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

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  • 1. 14Convegno Patologia Immune e Malattie Orfane 2011La Malattia di Gaucher come prototipo dimalattia genetica curabile: attuali certezze e nuove frontiereM.Domenica Cappellini Fondazione Ca Granda PoliclinicoUniversit di Milano

2. Treatment of Gaucher Disease Gaucher disease Chronic Multisystemic Highly variable (pattern, severity, progression) Disease heterogeneity management cannot behomogeneous Patient-centered Goal-oriented approach is critical for individualtailoring of therapy 3. Treatment of Gaucher DiseaseWhich kind of treatment ? Supportive and palliative measures Enzyme replacement Therapy(ERT)Substrate inhibition therapy (SIT)Small moleculesBone marrow transplantationGene therapy 4. Gaucher Treatment MilestonesGD Treatment MilestonesEnzyme ReplacementSubstrate ReductionTherapiesTherapies * 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 patientsAdapted fromPastores et al. Semin Hematol (suppl 5):4-14. 2004 6. Success of treatment with ImigluceraseTherapeutic 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 91,890,891,89079,5 78,5 Correction of symptomatic anemia (92%)Percentage of Patients80 70,368,27062,660 Reversion of hepatomegaly (91%)5045,6 Prevent hepatic fibrosis, cirrhosis, and portal hypertension4030 24,6 25,5 Reversion of splenomegaly (79%)20 Diminished reservoir of Gaucher cells=Prevent immunoproliferative disorders10 0 Haemaglobin Platelet countLiver 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 unachievableAverage dose of CZ over 4 yrs: 67.5 31.7 U/kg/4 wksWeinreb et al. Am. J. Hematol. 83:890895, 2008. 7. Patients who received higher doses of Imigluceraseachieved a greater number of therapeutic goalsMean dose Median Percentage of patients80100Percentage of Patients7080 Dose of Cerezyme60(U/kg/4wks)50604030402020100 0 1-3 out of 64 out of 65 out of 6 6 out of 6Total Number of Therapeutic Goals Achieved Average dose of Imiglucerase (U/kg/4 wks) by number of therapeutic goals achievedat 4 years after initiation of Imiglucerase Adapted from Table III.Weinreb et al. Am. J. Hematol. 83:890895, 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 populationWeinreb et al. Clin Genet, 71: 576588. 2007 9. Convenience: Infusion frequency and rateThe usual frequency of infusion is(p= 0,060) once every 2 weeksMaintenance 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 limitedAt initial infusions, Imiglucerase should be administered at a rate not exceeding 0.5 U/kg/minAt 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):164170, 2009; Imiglucerase SmPC, section 4.2 10. Imiglucerase is the gold standard of carefor Gaucher patients Imiglucerase is the gold standard of care with atrusted, proven and well understood clinical profileof safety and efficacy well documented for morethan 15 years, representing some 40,000accumulated years of patient use Genzyme continues to support the ICGG Registry,which provides physicians with the necessary toolsto optimally manage Gaucher patients and advancetheir knowledge of the disease 11. Gaucher Treatment MilestonesGD Treatment Milestones Enzyme ReplacementSubstrate ReductionTherapies TherapiesImiglucerase VelagluceraseTaligluceraseAlthough Cerezyme remains the standard care for the treatment of Gaucher disease and there is a burgeoningliterature on its use over time in the mature phase of enzyme therapy, two emerging biosimilar agents, also basedon the principle of macrophage targeting through the mannose lectin membrane receptor system, have beenintroduced. T.Cox. Dovepress J.Biologics:Targets and Therapy, Dec 210 11 12. Velaglucerase (VPRIV) This agent is generated by gene activation of theendogenous human glucocerebrosidase gene in animmortalized human fibrosarcoma cell line The engineered cells are cultured in a medium containingthe powerful inhibitor kifunesine which blocks the action ofone of the processing glycosidases and as a result, ahuman glucocerebrosidase protein displaying terminalmannose sugars is produced. 13. Velaglucerase granted marketing authorizationin EU (26 Aug 10) Velaglucerase granted marketing authorization byEuropean Commission Velaglucerase has been authorized as an orphan medicine throughthe Centralized Procedure, making it available in 30 countriesacross Europe Exact timing of launch will depend on local pricing andreimbursement procedures 850 patients on Velaglucerase therapy Capacity to support 1000 in 2010 Currently implementing a program to monitor and manage requestsfrom new patients13 14. Taliglucerase Taliglucerase is produced as arecombinant glycoprotein expressed ingenetically engineered plant cells. To secure secretion through the vacuolarpathway, the protein is modified: it harborsadditional amino acids, as well as xyloseand other sugars in its intermediate glycansequence 15. Taliglucerase- status in US and EU July 12, 2010: New Drug Application (NDA) for taliglucerase has beenaccepted 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 ofFebruary 25, 2011 Nov 29, 2010: Submission of a Marketing Authorization Application to theEMA for Taliglucerase Assuming a standard review period of 10 months, approval would beexpected in September 2011; an expedited review could push up thisdeadline 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 becomea top topic of discussion among KOLs Taliglucerase Different molecule + clinical data are scarce but approval in theEU & US moving forward16 17. Disadvantages of enzyme replacement therapy Bloodbrain barrier which is largely impermeable to proteins Enzyme therapy has no direct therapeutic effect on the neurologicalmanifestations of Gaucher disease Enzyme therapy has no direct therapeutic effect on the neurologicalmanifestations of Gaucher disease CostPS:hypersensitivity and immune reactions directed against the therapeutic proteins in type I Gaucherdisease are very rare, 18. Gaucher Treatment MilestonesGD Treatment Milestones Enzyme Replacement Substrate ReductionTherapiesTherapiesImigluceraseVelaglucerase Taliglucerase Eliglustat Miglustat 18 19. Substrate depletion (inhibitor) therapy The biochemical target for this stratagem in Gaucherdisease is the first committed step for glycosphingolipidbiosynthesis 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 pyrrolidinering that serve as ceramide analogs (Eliglustat) 20. Inhibitors of Glucosylceramide SynthaseOHOHHOO O NHO O HN O HO OH HNOOceramideglucoseCeramide-based analogueGenz-112638 HOCH2OH N HOOH Imino sugar-based analogueGlucosylceramide Miglustat (Zavesca) 21. Miglustat (Zavesca) At a dose of 100 mg thrice daily, the agent reducedvisceral enlargement and slowly improved hematologicparameters, as well as surrogate plasma biomarkers, inpatients with type I Gaucher disease Miglustat was considered to have acceptable safety andtolerability and to be effective for the long-termmaintenance of patients with type I Gaucher diseasewho had previouslyreceived enzyme therapyPastores GM, et al Clin Ther. 2005;27(8):12151227.Elstein et al. J Inherit Metab Dis. 2004;27(6):757766 22. Miglustat: Side effects An unwanted effect of Miglustat treatment wasdiarrhea, caused by an inhibition of intestinaldisaccharidase activity Some patients also developed tremor and/orperipheral neuropathy The drug has been licensed in the United Statesand Europe as a second-line treatment forpatients with mild to moderate type1 GaucherDiseaseGiraldo P, et al Haematologica. 2009;94(12):17711775. 23. Genz 112638: Phase I:Therapeutic Plasma Levels and Safety 1000Cardiac AEs In the Phase Ib 240 ng/mLclinical trial,Plasma Concentration (ng/mL)GI AEs 1.6 mg/kg/day> 100 ng/mL100 (50 mg BID) produceda mean Cmax ofTherapeutic 7 ng/mL 10window 6 ng/mLIn vitro IC50 Sub-therapeutic?1 24. Genz 112638: Phase II2 yrs treatment These trials were undertaken in adults with type IGaucher disease, for which the entry criteria requiredsplenic enlargement of at least 10-fold normal,togetherwith thrombocytopenia and/or anemia The dose of drug was either started at 50 mg twice dailyor with monitoring for pharmacokinetics adjusted to 100mg twice daily to ensure that rapid metabolizers wouldhave concentrations of the drug of 10 ng/mL.Lukina E et al. Blood. 2010;116(6):893899.. 25. 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 surrogatebiomarkers, including the chemokine CCL18-PARC andchitotriosidase 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 2years on the trialLukina 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 IGaucher disease, designed to compare the efficacy andsafety of eliglustat tartrate with that of Cerezyme.Recruited patients should have received enzyme therapyfor at least 3 years Randomized,blind, placebo-controlled study for patientswith 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 tocompare the effects of one daily dosing of eliglustattartrate with twice daily administration. 27. Treatment of Gaucher DiseaseWhich 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 therapyThe chaperone concept involves the binding ofthe agent to the active site of the mutantlysosomal protein,thus stabilizing it for deliveryto its normal site of action in the acidicenvironment of the organelle. AT2101(Plicera) Only for patients withmutations affecting theprotein folding Phase I/II completedParenti G. Treating lysosomal storage diseases with pharmacologicalchaperones:from concept to clinics. EMBO Mol Med.2009;1(5):268279. 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 andpreclinical studies, credible clinical trials couldsoon be initiated A key requirement, however, would be sustainedexpression of the therapeutic gene inhepatocytes transduced: an issue that has yet tobe overcome The location of appropriate investigative centersand selection of patients will be of criticalimportanceT. Cox. Dove press J, Biologics:targets and Therapy. Dec 2010 31. Conclusions Gaucher Disease was the first lysosomal disease forwhich a specific therapy was introduced in the USorphan legislative milieu The success of enzyme replacement therapy has drivenpharmaceutical investment in other lysosomal diseases Orphan drug legislation is anticompetitive, but we nowknow that even this cannot guarantee the survival of anygiven drug, particularly a biologic agent like a therapeuticenzyme The catastrophe has brought home not simply thedesirability but the absolute necessity of competition forthe safe provision of alternative biosimilar agents


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