A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1

Lukina, Elena; Watman, Nora; Arreguin, Elsa Ávila; Banikazemi, Maryam; Dragosky, Marta; Iastrebner, Marcelo; Rosenbaum, Hanna; Phillips, Mici; Pastores, Gregory M.; Rosenthal, Daniel I.; Kaper, Mathilde; Singh, Tarunraj; Puga, Ana Cristina; Bonate, Peter L.; Peterschmitt, Michel

doi:10.1182/blood-2010-03-273151

Cited by 140 publications

(129 citation statements)

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“…(36) Eliglustat, a more potent and specific inhibitor of glucosylceramide synthase that is currently in clinical trials for GD1, was reported to increase lumbar spine bone mineral density after 1 and 2 years of treatment, with major gains in DXA scores in osteopenic and osteoporotic patients. (37,38) The signature complication of GD1 in the skeleton is the occurrence of AVN, which is clinically devastating when it involves the cortical bone. As with fractures, we did not find any association of AVN with the severity of visceral disease or with biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Khan

Hangartner

Weinreb³

et al. 2012

Journal of Bone and Mineral Research

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We hypothesized that overall disease activity or the severity of involvement of individual disease compartments, as measured by clinical and surrogate markers, predict the risk of avascular osteonecrosis (AVN) or fractures in type 1 Gaucher disease (GD1). We applied our risk‐set matched case‐control method to identify four patient groups within the International Collaborative Gaucher Group (ICGG) Gaucher Registry based on the presence and absence of AVN and fractures. Characteristics of GD1 were examined by comparing the distributions of each risk factor in cases versus matched controls using conditional logistic regression to calculate adjusted odds ratios (OR). Potential risk factors included hematological and visceral parameters, GD1 biomarkers, white blood cells, GBA1 genotype, and spine and femur dual‐energy X‐ray absorptiometry (DXA) Z‐scores. In the total population of 5894 ICGG Gaucher Registry patients, 544 experienced at least one episode of AVN; 2008 reported no history of AVN. Clinical and surrogate markers of disease activity were similar in patients with and without AVN; patients with AVN were 1.6 times more likely to be anemic compared to matched controls (OR = 1.59; 95% confidence interval [CI], 1.06–2.38, p < 0.05). For fractures, 319 patients suffered fractures and 1233 had no prior history of fractures. Clinical and surrogate markers of disease in patients with and without fractures were similar, except for mean lumbar spine DXA Z‐scores. Among patients with fractures, 49.3% had DXA Z‐scores ≤ −1 compared to 31.0% in the control group. Compared to controls with Z‐scores > −1.0, GD1 patients exhibiting Z‐scores ≤ −1 had an OR of 5.55 (95% CI, 1.81–17.02, p < 0.01) for fracture. In GD1, after controlling for gender, year of birth, treatment status, and splenectomy status, we identified new risk factors for AVN and fractures. Concurrent anemia was associated with an increased risk for AVN. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in GD1. © 2012 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Khan

Hangartner

Weinreb³

et al. 2012

Journal of Bone and Mineral Research

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“…␤ -glucocerebrosidase as evidenced by reversal of spleen and liver enlargement, correction of anemia, and improvements in thrombocytopenia and bone density ( 6 ). Phase 3 trials with eliglustat tartrate are currently in progress.…”

Section: Gcs Activitymentioning

confidence: 99%

Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain

Larsen

Wilson

Abe

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org chaperone therapy, bone marrow transplantation, or gene therapy) ( 1 ). Enzyme replacement therapy is clinically approved for lysosomal storage diseases with peripheral manifestations but is limited by the absence of distribution of infused recombinant enzyme into the central nervous system (CNS) and by the frequent development of auto-antibodies to the protein in patients who carry null mutations. The second strategy involves synthesis inhibition therapy ( 2 ). Synthesis inhibition is a more recent therapeutic approach and has focused on identifying small molecule inhibitors of GCS. Two classes of these inhibitors have been described, including imino sugars and analogs of D-threo -1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP) ( 3 ). The imino sugar N-butyldeoxynojirimycin (NBDNJ) is limited by its micromolar level inhibitory activity and limited specifi city against the synthase. The latter trait is associated with a high level of untoward effects resulting from secondary sites of action unrelated to glycolipid synthesis inhibition. These effects most notably include diarrhea, weight loss, and tremor, and limit its approved use in the United States ( 4 ). However, one distinct advantage of NBDNJ over the PDMP-based homologs reported to date is its ability to distribute into the CNS.The active lead compound that is currently in clinical trials and is structurally related to PDMP is N- Two general strategies for the treatment of lysosomal storage diseases exist. The fi rst strategy includes the replacement or restoration of the defective or absent catabolizing enzyme (e.g., the infusion of recombinant enzyme, Abbreviations: BBB, blood-brain barrier; CNS, central nervous system; GlcCer, glucosylceramide; GCS, glucosylceramide synthase; HBA, number of hydrogen bond acceptors; HBD, number of hydrogen bond donors; MDR1, P-glycoprotein; MDR/WT, the ratio of MDR-MDCKII IC 50 divided by WT-MDCKII IC 50 ; MW, molecular weight; NBDNJ, Nbutyldeoxynojirimycin; PDMP, D-threo -1-phenyl-2-decanoylamino-3-morpholino-propanol; RotB, rotatable bonds; TPSA, topological polar surface area; WT, wild-type.

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“…2 We recently reported the pharmacokinetics and maximum tolerated doses of eliglustat tartrate from phase 1 studies in healthy normal subjects 3 as well as promising results from the 1-year primary analysis period of a phase 2 trial in GD1 patients. 4 Here we present longer-term efficacy and safety data obtained after 2 years of treatment in the phase 2 study and assess patient responses to eliglustat tartrate with reference to evidence-based therapeutic goals established for intravenous enzyme replacement therapy (ERT) with imiglucerase. 5 …”

Section: Introductionmentioning

confidence: 99%

Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study

Lukina

Watman

Arreguin

et al. 2010

Blood

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A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1

Abstract: Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1

Cited by 140 publications

References 20 publications

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain

Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study

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