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
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
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
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.
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
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
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.
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
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
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
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
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.
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
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
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
• 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
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,
Gaucher Treatment Milestones
GD Treatment Milestones
Enzyme Replacement Substrate Reduction
18
Enzyme ReplacementTherapies
Substrate Reduction Therapies
Velaglucerase Taliglucerase Eliglustat MiglustatImiglucerase
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)
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®)
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
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.
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
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..
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].
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.
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
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.
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
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
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