Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat

Objective: Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). Materials and methods Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18–55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. Results: Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9 % (14.2 %) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of −1.6 (1.1) to −0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56 %) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42 %) patients had focal bone lesions, which remained stable, and 7/19 (37 %) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. Conclusions: Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1

Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1. The ENGAGE Randomized Clinical Trial

Importance Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, −32.57% to −22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, −2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of −30.03% (95% CI, −36.82% to −23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, −11.37% to −1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non–treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial

BACKGROUND: Glucocerebrosidase gene (GBA) mutations influence risk and prognosis of Parkinson's disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. OBJECTIVE: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA-PD). METHODS: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18-80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. RESULTS: Participants (N = 29) received venglustat (Japanese, n = 9; non-Japanese, n = 13) or placebo (n = 3; n = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. CONCLUSION: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF

Clinical response to eliglustat in treatment-naïve patients with Gaucher disease type 1: Post-hoc comparison to imiglucerase-treated patients enrolled in the International Collaborative Gaucher Group Gaucher Registry

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-naïve patients in two clinical studies with the results of imiglucerase treatment among a cohort of treatment-naïve 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

Effects of oral eliglustat on skeletal manifestations in patients with type 1 Gaucher disease: Results from four completed clinical trials after long-term treatment

Debilitating bone complications are common among patients with Gaucher disease type 1 (GD1). We analyzed changes in bone parameters among 393 GD1 patients treated with oral eliglustat for 4–8 years in 4 Sanofi Genzyme-sponsored clinical trials (Phase 2/NCT00358150 [N=26]; Phase 3: ENGAGE/NCT00891202 [N=40]; ENCORE/NCT00943111 [N=157]; EDGE/NCT01074944 [N=170]. In treatment-naïve patients (Phase 2/ ENGAGE), mean spine T-scores moved from the osteopenic range at baseline to the healthy range after 2–3 years. Mean±SEM spine T score increased from 1.55±0.28 to 0.59±0.34 (n=14) after 8 years in Phase 2, and increased to 0.53±0.27 in ENGAGE after 4.5 years (n=9). In both trials, spine Z-scores improved and femur T- and Z-scores remained normal. In ENCORE (patients stabilized after a mean of 10 years of enzyme replacement therapy [ERT]), T- and Z-scores remained in reference ranges for up to 4 years; least-square mean spine Z-scores improved by 0.29 (P<0.0001). In EDGE (mostly ERT switch), patients stabilized during the Lead-In maintained normal T- and Z-scores through the dose-regimen arm and extension period. Mean total bone marrow burden scores improved from marked-to-severe to moderate in ENGAGE and remained stable (moderate) throughout ENCORE and EDGE. Proportions of patients experiencing bone pain decreased after treatment in all trials; reported pain became less severe. Bone crises were infrequent, with none in Phase 2 or ENGAGE patients and in 3/157 (1.9%) patients in ENCORE and 6/170 (3.5%) in EDGE (3 of whom had bone crises before trial entry). Median macrophage inflammatory protein-1β levels normalized in ENGAGE and remained normal in ENCORE and EDGE. Eliglustat was generally well-tolerated. Overall, 97% of adverse events were mild/moderate (97%) and 86% considered unrelated to eliglustat; 9 (2.3% overall) patients withdrew due to adverse events considered drug-related. In summary, bone-related parameters showed improvement in treatment-naïve patients and stability or improvement in switch patients.Sanofi Genzym

Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4years of treatment

AbstractEliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naïve patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm3), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: −1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of eliglustat reported at 1 and 2years to 4years

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

Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, EnglandHosp Ninos Dr Ricardo Gutierrez, Buenos Aires, DF, ArgentinaHEMORIO, Rio de Janeiro, BrazilMt Sinai Hosp, New York, NY 10029 USACincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USAUniversidade Federal de São Paulo, São Paulo, BrazilMinist Publ Hlth Russia, Hematol Res Ctr, Moscow, RussiaCedars Sinai Tower Hematol Oncol Med Grp, Beverly Hills, CA USAGenzyme, Cambridge, MA USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc