Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients

Abstract Purpose We retrospectively assessed bone and visceral manifestations in patients with Gaucher disease type 1 (GD1) with whole-body magnetic resonance imaging (WB-MRI) to determine the effects of different timing in initiating long-term enzyme replacement therapy. Materials and Methods In 17 patients with GD1, we performed 2 WB-MRI examinations at a median interval of 13 months. Patients had received enzyme replacement therapy with alglucerase/imiglucerase for a median of 13 years prior to the first examination. MRI results were retrospectively stratified based on treatment initiation into 2 groups: “early” (age ≤12 years, median 5 years) and “late” (during adulthood, median 32 years). We evaluated occurrence of irreversible avascular necroses (AVN) and applied several semi-quantitative scores, including the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), the Vertebra-Disc-Ratio (VDR), and the Gaucher disease type 1 Severity Scoring System (GD-DS3). Results MRI assessments showed no AVN in the “early” group. AVN were observed in 2 patients of the “late” group; one also had a splenic Gaucheroma. The follow-up examinations showed slight improvements in the BMB-score, DGS, and VDR, with similar tendencies in both treatment groups. The GD-DS3 score only improved in “late” group. Conclusion This retrospective study supported the ongoing clinical value of enzyme replacement therapy with alglucerase/imiglucerase, as WB-MRI-based scores stayed constant or slightly improved even after long-term treatment. Secondary complications were only observed in the late treatment group. Our results suggest that “early initiation” of enzyme replacement therapy may protect the bone.

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Encore - a Randomized, Controlled, Open-Label Non-Inferiority Study Comparing Eliglustat to Imiglucerase in Gaucher Disease Type 1 Patients Stabilized on Enzyme Replacement Therapy: 24-Month Results

Blood ◽

10.1182/blood.v124.21.1406.1406 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1406-1406 ◽

Cited By ~ 1

Author(s):

Barry E. Rosenbloom ◽

Timothy M. Cox ◽

Guillermo I. Drelichman ◽

Renata Cravo ◽

Manisha Balwani ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Liver Volume ◽

Disease Type ◽

Open Label ◽

Enzyme Replacement ◽

Gaucher Disease Type 1 ◽

Extension Period

Abstract Introduction: Eliglustat is a novel oral substrate-reduction therapy in development for adults with Gaucher disease type 1 (GD1). This open-label Phase-3 trial (ENCORE, NCT00943111, Genzyme, a Sanofi company, Cambridge, MA), the largest randomized, controlled trial in GD1 to date, evaluated eliglustat and imiglucerase treatment in patients who had previously reached pre-specified therapeutic goals after ≥3 years of enzyme replacement therapy. We report efficacy data from the 12-month primary analysis period (PAP) and the first 12 months of the extension period in which all patients received eliglustat. Methods: Patients were randomized 2 to 1 eliglustat to imiglucerase. The primary efficacy endpoint was percent of patients remaining stable on a pre-specified composite of spleen, liver, hemoglobin, and platelet parameters. As this was a non-inferiority trial, efficacy analyses were performed on the per-protocol population (99 eliglustat and 47 imiglucerase patients). Results: Eliglustat was non-inferior to imiglucerase: after 12 months of treatment, 85% of eliglustat and 94% of imiglucerase patients maintained all 4 goals (lower bound of 95% CI of difference [-17.6%] within the pre-specified [-25%] non-inferiority margin). Of the 159 patients treated in this study, 145 (91%) completed 24 months of treatment. During the 12-month extension period, continued stability was seen in most patients in both groups. Among 99 of 106 patients who continued on eliglustat, stability was seen in spleen volume (96% of patients), hemoglobin (97%), platelet count (94%), and liver volume (96%). In 47 of 53 patients who received imiglucerase in the PAP and then eliglustat in the trial extension, continued stability was seen also in spleen volume (97% of patients), hemoglobin (100%), platelet count (90%), and liver volume (95%). Most adverse events were mild or moderate in severity. No new safety concerns have arisen after 24 months. Conclusions: Eliglustat was non-inferior to imiglucerase in maintaining stability after 12 months of treatment in patients previously stabilized on enzyme replacement therapy. In the 12-month trial extension, clinical stability was maintained in most patients who remained on eliglustat for 24 months and in most patients who switched from imiglucerase to eliglustat. Disclosures Rosenbloom: Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Off Label Use: Eliglustat is an investigational drug for the treatment of Gaucher disease type 1. Cox:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Drelichman:Genzyme, a Sanofi Company: Consultancy, Honoraria. Cravo:Genzyme, a Sanofi Company: Consultancy, Honoraria. Balwani:Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel reimbursement Other. Burrow:Biomarin: Consultancy, Honoraria, Travel reimbursement, Travel reimbursement Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Martins:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Lukina:Shire: Consultancy, Honoraria, Travel reimbursement, Travel reimbursement Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Ross:Genzyme, a Sanofi Company: Employment. Angell:Genzyme, a Sanofi Company: Employment. Peterschmitt:Genzyme, a Sanofi Company: Employment.

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