Abstract 3791 Background: Gaucher disease type 1 (GD1), an inherited lysosomal storage disorder, is characterized by a deficiency of acid β-glucosidase and accumulation of glucosylceramide in lysosomes causing organomegaly, thrombocytopenia, anemia, and bone disease. Eliglustat tartrate (formerly Genz-112638) is a novel, specific inhibitor of glucosylceramide synthase under development as an oral substrate reduction therapy for the treatment of GD1. Purpose: To report updated efficacy and safety observations in GD1 patients after 2 years of treatment with eliglustat tartrate in an ongoing Phase 2 clinical trial. Methods: This is an open-label, uncontrolled, multicenter, Phase 2 clinical trial of eliglustat tartrate (50 or 100 mg bid, depending on trough plasma level of drug) in 26 previously untreated adults with GD1. Entry criteria required that patients have splenomegaly with thrombocytopenia (platelet count: 45,000 to 100,000 mm3) and/or anemia (hemoglobin: 8.0–10 g/dL, females; 8.0–11 g/dL, males). Efficacy results included changes from baseline in hemoglobin and platelet levels, spleen and liver volumes, biomarkers, bone mineral density (BMD), and other skeletal findings. Hematologic and visceral parameters were assessed centrally every 3 to 6 months; MRI, DXA, and X-rays were performed yearly and reviewed centrally. Achievement of Gaucher disease therapeutic goals for hemoglobin, platelet counts, and organ volume also was assessed at 2 years. Results: Thirty-month hematologic, organ volume, and biomarker data will be available for presentation. Six of the 26 enrolled patients discontinued the Phase 2 study. Results (mean changes from baseline ± SD) are currently available in up to 20 patients who completed 2 years of treatment with eliglustat tartrate. For these patients, hemoglobin level increased by 2.1±1.5 g/dL (11.2±1.6 to 13.3±1.5 g/dL), and platelet count increased by 81.5±56.0% (67,900±20,900/mm3 to 119,200±42,400/mm3). Spleen volume (as multiples of normal, MN) decreased by 52.4±10.7% (17.95 MN to 8.14 MN), and liver volume decreased by 23.9±12.8% (1.69 MN to 1.24 MN). Mean chitotriosidase and CCL18 decreased by 75.4% and 75.2%, respectively. Through 2 years, no bone crises or reductions in mobility were reported. Femur MRI showed improvement of the dark marrow signal in 8/18 patients, indicating reduction of the infiltration of the bone marrow by Gaucher cells; the rest of the patients remained stable (10/18 patients). In addition, there were no new lytic lesions or bone infarcts; existing lytic lesions remained stable, and of 7 existing infarcts, 1 improved and 6 remained stable. Mean lumbar spine BMD increased by 7.8±10.6% (P=0.010), DXA T-Score by 0.6±0.8 (P=0.012), and DXA Z-Score by 0.6±0.7 (P=0.003), with major gains among osteoporotic/osteopenic patients. After 2 years, most patients met short-term therapeutic goals published by Pastores et al (Semin Hematol 2004;41[suppl 5]:4–14); more patients met goals for hemoglobin (95%), liver volume (95%), and spleen volume (90%) than for platelet count (60%). Overall, 85% (17/20) of patients met established therapeutic goals for ≥3 of 4 parameters after 2 years. Eliglustat tartrate was well tolerated in this trial up to 2 years. Most adverse events (AEs) were mild and unrelated to treatment. The most common AEs reported during 2 years were viral infections (6 patients), and urinary tract infections, increased blood pressure, and abdominal pain (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients. Summary/Conclusions: In this Phase 2 study, eliglustat tartrate has shown promising efficacy as a potential oral substrate reduction therapy for GD1. After 2 years, patients with GD1 treated with eliglustat tartrate continued to show improvements in hematologic, organ volume, and bone parameters with a safety profile that supports ongoing treatment. Three controlled Phase 3 studies are underway: one in untreated patients (ENGAGE), one in patients switching from enzyme replacement therapy (ENCORE), and another that compares different dose regimens of eliglustat (EDGE). Disclosures: Lukina: Genzyme Corporation: Honoraria. Peterschmitt:Genzyme Corporation: Employment. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme Corporation: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Kaper:Genzyme Corporation: Employment. Haque:Genzyme Corporation: Employment. Puga:Genzyme Corporation: Employment.

Gaucher disease induces some metabolic abnormalities so increased serum ferritin appears in more than 60% at diagnosis. The storage of glucosylceramide in macrophages produces an inflammatory response with iron recycling deregulation and release of cytokines. Iron homeostasis is controlled by the circulating peptide hepcidin and its production is influenced by inflammatory cytokines.Iron damages cells by excess of catalyzing reactive oxygen species, removal of the excess iron has a positive influence on the response to treatment and survival in patients with iron overload.We have analyzed some inflammatory biomarkers of macrophage activation and related to the iron profile, including hepcidin and liver iron deposits determined by MRI, in 8 type 1 GD patients with hyperferritinemia. We have explored the changes in this profile after 4 months under therapy with two different iron chelators, deferoxamine or deferasirox, by evaluating response, adverse events and quality of life. We observed a significant reduction in serum ferritin and hepcidin levels and in liver iron deposits. No differences were observed in chitotriosidase activity, CCL18/PARC concentration and IL-4, IL-6, IL-7, IL-10, IL-13, MIP-1α, MIP-1β,TNF-α cytokine levels. After two years on follow-up, clinical and analytical data were improved and stable ferritin levels maintained less than 700 ng/dL.

Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean ± SD, 81% ± 56%), hemoglobin level (20% ± 15%), spleen volume (-52% ± 11%), and liver volume (-24% ± 13%). Mean platelet count increased ∼ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥ 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% ± 10.6% (P = .01) and T-score 0.6 ± 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150.

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). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.

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