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

3

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