1. Gaucher Disease: Problems and Solutions Seymour Packman, MD Department of Pediatrics Division of Medical Genetics Institute for Human Genetics University of California San Francisco

3. 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
Content from: M Judith Peterschmitt. Preclinical Information, Program Overview. 3/1/2011.
Gaucher Cell
Grabowski et al. MMBID Online
GMRB

4. Clinical Manifestations of Gaucher Disease Type 1
Reflect Cellular Sites of Substrate Accumulation
Monocytes
Spleen
Massive splenomegaly
Cytopenia
Hypermetabolic state:
fatigue
Marrow infiltration
Cytopenia
Macrophages
Tissue macrophages
Bone marrow
Lung
Infiltrative lung disease
Hepatomegaly
Liver
Bone
Kupffer cells
(Hepatocytes spared)
Alveolar macrophages
Osteoclasts
Avascular osteonecrosis
Osteoporosis
Pathological fractures
Chronic bone pain
Grabowski et al. MMBID Online 4

5. Gaucher Clinical Presentation
Patients with GD1 can present with any of these symptoms. Some may be severe and others completely absent.
General symptoms:
Fatigue
Easy bruising/bleeding
Menorraghia
Decreased appetite
Abdominal pain
Bone pain (63%) Bone crisis (33%)
Pathologic fracture (15%)
Hepatomegaly (79%) Splenomegaly (87%)
Joint collapse (8%)
There is wide variability in the clinical presentation of type 1 Gaucher, with occasional discordance between visceral and bone involvement. Early signs and symptoms that a primary care provider may observe include abdominal pain, growth retardation, bruising/bleeding, anemia, and fatigue. As the disease progresses, common features may include hepatosplenomegaly and bone disease characterized by osteopenia, osteonecrosis, and bone pain in the advanced stage.
Many of the signs and symptoms a primary care provider may see are shared with multiple other disorders.
Anemia (64%)
Thrombocytopenia (56%)
Erlenmeyer flask deformity (46%)
Osteonecrosis (25%)
Osteopenia (42%)
Bone marrow infiltration (40%)
Charrow J et al., Arch Intern Med. 2000;160:2835.
GMRB
Clinical Involvement

6. Milestones in Gaucher Disease Treatment
First recombinant human glucocerebrosidase ERT approved in US (Cerezyme®) in 1994 and in EU in 1997
2011: Placebo- controlled trial of eliglustat completed in treatment-naïve GD1 patients
1985: Glucocerebrosidase gene (GCB) cloned1 and mapped to chromosome 1q211,2
2003: IND filed for GZ (eliglustat)
2012
1980
1990
2000
2010
1983: First patient
with GD1 treated at NIH
with glucocerebrosidase purified from human placenta
1991: First
placental-derived glucocerebrosidase ERT approved in US
and EU (Ceredase ® )
2003: First SRT approved in patients with GD1 for whom ERT is not an option (Zavesca®)
Mainstay of treatment has been enzyme replacement therapy, which requires intravenous infusions typically administered every 2 weeks
Development of an oral drug that can treat the broad GD1 population is highly desirable.
Eliglustat is currently in late-stage clinical development as an oral substrate reduction therapy for the treatment of GD1
IND=Investigational New Drug;
ERT= enzyme replacement therapy; GD1=Gaucher disease type 1
1. Sorge. PNAS, 1985:82:7289; 2. Ginns, PNAS 1985;82:7101. 6

7. 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

8. 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
Leave enough time for this - this is an important concept!

9. Mannose-6-Phosphate Receptor
System P
Lysosome P
= Mannose-6-P P
Trans Golgi P
Rough ER
Cis Golgi

10. 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

16. 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

17. Restoring a Balance Between GL-1 Substrate Synthesis and Degradation
Synthesis (S) & Degradation (D) of glucosylceramide (GL-1)
Normal
Gaucher
Gaucher Disease
+ ERT
+ SRT S D
Shayman JA. ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease. Drugs Future 2010;35:
Two treatment approaches have been used to lower GL-1 accumulation in Gaucher disease. In both approaches, the goal is to restore the balance between synthesis and degradation of GL-1.
Enzyme replacement therapy (ERT) with recombinant acid ß-glucosidase augments the patient’s enzyme activity to break down accumulated GL-1.
Substrate reduction therapy (SRT) inhibits glucosylceramide synthase (GCS), thereby slowing down the production of GL-1.
For graphic illustration purposes only.
ERT=enzyme replacement therapy; SRT=substrate reduction therapy.
Shayman. Drugs Future. 2010:35:613.

20. 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%)

21. miglustat

22. Eliglustat (Cerdelga) Mechanism of Action
Glucosylceramide Synthase
Acid β-glucosidase Deficient in Gaucher disease
Eliglustat
Ceramide + Glucose
Glucosylceramide
Enzyme Replacement Therapy
Shayman. Drugs Future. 2010:35:613.
Shayman JA. ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease. Drugs Future 2010;35:
Gaucher disease type 1 (GD1) is an inherited, multi-systemic lysosomal storage disorder characterized by deficient activity of the enzyme acid β-glucosidase. This results in progressive accumulation of the enzyme substrate (glucosylceramide, GL-1) in lysosomes of tissue macrophages, causing hepatosplenomegaly, anemia, thrombocytopenia, and bone disease.
Two treatment approaches have been used to restore the balance between synthesis and degradation of GL-1 in GD1.
Enzyme replacement therapy (ERT) with recombinant acid β-glucosidase augments the patient’s enzyme activity to break down accumulated GL-1.
Substrate inhibition therapy (SRT) inhibits glucosylceramide synthase and slows the production of GL-1.
Eliglustat is a novel oral SRT in development for adults with GD1. It resembles the ceramide moiety of GL-1, and acts by specifically inhibiting glucosylceramide synthase, resulting in decreased accumulation of the substrate GL-1.
GMRB

23. Eliglustat Tartrate is a Novel Analog of GlucosylceramideOH HN O HO N O HN OH
Earlier substrate inhibitors studied, such as miglustat, were primarily analogs of glucose. In contrast, Eliglustat tartrate is an analog of glucosylceramide.
Glucosylceramide
Eliglustat tartrate
Ver. 10 May2010

24. Inhibitors of Glucosylceramide Synthase
Content from: M Judith Peterschmitt. Preclinical Information, Program Overview. 3/1/2011.
GMRB

25. Mannose-6-Phosphate Receptor
System P
Lysosome P
= Mannose-6-P P
Trans Golgi P
Rough ER
Cis Golgi

26. Chaperones

27. Chaperones

28. 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

29. TREATMENT APPROACHES for LYSOSOMAL DISORDERS
Enzyme replacement
Novel biochemical measures
substrate reduction
chaperones
other small molecules: regulate gene expression or protein function; encapsulated cells

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