Fabry disease: results of the enzyme
replacement therapy with agalsidase
                     beta


C. SPÂNU, C. DRUGAN, ...
Lysosomal storage disorders and
          enzyme replacement therapy (ERT)
Disease             Enzyme deficiency    ERT av...
ERT for Fabry Disease: Characteristics of Drugs

                        Agalsidase alfa                   Agalsidase beta...
Biosynthesis, secretion and recapture
              of α-GalA
 Endoplasmic reticulum                 Extracellular secreti...
ERT for Fabry disease : main clinical trials

•   Agalsidase α (Replagal)
     Schiffmann et al, JAMA, 2001 (randomized pl...
Current Guidelines for ERT in Fabry Disease
                  Patients
                  ( Eng CM et al, Genet Med, 2006)
...
Patients and methods
• 15 pts, 7 M ( 25 -46 yr) and 8 F ( 8-69 yr), from 3
  different families
     - 3 pts - index cases...
Clinical and biochemical findings in 7 males
      and 8 females with Fabry disease
                                 Males...
Results of ERT in 7 Fabry disease
                   patients
•   Patients: 5 males (25, 40, 43, 46 and 47 yrs of age)
   ...
Evaluation: baseline and after every 6
        months or any event

1. General clinical exam

2. Ophtalmology, neurology, ...
Baseline and follow-up serum creatinine in 5
   Fabry pts treated with agalsidase β

                            7

      ...
Baseline and follow-up GFR in 5 Fabry pts
        treated with agalsidase β
               140

               120

      ...
Baseline and follow-up proteinuria in 5 Fabry
       pts treated with agalsidase β


                          1.2


     ...
Effects of agalsidase β in 5 Fabry pts
              - non-renal manifestations-

• Heart: ↓ LVH

• Nervous system:
   - n...
Regression of angiokeratomas after 3 yr
   of treatment with agalsidase beta
                (M, 46 yr)
Conclusions

• Most of the studied patients have had advanced
  disease at the time of ERT initiation

• No major events r...
Acknowledgments


Genzyme Corporation :
   providing logistical support and
   Fabrazyme for treatment of our patients
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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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