR in 5 Fabry pts treated with agalsidase β 140 120 100 RFG (ml/min) 80 MP MI 60 BA 40 CO CM 20 0 0 luni 6 luni 12 luni 18 luni 24 luni 30 luni 36 luni
  13. 13. Baseline and follow-up proteinuria in 5 Fabry pts treated with agalsidase β 1.2 1 proteinurie (g/24 ore) 0.8 MP MI 0.6 BA 0.4 CO CM 0.2 0 0 luni 6 luni 12 luni 18 luni 24 luni 30 luni 36 luni
  14. 14. Effects of agalsidase β in 5 Fabry pts - non-renal manifestations- • Heart: ↓ LVH • Nervous system: - neuropathic pain : improvement in 3/3 pts - hearing loss: improvement in 2/3 pts aggravation in 1 pt • Skin: improvement (1 pt) or disappearance (1 pt) of angiokeratomas • Quality of life: improvement of general health status 4/5 pts
  15. 15. Regression of angiokeratomas after 3 yr of treatment with agalsidase beta (M, 46 yr)
  16. 16. Conclusions • Most of the studied patients have had advanced disease at the time of ERT initiation • No major events related to disease or therapy were noted during treatment period in the majority of patients • Renal and extrarenal manifestations in our Fabry patients were favorably influenced by ERT with agalsidase beta • ERT with agalsidase β is more efficient in early stages of Fabry disease
  17. 17. Acknowledgments Genzyme Corporation : providing logistical support and Fabrazyme for treatment of our patients

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