Gaucher Disease: Problems, Solutions, and

Problems

Seymour Packman, MD

Department of PediatricsDivision of Medical GeneticsInstitute for Human Genetics

University of California San Francisco

Gaucher Disease Type 1: Pathophysiology

Deficiency of the lysosomal enzyme acid β-glucosidase

Storage of glucosylceramide primarily in cells of the monocyte/macrophage lineage

Progressive, multi-organ dysfunction primarily involving the reticulo-

endothelial system

Gaucher Cell

Grabowski et al. MMBID Online. 2013.

GMRB-0125-01

Clinical Manifestations of Gaucher Disease Type 1

• Massive splenomegaly

• Cytopenia• Hypermetabolic

state: fatigue

• Infiltrative lung disease

• Avascular osteonecrosis• Osteoporosis• Pathological fractures• Chronic bone pain

• Hepatomegaly

• Marrow infiltration

• Cytopenia

Reflect Cellular Sites of Substrate Accumulation

Grabowski et al. MMBID Online. 2010.

Lung

Alveolar macrophages

Spleen

Tissue macrophages

Osteoclasts

BoneLiverKupffer cells

(Hepatocytes spared)

Bone marrow

Monocytes

Macrophages

Gaucher Clinical Presentation

Charrow J et al., Arch Intern Med. 2000;160:2835.

Clinical Involvement

Patients with GD1 can present with any of these symptoms.

Some may be severe and others completely absent.

Pathologic fracture (15%)

Osteonecrosis (25%)Osteopenia (42%)

Anemia (64%)Thrombocytopenia (56%)

Erlenmeyer flask deformity (46%)

Hepatomegaly (79%)Splenomegaly (87%)

Bone pain (63%)Bone crisis (33%)

Joint collapse (8%)

General symptoms:• Fatigue• Easy bruising/bleeding• Menorraghia • Decreased appetite• Abdominal pain

Bone marrow infiltration (40%)

GMRB-0125-01

Milestones in Gaucher Disease Treatment

1990 2000 2010

1985: Glucocerebrosidase gene (GCB) cloned1 and mapped to chromosome 1q211,2

First recombinant human glucocerebrosidase ERT approved in US (Cerezyme®) in 1994 and in EU in 1997

1991: First placental-derived glucocerebrosidase ERT approved in US and EU (Ceredase ® )

1983: First patient with GD1 treated at NIHwith glucocerebrosidase purified from human placenta

2011: Placebo- controlled trial of eliglustat completed in treatment-naïve GD1 patients

20121980

2003: IND filed for GZ-112638 (eliglustat)

2003: First SRT approved in patients with GD1 for whom ERT is not an option (Zavesca®)

IND=Investigational New Drug; ERT= enzyme replacement therapy; GD1=Gaucher disease type 11. Sorge. PNAS, 1985:82:7289; 2. Ginns, PNAS 1985;82:7101.

Approved Treatments for Gaucher Disease

– Alglucerase (Ceredase®); purified human placental enzyme. • Approved in 1991; no longer available

– Imiglucerase (Cerezyme®); recombinant human enzyme; produced in CHO cells.

• Approved in 1994.– Velaglucerase alfa (Vpriv®, Shire); recombinant human

enzyme, produced in human cells. • Approved in 2010.

– Taliglucerase alfa (ElelysoTM, Pfizer/Protalix), recombinant human enzyme, produced in carrot cells

• Approved in 2012 GMRB-0125-01

ENZYME REPLACEMENT THERAPY

• Replacement of defective enzyme with normal genetically engineered enzyme

• Engineered enzyme is tagged with a specific recognition signal for delivery to appropriate cell or organelle

• Administration by intermittent IV

Rough ER

P

Cis Golgi

P

Trans Golgi

Lysosome

P

Mannose-6-Phosphate ReceptorSystem

P = Mannose-6-P

GAUCHER DISEASE

• Enzyme Replacement Therapy hemoglobin in a few months

platelets

organomegaly in ~ 6 months

bone pain, bone crises

Slow change of bone X-ray abnormalities

Approved Treatments for Gaucher Disease

• Substrate reduction therapy (SRT); oral administration– Zavesca® (miglustat, Actelion); imino sugar-based analogue

• Approved in 2003. • Indicated only for adults with mild to moderate Gaucher

disease who are unable or unwilling to receive ERT– Cerdelga ® (eliglustat, Genzyme); ceremide-based analogue

• Approved in 2014• Indicated for the longterm treatment of adult patients with

Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by a genetic test

GMRB-0125-01

Synthesis (S) & Degradation (D) of glucosylceramide (GL-1)

Normal Gaucher GaucherGaucher Disease + ERT + SRT

S D S SSD D D

For graphic illustration purposes only.ERT=enzyme replacement therapy; SRT=substrate reduction therapy.Shayman. Drugs Future. 2010:35:613.

Restoring a Balance Between GL-1 Substrate Synthesis and

Degradation

Zavesca (miglustat)

• Effective in Gaucher treatment• FDA approved if cannot use ERT• Adverse reactions:

- peripheral neuropathy (tingling, numbness, burning)

- tremor (30%)- diarrhea (85%; reduce high CHO)- mild weight loss (65%)

miglustat

Eliglustat (Cerdelga) Mechanism of Action

Glucosylceramide Synthase

Acid β-glucosidaseDeficient in Gaucher disease

Eliglustat

Ceramide + Glucose Glucosylceramide

Enzyme Replacement Therapy

Shayman. Drugs Future. 2010:35:613.

GMRB-0125-01

Ver. 10 May2010 23

Eliglustat Tartrate is a Novel Analog of Glucosylceramide

Glucosylceramide Eliglustat tartrate

OH

HNO

OHOHO OH

OHO

N

O

O

O

HN

OH

Inhibitors of Glucosylceramide Synthase

GMRB-0125-01

Rough ER

P

Cis Golgi

P

Trans Golgi

Lysosome

P

Mannose-6-Phosphate ReceptorSystem

P = Mannose-6-P

Chaperones

Chaperones

SMALL MOLECULES: CHAPERONES

• Stabilize mutant enzyme

• Increase β-glucocerebrosidase levels in Gaucher patients’ cells

• In development for Gaucher

• In phase III clinical trial for other lysosomal disorders

TREATMENT APPROACHES for LYSOSOMAL DISORDERS

• Enzyme replacement• Novel biochemical measures

– substrate reduction– chaperones– other small molecules: regulate

gene expression or protein function; encapsulated cells

…out of nature’s certain course,A gift that rather was come late than soon.

W. Wordsworth