gaucher disease: overview and goals for current therapy ozlem goker-alpan, md lysosomal storage...
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Gaucher Disease: Overview and goals for current therapy
Ozlem Goker-Alpan, MDLysosomal Storage Disorders Research and Treatment
Unit, CFCT
Fairfax, VA
Gaucher Disease: A Lysosomal Storage Disorder
Gaucher Disease:
• Most common lysosomal storage disorder
• Autosomal recessive
• Genetic defect on chromosome 1
• Enzyme deficiency
• Reticuloendothelial system
• Progressive, multisystemic, multiorgan dysfunction
1. Pastores GM, et al. Semin Hematol. 2004;41 (suppl 5): 4–14.2. Ginns EI, et al. Proc Natl Acad Sci USA. 1985;82:7101–7105.
Philippe Gaucher1854 – 1918
Normal cell
Lysosome
Cell
Glucosylceramide
Enzyme
Nucleus
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Glycosphingolipids \build up in cells throughout the body due to a deficiency or absence of the lysosomal enzyme Glucocerebrosidase. The buildup interferes with the way certain cells and organs in the body work, enlarges both cells and certain organs, and leads to symptoms, many of which are serious.
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Gaucher Disease: Clinical Signs and Symptoms
Grabowski GA. Lancet. 2008;372:1263–1271.
Pulmonary involvement
Progressive neurologic symptoms*
Hepatosplenomegaly
Skeletal involvement
Thrombocytopeniaand anemia
* In neuronopathic subtypes only.
1 2 3 4 5 6 7 8 9 10 11
Adapted from Hruska, KS, et al. Human Mutation. 2008;29(5):567–583.
5` 3`
Gene (GBA)84GG1023C DEL1VS2+1
R120Q K157Q P122SD140H
A309V C342GW312C R359Q Y313H S364T T3231E326K
R463C L425E
R463Q
Complex Allele B (Rec TL)*D409H, L444P, A456P, V460V
A176N Y212HG202R P182TN188S* F213 I
R463CG478SR496H
W378G D399NN370S D409H *D380N D409VD380A P415R55 bp del* F417VV394L
Complex Allele A (Rec Nci)*L444P, A456P, V460V
F216YR257QR285C289L
• GBA- Located on chromosome 1 at 1q21
- 11 exons, mRNA 7604-bp- Potential promoters: 2 TATA & 2 CAT
- 2 ATG start sites, both equally efficient
Glucocerebroside
Ceramide Glucose
Glucocerebrosidase
Enzyme defect causing Gaucher disease
Source: Adapted from Sidranksy E. Mol Gen Metab. 2004.
Metabolic product (e.g., cell membrane of erythrocytes)
The Gaucher Cell
2 neurologic involvement
Adapted from Sidransky E. Mol Gen Metab. 2004;83:6–15.
The individual clinical manifestation, rather than the subtype or genotype, may be the best guide for predicting clinical outcome
Spectrum in Gaucher Disease
o
Asymptomatic
Skeletal disease
Visceral disease
Parkinsonian manifestations
Hydrocephalus, cardiac valve calcifications
Eye movement disorder
Myoclonic epilepsy
Progressive neurologic degeneration
Congenital icthyosis
Type 1 Type 3Type 2
Hydrops fetalis
Neurologic manifestations
When to Suspect Gaucher Disease and
Establishing the DiagnosisObservations Splenomegaly in any age group Nosebleeds and unexplained bruising Persistent anemia or thrombocytopenia Bone pain Failure to thrive
After clinical suspicion has been raised, diagnosis can be confirmed byEnzymatic analysis in white blood cell pellet in expert labMutation analysisBone marrow biopsy is NOT required for the diagnosis
Goker-Alpan O, et al. J Med Genet. 2005;42:e37.
Neurologic deterioration in a young infant Congenital ichthyosisHorizontal gaze disorder or visual apraxia
A Comprehensive Management Plan
• Developed in 2003–2004 by a group of physicians from around the world with clinical expertise in treating Gaucher patients (ICGG)
• Targeted areas of improvement:– Organ size
• Liver volume• Spleen volume
– Hematological– Pulmonary– Skeletal system– Pediatric patients– Functional health and well-being
• Time frames that are described are based on past experience with alglucerase/imiglucerase• Most patients will have multiple therapeutic goals
– To be completed within an expected timeframe
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.
Therapeutic Goals: Anemia and Thrombocytopenia*
Anemia Patients GoalTime Frame**
Adult female patients and children
Hb ≥ 11.0 g/dLYears 1 to 2
Male patients > 12 years Hb ≥ 12.0 g/dLYears 1 to 2
All patients Eliminate blood transfusion Reduce fatigue Maintain improved Hb levels
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.
* Please note regular assessments will be conducted* * Time frames that are described are based on past experience with alglucerase/imiglucerase
Therapeutic Goals: Anemia and Thrombocytopenia*
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.
Thrombocytopenia Patients
Goal Time Frame**
All patients Sufficient platelets to reduce
bleedingYear 1
Splenectomized patients Normalization of platelet counts Year 1
Intact spleenModerate thrombocytopenia
(> 60,000–< 120,000/mm3)Severe thrombocytopenia (< 60,000/mm3)
Approach low-normal platelet counts
Doubling by year 2 but normalization not expected
Year 2
Year 2
* Please note regular assessments will be conducted* * Time frames that are described are based on past experience with alglucerase/imiglucerase
Therapeutic Goals: Hepatosplenomegaly
Hepatomegaly*
Splenomegaly*
Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.
Patients Goal Time Frame**
All patients Reduce liver volume to 1–1.5 times normal and maintain
All patients Reduce liver volume by 20–30%
Reduce liver volume by 30–40%
Years 1 to 2
Years 3 to 5
Patients Goal Time Frame**
All patients Reduce spleen volume to ≤ 2 to 8 times normal and maintain
All patients Reduce spleen volume by 30–50%
Reduce spleen volume by 50–60%
Year 1
Years 2 to 5
All patients Alleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarction
Eliminate hypersplenism * Please note regular assessments will be conducted* * Time frames that are described are based on past experience with alglucerase/imiglucerase
• For bone disease, what may not be an expected outcome in patient with GD?
(D)
A. Lessen or eliminate bone pain
B. Prevent osteonecrosis
C. Improve Bone Mineral Density
D. Decrease cystic changes
Challenges in Counseling Based on the carrier frequency many if not most adult patients are
undiagnosed or asymptomatic
Counseling on clinical prognosis is limited because of the broad phenotypic spectrum within and between families
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New(er) Enzymes for the treatment of Gaucher disease
New enzymes are not generic and developed as “novel” proteins (biosimilars)
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Comparison of different enzyme preparationsImiglucerase
Cerezyme
Velaglucerase
VPRIV
Taliglucerase
Uplyso
Company Genzyme Shire-HGT Protalix-Pfizer
Source Mammalian Human Plant
Structure Differs one aminoacid from human enzyme
Same as human enzyme structure
Differs one aminoacid from human enzyme
Sugar attachments Chitobioso core glycan (fucosylation)
(requires a second step)
High mannose type (nine mannose residues)
(requires a second step)
Plant -type high mannose residues , more consistent glycosylation
(no modification)
Safety Antibodies 15 %
6.6 reactions
1 in 54 naïve subjects developed antibodies
Antibodies 8%
6% reactions
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New enzyme preparations for Gaucher disease
Re-evaluate indications and initiation of ERT in both naïve and switch patients
Management of patients that fail to respond to other ERT products
Cost-benefit maintenance therapy
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Oral enzyme therapy for Gaucher disease
Oral delivery of enzyme in a solution
Plant cellulose wall protect against degradation
Rats fed with carrot cells expressing enzyme accumulated active enzyme in liver and spleen
Phase 2 (early) studies are underway
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Small molecule therapies in Gaucher disease
Smaller molecular size allows it to easily penetrate affected cellsUses the available enzyme in the cellDecrease the amount of accumulated abnormal lipidIncrease the function of the enzyme (Enyzme Enhancement or Chaperone Therapy)
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•Eliglustat tartrate is an analogue for ceramide (basic structure resembles ceramide, the accumulated lipid)
•As a substrate synthesis inhibition therapy, eliglustat tartrate slows the body’s production of fatty substances so they do not build up in cells.
Eliglustat Tartrate- Cerdelga
Glucocerebroside + H20 Ceramide + GlucoseGlucocerebrosidase
Pharmacogenomics
• Study of genetic factors related to individual variability for response to a drug
• In many patients , certain drugs do not work well as expected, and in some cause side effects even at lower doses
• Cerdelga® is one of the unique examples, that by labeling pharmacogenomic testing is mandated by the FDA for dosing
• Genetic diversity of cytochrome P450 substrates• CYP2D6 is required for critical step in metabolic activation of
multiple drugs• Extensive, intermediate, ultra-rapid and poor metabolizers
Pharmacogenomics: Why drugs do not work in some patients?
Kitzmiller et al, 2011 Clev Clin J Med
Kitzmiller et al, 2011 Clev Clin J Med
Drugs that inhibit CYP2D6 (can reduce the effects of Cerdelga®, or pain medication/codeine)
Kitzmiller et al, 2011 Clev Clin J Med