gaucher disease type 1 ( gd1 ) is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme acid -glucosidase . as a result
, glucosylceramide accumulates primarily in lysosomes of tissue macrophages leading to multisystem manifestations , including hepatosplenomegaly , anemia , thrombocytopenia , and bone disease , .
two treatment approaches have been used in gd1 to restore the balance between glucosylceramide synthesis and degradation .
enzyme replacement therapy ( ert ) with recombinant acid -glucosidase , the standard of care for more than two decades , augments the patient 's residual enzyme activity to break down accumulated glucosylceramide and can improve or reverse hematologic , visceral , and skeletal manifestations , , .
substrate reduction therapy ( srt ) inhibits glucosylceramide synthase , thereby slowing production of the substrate glucosylceramide and decreasing its accumulation .
eliglustat ( cerdelga , sanofi genzyme , cambridge , ma , usa )   is an oral srt recently approved by the united states ( us ) food and drug administration and the european medicines agency as a first - line treatment for adults with gd1 who are cyp2d6 extensive , intermediate , or poor metabolizers ( >  90% of patients ) .
clinical trials demonstrated that eliglustat reduces spleen and liver volumes and increases hemoglobin levels and platelet counts in treatment - nave adults with gd1 ,   and maintains stability long - term , .
the relevant comparison of treatment - nave gd1 patients treated with eliglustat ( srt ) and imiglucerase ( ert ) has not been studied .
a head - to - head trial comparing eliglustat to ert in treatment - nave patients is not feasible due to the difficulty of enrolling the large number of patients such a trial would require , given the rarity and heterogeneity of gd and the availability of effective intravenous treatments .
the post - hoc analysis we describe compares clinical response to eliglustat in treatment - nave patients in the eliglustat clinical trials with clinical response to imiglucerase in selected treatment - nave patients from an observational database .
this evaluation was prepared for european regulatory authorities during their assessment of eliglustat , given that a clinical trial comparing eliglustat to imiglucerase in treatment - nave patients was not feasible .
we performed a post - hoc analysis of treatment - nave patients comparing the results of eliglustat treatment in two clinical studies ( 12-month data from the phase 2 open - label , single - arm clinical study [ nct00358150 ]   and 912-month data from the phase 3 double - blind , placebo - controlled engage trial [ nct00891202 ] , ) with the results of imiglucerase treatment for up to 12  months in the international collaborative gaucher group ( icgg ) gaucher registry ( nct00358943 ) , an ongoing sanofi genzyme - sponsored , international , observational and voluntary program that , since its establishment in 1991 , has tracked demographics and clinical outcomes for approximately 6000 gaucher patients in a real - world setting regardless of treatment status .
no experimental intervention is given ; patients in the gaucher registry undergo clinical assessments and receive the standard of care as determined appropriate by their treating physicians in accordance with current gd management guidelines .
all participants in the eliglustat clinical trials and the gaucher registry provided written informed consent allowing post - hoc analysis of anonymous data . inclusion and exclusion criteria from the two eliglustat clinical studies ,  
were used to select a similar population of imiglucerase - treated patients from the registry for comparison of organ volume , hematologic , and skeletal outcomes with eliglustat - treated patients .
these criteria included known date of gd1 diagnosis ; imiglucerase treatment initiation at age 1665  years ; no splenectomy ; baseline hemoglobin 816  g / dl , platelet count 30120    10/l , spleen volume 5.065.0 multiples of normal ( mn ) , and liver volume 0.54.0 mn ; all baseline values for spleen , hemoglobin , liver , and platelets available and any of the 9-month ( 8    10.5  months after treatment initiation ) or any of the 12-month ( >  10.513  months after treatment initiation ) values available .
baseline was defined as the last assessment prior to the first infusion of ert . as
the registry is an observational and voluntary database , timing of assessments varies ; thus ,  and/or  conditions were allowed to ensure that the comparator population would be large enough for comparison .
all patients had to have started ert before june 25 , 2007 and all subsequent data points had to be before june 25 , 2009 to ensure that their clinical responses were not affected by dose reductions or treatment interruptions that occurred during the imiglucerase supply constraint from 2009 to 2011 . among the evaluated registry cohort of patients , sufficient data on bone ( i.e. , bone mineral density , bone pain , and bone crises ) were not available ; therefore , bone disease parameters were excluded from this analysis .
the study population consisted of 46 eliglustat - treated patients ( 26 from phase 2 , 20 from phase 3 engage ) and 75 imiglucerase - treated registry patients who met the inclusion criteria and had an imiglucerase dose   15  u / kg/2  weeks ( mean : 35 , range : 1560 ) .
the three groups were similar with respect to percent male ( 3849% ) , mean age at diagnosis ( 2225  years ) , and mean age at first treatment ( 3235  years ) .
registry data were mostly complete through 12  months ( n  =  64/71 for organ volumes , n  =  71/75 for hematologic parameters ) .
eliglustat - treated and imiglucerase - treated patients were comparable on baseline hematologic parameters ; baseline spleen and liver volumes were higher in the eliglustat phase 2 study patients than in the engage and registry patients ( fig .
1 ) . mean spleen and liver volumes decreased from baseline with eliglustat treatment , with time courses and degrees of improvement similar to the imiglucerase - treated patients from the registry ( fig .
the rate and extent of increase for platelet counts and hemoglobin level were similar across the eliglustat - treated and imiglucerase - treated cohorts ( fig .
1c and 1d ) . limitations of this analysis include the post - hoc design and comparison of eliglustat - treated patients in clinical studies with imiglucerase - treated patients in a real - world setting .
although the imiglucerase - treated patients met the same inclusion and exclusion criteria as the patients in the phase 2 and phase 3 engage studies , baseline spleen and liver volumes differed across the cohorts , and bone data for the registry patients were too limited to allow for a meaningful comparison .
furthermore , because adverse event data are not recorded in the icgg registry , it is not possible to make comparisons or draw conclusions about the safety of eliglustat versus imiglucerase .
we could not completely control for baseline characteristics or for imiglucerase dose , both of which can influence treatment response . with regard to eliglustat dosing , the dose - titration scheme utilized in the clinical trials to ensure plasma eliglustat steady - state pre - dose concentrations above
5  ng / ml differs from the approved eliglustat dosing in the us and european product labels , which is determined by the patient 's cyp2d6 metabolizer phenotype ( i.e. , extensive , intermediate , or poor metabolizer ) .
pharmacokinetic analyses from the clinical trials showed that pre - dose concentrations >  5  ng / ml were not required for therapeutic efficacy and that cyp2d6 phenotype was the most significant determinant of eliglustat exposure .
although lacking the rigor of a head - to - head trial , the findings of this post - hoc analysis in treatment - nave gd1 patients suggest that , during the initial 912  months of treatment , oral eliglustat therapy results in improved organ volumes and hematologic parameters that are comparable to those observed with imiglucerase infusions .
contributions : mjp , ja , and jst designed the analysis ; ja performed the eliglustat statistical analyses and jst the icgg gaucher registry statistical analyses .
ji , ja , lu and mjp analyzed and interpreted the results and wrote the manuscript .
all authors reviewed early and final drafts of the manuscript and were fully responsible for the content and editorial decisions related to this manuscript .
 eliglustat is a recently approved oral therapy in the united states and europe for adults with gaucher disease type 1 who are cyp2d6 extensive , intermediate , or poor metabolizers ( >  90% of patients ) that has been shown to decrease spleen and liver volume and increase hemoglobin concentrations and platelet counts in untreated adults with gaucher disease type 1 and maintain these parameters in patients previously stabilized on enzyme replacement therapy . in a post - hoc analysis , we compared the results of eliglustat treatment in treatment - nave patients in two clinical studies with the results of imiglucerase treatment among a cohort of treatment - nave patients with comparable baseline hematologic and visceral parameters in the international collaborative gaucher group gaucher registry . 
 organ volumes and hematologic parameters improved from baseline in both treatment groups , with a time course and degree of improvement in eliglustat - treated patients similar to imiglucerase - treated patients . 
Introduction
Materials and methods
Results and discussion
Conclusions
Authorship and conflict-of-interest statements