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Page 1: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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 CappelliniFondazione “Ca Granda” Policlinico

Università di Milano

Page 2: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Treatment of Gaucher Disease

• Gaucher disease– Chronic– Multisystemic– Highly variable (pattern, severity, progression)– Highly variable (pattern, severity, progression)

• Disease heterogeneity�management cannot be homogeneous

• Patient-centered • Goal-oriented approach is critical for individual

tailoring of therapy

Page 3: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Treatment of Gaucher Disease

Which kind of treatment ?• Supportive and palliative measures• Enzyme replacement Therapy

(ERT)(ERT)• Substrate inhibition therapy (SIT)• Small molecules• Bone marrow transplantation• Gene therapy

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Gaucher Treatment Milestones

GD Treatment Milestones

Enzyme Replacement Substrate Reduction

4

Enzyme ReplacementTherapies

Substrate Reduction Therapies

Imiglucerase** A recombinant human glucocerebrosidase expressed in genetically engineered Chinese hamster ovary cells.

Page 5: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Achievement of Therapeutic Goals:Are to “achieve normal life expectancy & well-being for Gaucher patients”

Adapted fromPastores et al. Semin Hematol (suppl 5):4-14. 2004

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Success of treatment with ImigluceraseTherapeutic Goals

• Prevention of bone crisis (99%)

• Amelioration of bone pain (71%)– Persistence of bone pain= Burden of pre-treatment irreversible

skeletal complications*

• Correction of symptomatic anemia (92%)

• Reversion of hepatomegaly (91%)– Prevent hepatic fibrosis, cirrhosis, and portal hypertension

Patients achieving therapeutic goals (%)by clinical parameter around initiation

and at 4 years after initiation of Imiglucerase:

68,2

45,6

62,6

91,891,8

79,5

90,8

78,5

70,3

99

50

60

70

80

90

100

Per

cent

age

of P

atie

nts

– Prevent hepatic fibrosis, cirrhosis, and portal hypertension

• Reversion of splenomegaly (79%)– Diminished reservoir of Gaucher cells= Prevent

immunoproliferative disorders

• Improvement of platelet counts (80%)– Prevent the risk of spontaneous, post-traumatic, surgical or

obstetrical bleeding– Splenic fibrosis may limit spleen response= Persistent

hypersplenism renders goal platelet count unachievable

Weinreb et al. Am. J. Hematol. 83:890–895, 2008.

Average dose of CZ over 4 yrs:67.5 ± 31.7 U/kg/4 wks

24,6

45,6

25,5

0

10

20

30

40

50

Haemaglobin Platelet count Liver volume Spleen volume B one pain Bone crisis

Clinical Parameters

Per

cent

age

of P

atie

nts

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30

40

50

60

70

80

Dos

e of

Cer

ezym

e (U

/kg/

4wks

)

40

60

80

100

Per

cent

age

of P

atie

nts

Mean dose Median Percentage of patients

Patients who received higher doses of Imiglucerase achieved a greater number of therapeutic goals

0

10

20

30

1-3 out of 6 4 out of 6 5 out of 6 6 out of 6 Total

Number of Therapeutic Goals Achieved

Dos

e of

Cer

ezym

e (U

/kg/

4wks

)

0

20

40

Per

cent

age

of P

atie

nts

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.

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Clinical BenefitsQuality 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

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Convenience: Infusion frequency and rate

• The usual frequency of infusion isonce 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

(p= 0,060)

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

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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 profil e of safety and efficacy well documented for more than 15 years, representing some 40,000 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

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Gaucher Treatment Milestones

GD Treatment Milestones

Enzyme Replacement Substrate Reduction

11

Enzyme ReplacementTherapies

Substrate Reduction Therapies

Velaglucerase TaligluceraseImiglucerase

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

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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 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.

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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

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Taliglucerase

• Taliglucerase is produced as a recombinant glycoprotein expressed in genetically engineered plant cells.

• To secure secretion through the vacuolar • 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

Page 15: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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, 2011February 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

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• 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

Clinical data

16

– 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

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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,

Page 18: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Gaucher Treatment Milestones

GD Treatment Milestones

Enzyme Replacement Substrate Reduction

18

Enzyme ReplacementTherapies

Substrate Reduction Therapies

Velaglucerase Taliglucerase Eliglustat MiglustatImiglucerase

Page 19: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Substrate depletion (inhibitor) therapy

• The biochemical target for this stratagem in Gaucher disease is the first committed step for glycosphingolipidbiosynthesis catalyzed by uridine diphosphate (UDP) glucosylceramide synthetase (UDP-glucose: N-acylsphingosine transferase)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 pyrrolidinering that serve as ceramide analogs (Eliglustat)

Page 20: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

OH

HNO

OHO

HO OH

O

HO

Inhibitors of Glucosylceramide Synthase

NO

O

OH

OHN

Glucosylceramide

Ceramide-based analogueGenz-112638

glucoseceramide

HO

OH

N

CH2OHHO

Imino sugar-based analogueMiglustat (Zavesca®)

Page 21: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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

Page 22: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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 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.

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Genz 112638: Phase I: Therapeutic Plasma Levels and Safety

Cardiac AEs

Pla

sma

Con

cent

ratio

n (n

g/m

L)

> 100 ng/mL

240 ng/mL

GI AEs100

1000

In the Phase Ib clinical trial,

1.6 mg/kg/day (50 mg BID) produced

a mean C of

Therapeutic window

Pla

sma

Con

cent

ratio

n (n

g/m

L)

6 ng/mLIn vitro IC50

1

10

Sub-therapeutic?

a mean Cmax of7 ng/mL

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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..

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Genz 112638: Phase II 2 yrs treatment outcomes

• Continuing improvement in spleen and liver volumes (the formerdecreased by a mean of 52%) with improvement inhemoglobin concentration and a rise in platelet counts havebeen observed.

• All these changes were accompanied by improvements in surrogate • 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 identifiedon magnetic resonance imaging, six had improved by 1year 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].

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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 • 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.

Page 27: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Treatment of Gaucher Disease

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

Page 28: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

Chaperone therapy

• AT2101(Plicera)

The chaperone concept involves the binding ofthe 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.

Page 29: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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 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

Page 30: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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 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

Page 31: Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt

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 • 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


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