1. 14°Convegno Patologia Immune e Malattie
Orfane 2011
La Malattia di Gaucher come prototipo di
malattia genetica curabile: attuali certezze e
nuove frontiere
M.Domenica Cappellini
Fondazione “Ca Granda” Policlinico
Università di Milano

2. Treatment of Gaucher
Disease
• Gaucher disease
– Chronic
– Multisystemic
– Highly variable (pattern, severity, progression)
• Disease heterogeneity management cannot be
homogeneous
• Patient-centered
• Goal-oriented approach is critical for individual
tailoring of therapy

3. Treatment of Gaucher Disease
Which kind of treatment ?
• Supportive and palliative measures
• Enzyme replacement Therapy
(ERT)
• Substrate inhibition therapy (SIT)
• Small molecules
• Bone marrow transplantation
• Gene therapy

4. Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
Therapies Therapies
* A recombinant human glucocerebrosidase
Imiglucerase* expressed in genetically engineered Chinese
hamster ovary cells.
4

5. Achievement of Therapeutic Goals:
Are to “achieve normal life expectancy & well-being for Gaucher patients”
Adapted from
Pastores et al. Semin Hematol (suppl 5):4-14. 2004

6. Success of treatment with Imiglucerase
Therapeutic Goals
Patients achieving therapeutic goals (%) • Prevention of bone crisis (99%)
by clinical parameter around initiation
and at 4 years after initiation of Imiglucerase:
• Amelioration of bone pain (71%)
– Persistence of bone pain= Burden of pre-treatment irreversible
skeletal complications*
99
100
91,8 90,8 91,8
90
79,5 78,5
• Correction of symptomatic anemia (92%)
Percentage of Patients
80
70,3
68,2
70
62,6
60 • Reversion of hepatomegaly (91%)
50 45,6 – Prevent hepatic fibrosis, cirrhosis, and portal hypertension
40
30 24,6 25,5 • Reversion of splenomegaly (79%)
20
– Diminished reservoir of Gaucher cells= Prevent
immunoproliferative disorders
10
0
Haemaglobin Platelet count Liver volume Spleen volume Bone pain Bone crisis
• Improvement of platelet counts (80%)
Clinical Parameters
– Prevent the risk of spontaneous, post-traumatic, surgical or
obstetrical bleeding
– Splenic fibrosis may limit spleen response= Persistent
hypersplenism renders goal platelet count unachievable
Average dose of CZ over 4 yrs:
67.5 ± 31.7 U/kg/4 wks
Weinreb et al. Am. J. Hematol. 83:890–895, 2008.

7. Patients who received higher doses of Imiglucerase
achieved a greater number of therapeutic goals
Mean dose Median Percentage of patients
80 100
Percentage of Patients
70
80
Dose of Cerezyme
60
(U/kg/4wks)
50 60
40
30 40
20
20
10
0 0
1-3 out of 6 4 out of 6 5 out of 6 6 out of 6 Total
Number of Therapeutic Goals Achieved
Average dose of Imiglucerase (U/kg/4 wks) by number of therapeutic goals achieved
at 4 years after initiation of Imiglucerase
Adapted from Table III.
Weinreb et al. Am. J. Hematol. 83:890–895, 2008.

8. Clinical Benefits
Quality of Life
Adapted from Fig.2
• After 48 months of treatment with Imiglucerase®, the majority of
patients achieve normal mean physical and mental standardized
aggregate scores as compared to the U.S. reference population
Weinreb et al. Clin Genet, 71: 576–588. 2007

9. Convenience: Infusion frequency and rate
• The usual frequency of infusion is
(p= 0,060) once every 2 weeks
• Maintenance therapy every 4 weeks
(Q4) at the same cumulative dose as
the bi-weekly (Q2) may be a
therapeutic option for some adult
patients with stable residual Gaucher
disease, but clinical data remain
limited
• At initial infusions, Imiglucerase®
should be administered at a rate not
exceeding 0.5 U/kg/min
• At subsequent administrations,
infusion rate may be increased but
should not exceed 1 U/kg/min
Difference not statistically significant
(95% CI)
Kishnani et al. Mol Genet Metab. 96(4):164–170, 2009; Imiglucerase SmPC, section 4.2

10. Imiglucerase® is the gold standard of care
for Gaucher patients
• Imiglucerase is the gold standard of care with a
trusted, proven and well understood clinical profile
of safety and efficacy well documented for more
than 15 years, representing some 40,000
accumulated years of patient use
• Genzyme continues to support the ICGG Registry,
which provides physicians with the necessary tools
to optimally manage Gaucher patients and advance
their knowledge of the disease

11. Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
Therapies Therapies
Imiglucerase Velaglucerase Taliglucerase
Although Cerezyme remains the standard care for the treatment of Gaucher disease and there is a burgeoning
literature on its use over time in the mature phase of enzyme therapy, two emerging biosimilar agents, also based
on the principle of macrophage targeting through the mannose lectin membrane receptor system, have been
introduced. T.Cox. Dovepress J.Biologics:Targets and Therapy, Dec 210 11

12. Velaglucerase (VPRIV)
• This agent is generated by gene activation of the
endogenous human glucocerebrosidase gene in an
immortalized human fibrosarcoma cell line
• The engineered cells are cultured in a medium containing
the powerful inhibitor kifunesine which blocks the action of
one of the processing glycosidases and as a result, a
human glucocerebrosidase protein displaying terminal
mannose sugars is produced.

13. Velaglucerase granted marketing authorization
in EU (26 Aug ‘10)
• Velaglucerase granted marketing authorization by
European Commission
– Velaglucerase has been authorized as an orphan medicine through
the Centralized Procedure, making it available in 30 countries
across Europe
– Exact timing of launch will depend on local pricing and
reimbursement procedures
• ≈ 850 patients on Velaglucerase therapy
– Capacity to support ≈1000 in 2010
– Currently implementing a program to monitor and manage requests
from new patients
13

14. Taliglucerase
• Taliglucerase is produced as a
recombinant glycoprotein expressed in
genetically engineered plant cells.
• To secure secretion through the vacuolar
pathway, the protein is modified: it harbors
additional amino acids, as well as xylose
and other sugars in its intermediate glycan
sequence

15. Taliglucerase-α status in US and EU
• July 12, 2010: New Drug Application (NDA) for taliglucerase has been
accepted for review by FDA
– The FDA granted Taliglucerase a standard review time of 10 months,
assigning a Prescription Drug User Fee Act (PDUFA) action date of
February 25, 2011
• Nov 29, 2010: Submission of a Marketing Authorization Application to the
EMA for Taliglucerase
– Assuming a standard review period of 10 months, approval would be
expected in September 2011; an expedited review could push up this
deadline to July 2011.
15

16. Clinical data
• Velaglucerase
– “Non-inferiority” and NOT “superiority” for Velaglucerase at 60U/kg
– Robustness of bone data still to be demonstrated
– No pregnancy data
– Antigenic differences in patients receiving vela or Cz has become
a top topic of discussion among KOLs
• Taliglucerase
– Different molecule + clinical data are scarce… but approval in the
EU & US moving forward
16

17. Disadvantages of enzyme
replacement therapy
• Blood–brain barrier which is largely impermeable to proteins
• Enzyme therapy has no direct therapeutic effect on the neurological
manifestations of Gaucher disease
• Enzyme therapy has no direct therapeutic effect on the neurological
manifestations of Gaucher disease
• Cost
PS:hypersensitivity and immune reactions directed against the therapeutic proteins in
type I Gaucherdisease are very rare,

18. Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
Therapies Therapies
Imiglucerase Velaglucerase Taliglucerase Eliglustat Miglustat
18

19. Substrate depletion (inhibitor)
therapy
• The biochemical target for this stratagem in Gaucher
disease is the first committed step for glycosphingolipid
biosynthesis catalyzed by uridine diphosphate (UDP)
glucosylceramide synthetase (UDP-glucose: N-
acylsphingosine transferase)
• Two chemical classes of inhibitor are undergoing
comprehensive therapeutic exploration:
- iminosugars (Miglustat) derived from naturally
occurring plant products
- another class of compounds containing a pyrrolidine
ring that serve as ceramide analogs (Eliglustat)

20. Inhibitors of Glucosylceramide
Synthase
OH OH
HO
O O
N
HO O
HN O
HO OH HN O
O
ceramide
glucose Ceramide-based analogue
Genz-112638
HO CH2OH
N
HO
OH
Imino sugar-based analogue
Glucosylceramide Miglustat (Zavesca®)

21. Miglustat (Zavesca)
• At a dose of 100 mg thrice daily, the agent reduced
visceral enlargement and slowly improved hematologic
parameters, as well as surrogate plasma biomarkers, in
patients with type I Gaucher disease
• Miglustat was considered to have acceptable safety and
tolerability and to be effective for the long-term
maintenance of patients with type I Gaucher disease
who had previouslyreceived enzyme therapy
Pastores GM, et al Clin Ther. 2005;27(8):1215–1227.
Elstein et al. J Inherit Metab Dis. 2004;27(6):757–766

22. Miglustat: Side effects
• An unwanted effect of Miglustat treatment was
diarrhea, caused by an inhibition of intestinal
disaccharidase activity
• Some patients also developed tremor and/or
peripheral neuropathy
• The drug has been licensed in the United States
and Europe as a second-line treatment for
patients with mild to moderate type1 Gaucher
Disease
Giraldo P, et al Haematologica. 2009;94(12):1771–1775.

23. Genz 112638: Phase I:
Therapeutic Plasma Levels and Safety
1000
Cardiac AEs In the Phase Ib
240 ng/mL clinical trial,
Plasma Concentration (ng/mL)
GI AEs 1.6 mg/kg/day
> 100 ng/mL
100
(50 mg BID) produced
a mean Cmax of
Therapeutic 7 ng/mL
10
window
6 ng/mL
In vitro IC50
Sub-therapeutic?
1

24. Genz 112638: Phase II
2 yrs treatment
• These trials were undertaken in adults with type I
Gaucher disease, for which the entry criteria required
splenic enlargement of at least 10-fold normal,together
with thrombocytopenia and/or anemia
• The dose of drug was either started at 50 mg twice daily
or with monitoring for pharmacokinetics adjusted to 100
mg twice daily to ensure that rapid metabolizers would
have concentrations of the drug of ≈10 ng/mL.
Lukina E et al. Blood. 2010;116(6):893–899..

25. Genz 112638: Phase II
2 yrs treatment outcomes
• Continuing improvement in spleen and liver volumes (the former
decreased by a mean of 52%) with improvement in
hemoglobin concentration and a rise in platelet counts have
been observed.
• All these changes were accompanied by improvements in surrogate
biomarkers, including the chemokine CCL18-PARC and
chitotriosidase activity
• Of the 18 patients with abnormal dark signal independently identified
on magnetic resonance imaging, six had improved by 1
year and an additional two patients had shown improvements by 2
years on the trial
Lukina E, Watman N, Avila Arreguin E, et al. Blood. 2010 Aug 16. [Epub ahead of print].

26. Genz 112638: Phase III
• Randomized, open-label study foradults with type I
Gaucher disease, designed to compare the efficacy and
safety of eliglustat tartrate with that of Cerezyme.
Recruited patients should have received enzyme therapy
for at least 3 years
• Randomized,blind, placebo-controlled study for patients
with a confirmed diagnosis of type I Gaucher disease,
who have not been treated for at least 12 months
• A final trial has been registered, which will seek to
compare the effects of one daily dosing of eliglustat
tartrate with twice daily administration.

27. Treatment of Gaucher Disease
Which kind of treatment ?
• Supportive and palliative measures
• Enzyme replacement Therapy (ERT)
• Substrate inhibition therapy (SIT)
• Small molecules (chaperone therapy)
• Bone marrow transplantation
• Gene therapy

28. Chaperone therapy
The chaperone concept involves the binding of
the agent to the active site of the mutant
lysosomal protein,thus stabilizing it for delivery
to its normal site of action in the acidic
environment of the organelle.
• AT2101(Plicera)
• Only for patients with
mutations affecting the
protein folding
• Phase I/II completed
Parenti G. Treating lysosomal storage diseases with pharmacologicalchaperones:
from concept to clinics. EMBO Mol Med.2009;1(5):268–279.

29. Bone Marrow transplantation
• Bone marrow and contemporary hematopoietic
stem-cell transplantation is not in current general
use for Gaucher disease,partly because of the
shortage of ideal donors (human leukocyte
antigen matched) and procedural risks, as well
as the introduction of successful enzymatic
augmentation which has superseded this
treatment in many countries.
T. Cox. Dove press J, Biologics:targets and Therapy. Dec 2010

30. Gene Therapy
• Given the current state of knowledge and
preclinical studies, credible clinical trials could
soon be initiated
• A key requirement, however, would be sustained
expression of the therapeutic gene in
hepatocytes transduced: an issue that has yet to
be overcome
• The location of appropriate investigative centers
and selection of patients will be of critical
importance
T. Cox. Dove press J, Biologics:targets and Therapy. Dec 2010

31. Conclusions
• Gaucher Disease was the first lysosomal disease for
which a specific therapy was introduced in the US
orphan legislative milieu
• The success of enzyme replacement therapy has driven
pharmaceutical investment in other lysosomal diseases
• Orphan drug legislation is anticompetitive, but we now
know that even this cannot guarantee the survival of any
given drug, particularly a biologic agent like a therapeutic
enzyme
• The catastrophe has brought home not simply the
desirability but the absolute necessity of competition for
the safe provision of alternative biosimilar agents