Cappellini m.domenica la malattia di gaucher-torino gennaio 2011- 14° convegno patologia immune e malatt
14°Convegno Patologia Immune e Malattie Orfane 2011La Malattia di Gaucher come prototipo dimalattia genetica curabile: attuali certezze e nuove frontiere M.Domenica Cappellini Fondazione “Ca Granda” Policlinico Università di Milano
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
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
Gaucher Treatment Milestones GD Treatment MilestonesEnzyme Replacement Substrate Reduction Therapies Therapies * A recombinant human glucocerebrosidase Imiglucerase* expressed in genetically engineered Chinese hamster ovary cells. 4
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 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.
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.
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: 576–588. 2007
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
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
Gaucher Treatment Milestones GD Treatment Milestones Enzyme Replacement Substrate Reduction Therapies Therapies Imiglucerase Velaglucerase TaligluceraseAlthough 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
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.
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 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, 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
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
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• CostPS:hypersensitivity and immune reactions directed against the therapeutic proteins in type I Gaucherdisease are very rare,
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)
Inhibitors of Glucosylceramide Synthase OH OH HO O O NHO O HN O HO OH HN O O ceramideglucose Ceramide-based analogue Genz-112638 HO CH2OH N HO OH Imino sugar-based analogue Glucosylceramide Miglustat (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 therapyPastores 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• The drug has been licensed in the United States and Europe as a second-line treatment for patients with mild to moderate type1 Gaucher DiseaseGiraldo P, et al Haematologica. 2009;94(12):1771–1775.
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
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 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 trialLukina 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 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)• Substrate inhibition therapy (SIT)• Small molecules (chaperone therapy)• Bone marrow transplantation• Gene therapy
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 with mutations affecting the protein folding • Phase I/II completedParenti 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 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 hepatocytes transduced: an issue that has yet to be overcome• The location of appropriate investigative centers and selection of patients will be of critical importanceT. 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 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