Treatment Of Gaucher Disease Type Research Articles

Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2.

Our aim was to compare the costs and efficacy of ambroxol in combination with imiglucerase with the costs and efficacy of imiglucerase only in the treatment of Gaucher disease type 2 (GD2) in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was 6 years. The main outcomes of the study were quality-adjusted life years gained with ambroxol + imiglucerase and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Markov chain model. The model results were obtained after Monte Carlo microsimulation of a sample with 1,000 virtual patients. Treatment with ambroxol in combination with imiglucerase was cost-effective when compared with imiglucerase only and was associated with positive values of net monetary benefit regardless of the onset of the disease. Such beneficial result for ambroxol and imiglucerase combination is primarily driven by the low cost of ambroxol and its considerable clinical effectiveness in slowing the progression of neural complications of GD2. If ambroxol and imiglucerase are used in combination for the treatment of GD2, it is more cost-effective than using imiglucerase alone.

Velaglucerase alfa for treatment in children with Gaucher disease type 1: the Russian experience

The current gold standard for the treatment of Gaucher disease type 1 in children is enzyme replacement therapy. The efficacy and safety of treatment with velaglucerase alfa have been assessed in only a few large studies involving pediatric patients as subjects of research. In the Russian literature, there are no data available on the use of velaglucerase alfa in drug-naïve patients with Gaucher disease type 1. The aim of our study was to assess the efficacy and safety of treatment with velaglucerase alfa in children with Gaucher disease type 1. The study was approved by the Independent Ethics Committee and the Scientific Council of the National Medical Research Center for Children's Health of Ministry of Healthcare of the Russian Federation. All patients and/or their legal representatives gave their informed consent to the study. The efficacy of treatment with velaglucerase alfa in children with Gaucher disease type 1 was assessed by analyzing monitoring data of 15 patients aged 2 to 15 years who had been registered in the Russian Pediatric Gaucher Registry established at National Medical Research Center for Children's Health of Ministry of Healthcare of Russia over the period from 2015 to 2023. None of the patients had ever undergone enzyme replacement therapy before they were included in this study. The median age at the start of treatment was 6.5 years. We analyzed the patients' anthropometric, laboratory and instrumental data at 0, 6, 12, 24 and 36 months. The initial dose of enzyme replacement therapy ranged from 30 to 60 units/kg (with the median of 43 units/kg per infusion) once every 2 weeks based on disease severity. In as little as 6 months after the initiation of therapy with velaglucerase alfa, patients with Gaucher disease type 1 showed a statistically significant improvement in all measured parameters (p < 0.001): normalization of the median hemoglobin concentration and platelet count (from 113 to 125 g/L and from 111 to 163 × 109/L, respectively); a reduction in degree of liver and spleen enlargement (in terms of volume, from 45.1 to 17.9% and from 39.4 to 15.5%, respectively); a reduction in degree of the right liver lobe enlargement (in terms of linear measurements, from 27.2 to 11.1%); a reduction in degree of spleen enlargement (in terms of its length and width, from 73.4 to 37.8% and from 60.3 to 17.5%, respectively). Our patients had a remarkable decrease in biomarker activity after 3 years of therapy: chitotriosidase activity decreased from 2699 to 227 nmol/mL/h and glucosylsphingosine level was reduced from 204.0 to 35.3 ng/mL (р < 0.001). There were no adverse events during the course of treatment. After 6 months and 1 year of regular enzyme replacement therapy with appropriate doses of velaglucerase alfa initiated in a timely manner, children with Gaucher disease type 1 achieve normal hemoglobin concentrations and platelet counts, a reduction in biomarker activity, and a decrease in liver and spleen volumes. After 3 years of enzyme replacement therapy, patients achieve their main therapeutic goals such as the resolution of anemia and thrombocytopenia, an almost complete regression of hepatosplenomegaly and the normalization of bone mineral density and height adjusted for age.

The Clinical Efficacy of Imiglucerase versus Eliglustat in Patients with Gaucher's Disease Type 1: A Systematic Review.

Gaucher's disease (GD) is one of the most common lysosomal diseases in humans. It results from β-glucosidase deficiency and leads to necrosis, especially in macrophages with the accumulation of glucosylceramidase in cells. Most of the deleterious effects of the disease are seen in the liver, spleen, and bone marrow. The aim of this study was to compare the efficacy of Imiglucerase with Eliglustat in treating patients with GD. PubMed/Medline, Cochrane Library, Scopus, Web of Science, Embase, and Google Scholar were searched from inception to August, 2018. Predefined inclusion criteria for included studies were based on search methodology and are as follows: All randomized, quasi-randomized controlled, and cohort studies about patients with GD Type 1 that Imiglucerase was compared with Eliglustat were included. Two authors independently choose the papers based on the inclusion criteria. From 2979 recognized studies, three studies including two randomized clinical trials and one cohort study were recognized to meet the inclusion criteria. The primary outcomes were hemoglobin level, platelets count, liver, and spleen size, and the secondary outcomes were the immunological side effects of the medicines and bone complications. The results showed that there is no meaningful difference between the two medicines in terms of increasing blood hemoglobin, platelets count, and reducing the liver and spleen size. The findings of this review showed that both medicines are effective in the treatment of GD Type 1 and there is no statistically significant difference between their efficacies.

Highly phosphorylated β-glucocerebrosidase (M011) has much broader tissue targeting and superior substrate reduction with potential for alternative dosing strategies for the treatment of Gaucher disease type I

Highly phosphorylated β-glucocerebrosidase (M011) has much broader tissue targeting and superior substrate reduction with potential for alternative dosing strategies for the treatment of Gaucher disease type I

Inhibitors of Glucosylceramide Synthase.

Glucosylceramide synthase can be targeted by high affinity small molecular weight inhibitors for the study of glycosphingolipid metabolism and function or for the treatment of glycosphingolipid storage disorders, including Gaucher and Fabry disease. This work is exemplified by the discovery and development of eliglustat tartrate, the first stand-alone small chemical entity approved for the treatment of Gaucher disease type 1. The development of inhibitors of glucosylceramide synthase that have utility for either research or clinical purposes begins with a testing funnel for screening candidate inhibitors for activity against this enzyme and for activity in lowering the content of glucosylceramide in intact cells. Two common assays for glucosylceramide synthase, one enzyme based and another cell based, are the focus of this chapter.

Generation of β-Glucocerebrosidase variants with increased half-life in human plasma for liver directed AAV gene therapy aimed at the treatment of Gaucher disease type 1

Generation of β-Glucocerebrosidase variants with increased half-life in human plasma for liver directed AAV gene therapy aimed at the treatment of Gaucher disease type 1

Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: A case report.

The prevalence of Gaucher disease (GD) in Japan is much lower than that in Western countries; therefore, data on Japanese pediatric patients with GD type 1 are currently limited. The present study reports on the case of a Japanese pediatric patient with GD type 1 who was diagnosed when she presented with hepatosplenomegaly, thrombocytopenia and slight anemia at the age of 2 years. Serology tests revealed high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE). A bone marrow biopsy revealed the presence of Gaucher cells. Abdominal MRI indicated huge hepatosplenomegaly. Erlenmeyer flask deformity was observed on X-ray examination. MRI of the femora featured a high-intensity area within the diaphysis region. The enzymatic activity of leukocyte β-glucosidase, the measurement of which is necessary for a definitive diagnosis of GD, had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg). Based on these results, the patient was clinically diagnosed with GD. Glucocerebrosidase gene analysis identified the compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11. Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week was initiated following diagnosis. Hemoglobin levels and the platelet count gradually improved and normalized after two years. ACP and ACE levels, biomarkers of the progression of GD, also improved. Abdominal MRI at six months after the initiation of ERT revealed a decrease in the size of the liver and spleen, which normalized after 1 year. Conversely, MRI of the femora indicated no improvement in the high-intensity area within the diaphysis region for 10 years.

The Long-Term Adverse Event Profile of Oral Eliglustat for the Treatment of Gaucher Disease Type 1: Pooled Analysis of Data from 393 Patients in 4 Completed Trials

Background:Gaucher disease type 1 (GD1) is a multi-systemic disorder resulting from deficient activity of the lysosomal enzyme acid β-glucosidase leading to lysosomal accumulation of glucosylceramide (GL-1), primarily in macrophages (Gaucher cells). Thrombocytopenia, anemia, hepatosplenomegaly, and skeletal disease are common presenting symptoms, and hematologists often identify and manage the disease. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with GD1 who have extensive, intermediate, or poor CYP2D6 metabolizer phenotypes (>90% of patients). The clinical trial program for eliglustat is the largest to date for Gaucher disease, and encompasses 2 trials in treatment-naïve patients, 1 trial in stable patients switching to eliglustat after long-term enzyme replacement therapy (the historic standard of care), and a dose regimen study in mostly switch patients.Methods:We analyzed pooled treatment-emergent adverse event (AE) data from all 393 patients with GD1 from 29 countries who received at least 1 eliglustat dose in 4 completed clinical trials sponsored by Sanofi Genzyme: Phase 2 (NCT00358150, N=26), Phase 3 ENGAGE (NCT00891202, N=40), Phase 3 ENCORE (NCT00943111, N=157), and Phase 3 EDGE (NCT01074944, N=170).Results:Mean overall treatment duration in all 393 patients from the 4 completed trials was 3.6 years (maximum: 9.3 years), representing 1400 patient-years of eliglustat exposure. Overall, 81% (n=319) of patients remained in their trial until the availability of commercial eliglustat or study completion. Twenty-five (6%) patients withdrew due to AEs, including 9 patients (2%) with AEs considered related to eliglustat: mild thrombocytopenia (1 patient); mild ventricular tachycardia (1 patient); mild vertigo (1 patient); mild lethargy and mild exfoliative rash (1 patient); mild nausea, mild headache, and moderate anemia (1 patient); moderate arrhythmia (1 patient); moderate palpitations (1 patient); moderate gastroesophageal reflux disease and moderate dyspepsia (1 patient); severe upper abdominal pain (1 patient). Other reasons for study withdrawals were: patient wished to withdraw (n=25, 6%), pregnancy (n=15, 4%), noncompliance (n=3, 1%), and “other” (n=6, 2%). There were 2 on-treatment deaths, neither of which were considered related to eliglustat (downhill skiing accident and cardiac arrest due to hemorrhage after blunt abdominal trauma). Most AEs were mild or moderate (97%) in severity and considered unrelated to eliglustat (86%). Four AEs considered related to eliglustat were reported in ≥5% of patients: dyspepsia (6%), headache (5%), abdominal pain upper (5%), and dizziness (5%). Most of these common related AEs were mild or moderate, occurred only once per patient, and lasted less than 2 weeks. A total of 77 (20%) patients reported at least 1 serious AE, the majority of which were due to hospitalizations for intercurrent illnesses (e.g., appendicitis) and underlying diseases for which Gaucher patients are at increased risk (e.g., femur fracture, joint dislocation, hepatocellular carcinoma, and cholecystitis). Eight patients (2%) had at least 1 serious AE considered related by the investigator: ventricular tachycardia; atrioventricular block and atrioventricular block second degree; peripheral neuropathy; intestinal obstruction; syncope (2 patients); syncope and muscular weakness; arrhythmia. Most were mild or moderate, recovered/resolved, and did not lead to study withdrawal. Most reported cardiac AEs were findings detected in asymptomatic patients during protocol-defined periodic 24‐hour Holter monitoring, were classified as mild, and did not lead to study withdrawal. No clinically significant prolongations of the QTcF interval were observed during extensive electrocardiographic and Holter monitoring in the clinical studies. No differences were observed for the overall frequency of AEs by age group, CYP2D6 metabolizer phenotype, or upper 10th percentile for plasma eliglustat exposure. The proportion of patients reporting AEs decreased over time on eliglustat.Conclusions:This pooled analysis of AE data from one Phase 2 and three Phase 3 completed eliglustat trials demonstrates long-term safety and tolerability of eliglustat in the treatment of adults with GD1. DisclosuresPeterschmitt:Sanofi Genzyme: Employment. Freisens:Sanofi Genzyme: Employment. Hou:Sanofi Genzyme: Employment. Underhill:Sanofi Genzyme: Employment. Foster:Sanofi Genzyme: Employment. Gaemers:Sanofi Genzyme: Employment.

Budget Impact Analysis of Eliglustat for the Treatment of Gaucher Disease Type 1 in the United States.

Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings. To evaluate the budget impact from a U.S. payer perspective associated with transitioning patients receiving ERTs to the oral SRT eliglustat for the treatment of adults with GD1. A budget impact model estimated the change in pharmaceutical and administration costs resulting from increasing the market share of eliglustat from 12% (current) to 44% (new). The market share for eliglustat was drawn equally from existing shares of imiglucerase (40%) and velaglucerase alfa (40%) and assumed to be static over the analysis period. ERT costs were adjusted to account for site of care-based markup and the proportion of patients receiving infusions in each site of care (home, infusion center, or hospital outpatient). Annual ERT costs were calculated assuming a biweekly dose of 47.4 U per kg, a 72-kg patient weight, and 24 infusions per year. The effect of key variables was tested in the sensitivity analyses. All costs are expressed in 2017 U.S. dollars. In a new plan with 5 million members and 25 GD1 treated patients, increased use of eliglustat resulted in an annual savings of $1,526,710 and a total savings of $4,580,130 (13.6%) over 3 years. The corresponding annual per member per month savings was $0.025. This is further illustrated in the sensitivity and scenario analyses where the use of eliglustat was cost saving in all cases. Shifting more patients receiving ERT in the hospital outpatient setting to eliglustat resulted in increased savings. Based on these analyses, increased use of eliglustat resulted in meaningful cost savings to a payer's overall budget. Cost savings are highest among patients switching from ERT administered in a hospital outpatient setting. The results suggest that cost savings are also likely achievable from initiating patients on oral eliglustat instead of infusion-based therapy from the outset of treatment. This study was sponsored by Sanofi Genzyme. Evidera received funding from Sanofi Genzyme to conduct this study and prepare the manuscript. The sponsor collaborated on the study design, analysis, interpretation of results, and writing of the manuscript. Nalysnyk is an employee of and shareholder in Sanofi Genzyme. Ward, Cele, and Uyei are employees of Evidera, which provides consulting and other research services to biopharmaceutical companies. Sugarman was also an Evidera employee when the study was being conducted and the manuscript written. This study was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2016, October 3-6, 2016; National City, MD, and at the International Society for Pharmacoeconomics and Outcomes Research, 22nd Annual International Meeting; May 20-24, 2017; Boston, MA.

The Clinical Efficacy of Imiglucerase versus Eliglustat in Patients with Gaucher's Disease Type 1

Gaucher's disease (GD) is one of the most common lysosomal diseases in humans. It results from β-glucosidase deficiency and leads to necrosis, especially in macrophages with the accumulation of glucosylceramidase in cells. Most of the deleterious effects of the disease are seen in the liver, spleen, and bone marrow. The aim of this study was to compare the efficacy of Imiglucerase with Eliglustat in treating patients with GD. PubMed/Medline, Cochrane Library, Scopus, Web of Science, Embase, and Google Scholar were searched from inception to August, 2018. Predefined inclusion criteria for included studies were based on search methodology and are as follows: All randomized, quasi-randomized controlled, and cohort studies about patients with GD Type 1 that Imiglucerase was compared with Eliglustat were included. Two authors independently choose the papers based on the inclusion criteria. From 2979 recognized studies, three studies including two randomized clinical trials and one cohort study were recognized to meet the inclusion criteria. The primary outcomes were hemoglobin level, platelets count, liver, and spleen size, and the secondary outcomes were the immunological side effects of the medicines and bone complications. The results showed that there is no meaningful difference between the two medicines in terms of increasing blood hemoglobin, platelets count, and reducing the liver and spleen size. The findings of this review showed that both medicines are effective in the treatment of GD Type 1 and there is no statistically significant difference between their efficacies.

Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease.

The purpose of this article is to review eliglustat tartrate, a substrate reduction therapy, for the treatment of Gaucher disease type 1 (GD1). GD is an rare inborn error of metabolism caused by accumulation of lipid substrates such as glucosylceramide within the monocyte-macrophage system that affects the body by causing enlargement of the spleen and liver, destruction of bone, and abnormalities of the lungs and blood, such as anemia, thrombocytopenia, and leukopenia. GD is classified into three types: GD1, a chronic and non-neuronopathic disease accounting for 95% of GD cases; and types 2 and 3 (GD2 GD3) which are more progressive diseases with no approved drugs available at this time. Treatment options for GD1 include enzyme replacement therapy and substrate reduction therapy. Eliglustat works by inhibiting UDP-glucosylceramide synthase, the first enzyme that catalyzes the biosynthesis of glycosphingolipids, thus reducing the load of glucosylceramide influx into the lysosome. Eliglustat was approved by the US Food and Drug Administration after three Phase I, two Phase II, and two Phase III clinical trials. The dose of eliglustat is 84 mg twice a day or once daily depending on the cytochrome P450 2D6 genotype of the patient.

Velaglucerase alfa in the treatment of Gaucher disease type 1: an update

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme acid β-glucosidase. Enzyme replacement therapy is the standard of care for the treatment of GD type I. Currently, three preparations, including imiglucerase (Cerezyme®, Genzyme Corporation, MA, USA), taliglucerase alfa (Elelyso®, Pfizer Inc., NY, USA) and velaglucerase alfa (VPRIV®, Shire Human Genetic Therapies Inc., Dublin, Ireland), are commercially available. Here, we will review the recent literature addressing the safety and efficacy of velaglucerase, particularly as compared with the other enzyme replacement therapy products, as well as the treatment of GD type 1 with velaglucerase alfa.

Engage - a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Eliglustat in Adults with Gaucher Disease Type 1: Results after 18 Months

▪Introduction: Eliglustat, a ceramide analogue, is a novel, oral substrate-reduction therapy in development for Gaucher disease type 1 (GD1). We present 18-month results from ENGAGE (NCT00891202), a randomized, double-blind, placebo-controlled, Phase-3 trial (sponsored by Genzyme, a Sanofi company, Cambridge, MA) investigating the efficacy and safety of eliglustat in untreated adults with GD1.Methods: During the primary analysis period (PAP), 40 patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months and then entered a 9-month, open-label extension phase in which all patients received eliglustat. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Secondary endpoints included changes in hemoglobin levels, liver volume, and platelet counts. Bone efficacy endpoints included changes in bone marrow burden (BMB) scores, total bone mineral density (BMD), and T- and Z-scores.Results: In the 9-month PAP, eliglustat was superior to placebo in all primary and secondary endpoints; no patients discontinued due to an adverse event. For 18 of 20 patients who received 18 months of eliglustat, mean improvements from baseline continued (spleen: -45%, hemoglobin: +1.02 g/dL; liver: -11%; platelets: +58%). For 20 of 20 patients previously receiving placebo for 9 months who then crossed-over to eliglustat during the extension phase, mean improvements after 9 months of eliglustat were consistent with what was seen in the PAP in the eliglustat-treated patients: spleen: -31%; hemoglobin: +0.79 g/dL; liver: -7.3%; and platelets: +40%. During the PAP, BMB scores, indicating bone marrow infiltration, decreased in eliglustat patients and were unchanged in placebo patients; changes in total BMD and in T- and Z-scores showed a positive trend with eliglustat compared with placebo, although changes were not statistically significant. Eliglustat-treated patients showed continued improvements in bone parameters during the 9-month extension period. No new safety concerns were identified.Conclusion: ENGAGE met its primary and secondary efficacy endpoints in the PAP. Placebo cross-over patients showed improvements during the extension period similar to the eliglustat-treated patients during the PAP. Patients in the eliglustat-treatment group showed continued improvements in the first 9 months of the extension phase. DisclosuresAmato:Protalix-Pfizer: Consultancy, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Actelion: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Shire: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; 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. Dasouki:Genzyme, a Sanofi Company: Consultancy, Travel reimbursement Other. Packman:Genzyme, a Sanofi Company: Consultancy, Research Funding, Travel reimbursement Other. Pastores:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Balwani:Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel reimbursement Other. Mistry:Genzyme, a Sanofi Company: Consultancy, Honoraria, Research Funding, Travel reimbursement, Research grants Other. Shankar:Biomarin: Consultancy, received funds for fellowship training, for educational and patient meetings , received funds for fellowship training, for educational and patient meetings Other; Protalix-Pfizer: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Shire: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Actelion: Consultancy, received funds for fellowship training, for educational and patient meetings Other. Solano: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.

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

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. DisclosuresRosenbloom: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.

Eliglustat: First Global Approval

Eliglustat [Cerdelga™ (US, EU)], a small-molecule oral glucosylceramide analogue that inhibits the enzyme glucosylceramide synthase has been developed by Genzyme Corporation (a subsidiary of Sanofi) for the treatment of Gaucher disease type 1 in adults. Inhibition of this enzyme reduces the accumulation of the lipid glucosylceramide in the liver, spleen, bone marrow and other organs. Eliglustat received its first global approval in this indication in the US, for use in treatment-naïve and treatment-experienced adult patients. It is also under regulatory review in the EU and Japan. This article summarizes the milestones in the development of eliglustat leading to this first approval for Gaucher disease type 1.

Engage: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multi-center Study To Investigate The Efficacy and Safety Of Eliglustat In Adults With Gaucher Disease Type 1: 9 Month Results

BackgroundGaucher disease type 1 is one of the most common lysosomal storage disorders. Deficiency of the lysosomal enzyme acid-β-glucosidase leads to accumulation of glucosylceramide (GL-1) in the spleen, liver, and bone marrow. Enzyme replacement therapy has been the mainstay of therapy for the last 20 years. Substrate reduction therapy is another treatment approach that inhibits GL-1 synthase and ultimately restores the balance between synthesis and degradation of the substrate. Eliglustat is a novel oral substrate reduction therapy that is currently in development for the treatment of Gaucher disease type 1. ENGAGE (NCT00891202) is a randomized, double-blind, placebo-controlled, Phase 3 trial sponsored by Genzyme, a Sanofi company investigating the efficacy and safety of eliglustat in untreated adults with Gaucher disease type 1. MethodForty patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Other efficacy measures included hemoglobin, liver volume, and platelets. Bone endpoints included bone marrow burden (BMB) scores and bone mineral density changes (DXA). Quality of life assessments included the Gaucher Disease Severity Scoring System (DS3). Safety monitoring included adverse event reporting, and lab and electrocardiogram evaluations. ResultsIn patients receiving eliglustat vs. placebo, mean spleen volume decreased (-28% vs. +2%, P<0.0001), mean hemoglobin increased (0.69 vs. -0.54 g/dL, P<0.0006), liver volume decreased (-5.20% vs. +1.44%, P<0.0072), and platelets increased (+32% vs. -9.06%, P<0.0001). Significant improvements (eliglustat vs. placebo) were observed for total (-1.1 vs. 0.0, p=0.002), spine (-0.6 vs. 0.1, p=0.002), and femur (-0.5 vs. 0.0, p=0.026) BMB scores. Although patients with symptomatic bone disease were excluded, absolute change in total spine DXA Z-scores approached significance (least square mean treatment difference=0.2, p=0.06). Burden of disease, as measured by the Gaucher DS3, was significantly reduced following treatment with eliglustat vs. placebo (least square mean treatment difference=-0.3, p=0.0452). No patients discontinued due to an adverse event, all of which were classified as mild to moderate, and 39/40 patients transitioned into the ongoing open-label trial. Arthralgia and nasopharyngitis occurred in >10% of eliglustat vs. placebo patients. ConclusionENGAGE met its primary and secondary efficacy endpoints. Significant effects on bone marrow and a trend toward BMD improvement in spine were observed. Eliglustat treatment was effective and well-tolerated in untreated adults with Gaucher disease type 1. Disclosures:Shankar:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lukina:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau. Amato:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Packman:Genzyme, a Sanofi company: Consultancy, Research Funding. Pastores:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Balwani:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Research Funding. Ross:Genzyme, a Sanofi company: Employment. Marulkar:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase

Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program.

Velaglucerase alfa in the treatment of Gaucher disease type 1

Gaucher disease is an autosomal recessively inherited lysosomal storage disease that results from the defective activity of the enzyme acid β-glucosidase (glucocerebrosidase). Velaglucerase alfa was recently developed and approved as an alternative form to imiglucerase enzyme therapy. Despite differences in primary structure and glycosylation patterns, recent preclinical and clinical trials of the preparation have shown similar efficacy and safety profiles to those of imiglucerase. The development of alternative therapies, such as velaglucerase alfa for Gaucher disease, is providing clinicians with a larger armamentarium of therapies, allowing for a more personalized approach to patient care.

Genz-112638 for Gaucher Disease Type 1: Phase 2 Clinical Trial Results After 18 Months of Treatment.

Abstract 1349▪▪This icon denotes an abstract that is clinically relevant. IntroductionGenz-112638, a novel oral small molecule inhibitor of glucosylceramide synthase, is under development for the treatment of Gaucher disease type 1 (GD1). An open-label, multicenter Phase 2 clinical trial to evaluate the efficacy, safety, and pharmacokinetics of Genz-112638 in patients with GD1 has completed its primary analysis period and is ongoing. MethodsThis trial of Genz-112638, given 50 mg or 100 mg twice per day orally, treated 26 adults with GD1 (16 females, 10 males; mean age 34 years, range 18-60; all Caucasian) at 7 sites in 5 countries. Inclusion criteria included splenomegaly (volume ≥10 multiples of normal [MN]) and either thrombocytopenia (platelet count 45,000-100,000/mm3) or anemia (hemoglobin level 8-10 g/dL [females] or 8-11 g/dL [males]). Patient had not received enzyme replacement or substrate reduction therapy in the prior 12 months. The primary efficacy endpoint was a composite of 52-week improvements in at least 2 of 3 parameters that were abnormal at baseline: spleen volume (–15%), hemoglobin level (+0.5 g/dL) or platelet count (+15%). Bone status was evaluated by central review of MRI, DXA and X-ray. Data were analyzed after 1 year; an additional analysis at 18 months is underway. Long-term treatment and monitoring is ongoing. ResultsTwenty-two patients completed 52 weeks of treatment; 4 withdrew. Twenty patients continued beyond 52 weeks and have now completed 18 months of treatment. The 52-week primary endpoint was met by 77% (20/26) of all patients and by 91% of 22 patients completing 52 weeks. At 52 weeks, mean hemoglobin improved by 1.6 ± 1.3 g/dL and platelet count by 40 ± 37%. Mean spleen volume decreased by 39 ± 11% and mean liver volume by 17 ± 10%. Chitotriosidase and CCL-18 had median decreases of 52% and 55%, respectively. Plasma glucosylceramide levels normalized in all patients. No bone crises or reductions in mobility were reported. Femur MRI showed improved dark marrow signal in 7 patients and stable findings in the remaining 13 patients with data. There were no new lytic lesions or infarcts; one pre-existing infarct progressed. Lumbar spine bone mineral density (DXA Z-score) was -1.32 ± 1.02 at baseline and improved by a mean of 0.31 ± 0.48 (p=0.0146; n=18). Genz-112638 was well tolerated with an acceptable safety profile. In all, 91% of AEs were unrelated to drug treatment and most were mild in severity. The most common AEs overall were urinary tract infection and GI symptoms; no single AE occurred in more than 3 patients. Seven drug-related AEs occurred in 6 patients early in treatment and were mild and transient. Updated 18-month safety and efficacy results will be available for presentation. ConclusionGenz-112638 improved hematologic, visceral and bone manifestations in GD1 and was well tolerated in the primary analysis period of this Phase 2 study. Longer-term results will provide important additional safety and efficacy information. Randomized phase 3 studies of Genz-112638 in previously untreated and Cerezyme-stabilized patients will begin in the autumn of 2009. DisclosuresPeterschmitt:Genzyme Corporation: Employment. Watman:Genzyme Corporation: Participated in an adivosory board. Arreguin:Genzyme Corporation: Research Funding. Pastores:Genzyme Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaper:Genzyme Corporation: Employment. Singh:Genzyme Corporation: Employment. Puga:Genzyme Corporation: Employment.

Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1

Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism, associated with multisystemic manifestations resulting from the lysosomal accumulation of an incompletely degraded material (glucosylceramide) within cells of monocyte/macrophage lineage. In the majority of GD patients with non-neurological involvement (type 1), the clinical features are dominated by haematological, visceral (hepatic and splenic) and skeletal complications. Infrequently, cardiopulmonary involvement may develop and lead to major morbidity. Investigations of substrate turnover within cellular compartments, such as the lysosome, indicate that progressive tissue storage occurs when the activity of the responsible hydrolytic enzyme declines. Thus, the provision of functional enzyme to deficient cells is a straightforward means of achieving metabolic correction. Conversely, the concentration of stored substrate within cells bearing particular affected enzymes (i.e., expressing residual activity) may be controlled by a reduction of the ‘load’. This means that metabolic homeostasis can also be restored by restricting the amount of substrate presented to disease cells to a level that can be hydrolysed by the existing enzyme activity. Proof-of-concept for both approaches has been demonstrated through enzyme replacement therapy using alglucerase/imiglucerase and more recently, substrate reduction therapy by miglustat. Enzyme replacement therapy is proven to be safe and effective in the treatment of GD type 1, establishing imiglucerase as the current standard of care. The experience with substrate reduction therapy, specifically miglustat, is limited but encouraging. This review is an attempt to examine the potential role of this latter approach in light of current patient management. The consideration of miglustat as a therapeutic option requires the appropriate selection of patients (amongst those unwilling or unsuitable to receive enzyme replacement therapy), a definition of the therapeutic objectives and monitoring not only for response but potential adverse effects.