97 research outputs found
Review of the safety and efficacy of imiglucerase treatment of Gaucher disease
Most patients who suffer from symptomatic Gaucher disease will benefit from enzyme replacement therapy (ERT) with imiglucerase. The safety profile is excellent, only a small percentage of those exposed developing antibodies; similarly, very few patients require pre-medication for allergic reactions. Within 3 to 5 years of imiglucerase therapy, best documented at doses of 30 to 60 units/kg/infusion, hepatosplenomegaly can be expected to be reduced so that the liver volume will be maintained at 1 to 1.5 times normal (30% to 40% reduction from advent of ERT) and spleen volume to ≤ 2 to 8 times normal (50% to 60% reduction from advent of ERT). For anemic and thrombocytopenic patients, with 2 to 5 years of imiglucerase, hemoglobin levels are expected to be ≥ 11 g/dL for women and children and ≥ 12 g/dL for men; and platelet counts in patients with an intact spleen, depending on the baseline value, should approximately be doubled. Bone crises and bone pain but not irreversible skeletal damage will improve in most patients. Nonetheless, some features and some symptomatic patients apparently do not respond equally well and/or perhaps inadequately. The benefit for patients with the neuronopathic forms is primarily in improved visceral and hematological signs and symptoms. There are still several unresolved issues, the high per-unit cost being an important one, which have spurred the development of biosimilar enzymes as well as chaperone therapies currently in clinical trials
Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.
Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc
Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease
Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm3). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187
Bone Mineral Density in Gravida: Effect of Pregnancies and Breast-Feeding in Women of Differing Ages and Parity
Changes of bone during pregnancy and during lactation evaluated by bone mineral density (BMD) may have implications for risk of osteoporosis and fractures. We studied BMD in women of differing ages, parity, and lactation histories immediately postpartum for BMD, -scores, and -scores. Institutional Review Board approval was received. All women while still in hospital postpartum were asked to participate. BMD was performed by dual-energy X-ray absorptiometry (DXA) machine at femoral neck (FN) and lumbar spine (LS) by a single technician. Of 132 participants, 73 (55.3%) were ≤30 years; 27 (20.5%) were primiparous; 36 (27.3%) were grand multiparous; 35 (26.5%) never breast fed. Mean FN -scores and -scores were higher than respective mean LS scores, but all means were within the normal limits. Mean LS -scores and -scores were highest in the grand multiparas. There were only 2 (1.5%) outliers with low -scores. We conclude that, in a large cohort of Israeli women with BMD parameters assessed by DXA within two days postpartum, mean -scores and -scores at both the LS and FN were within normal limits regardless of age (20-46 years), parity (1-13 viable births), and history of either no or prolonged months of lactation (up to 11.25 years)
Dental profile of patients with Gaucher disease
BACKGROUND: This study was conducted to determine whether patients with Gaucher disease had significant dental pathology because of abnormal bone structure, pancytopenia, and coagulation abnormalities. METHODS: Each patient received a complete oral and periodontal examination in addition to a routine hematological evaluation. RESULTS: Gaucher patients had significantly fewer carious lesions than otherwise healthy carriers. Despite prevalence of anemia, there was no increase in gingival disease; despite the high incidence of thrombocytopenia, gingival bleeding was not noted; and despite radiological evidence of bone involvement, there was no greater incidence loss of teeth or clinical tooth mobility. CONCLUSIONS: These data represent the first survey of the oral health of a large cohort of patients with Gaucher disease. It is a pilot study of a unique population and the results of the investigation are indications for further research. Based on our findings, we recommend regular oral examinations with appropriate dental treatment for patients with Gaucher disease as for other individuals. Consultation between the dentist and physician, preferably one with experience with Gaucher disease, should be considered when surgical procedures are planned
A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk
Carriers of GBA1 gene variants have a significant risk of developing Parkinson's disease (PD). A cohort study of GBA carriers between 40-75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40-74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7-33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14-32%), Unified Parkinson's Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2-26.4%), smell assessment (12.4%, 95% CI 6.6-20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7-19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as "abnormal". Then we calculated the percentage of "abnormal" tests for each subject; the median (range) was 4.55 (0-43.5%). Twenty-two subjects had more than 15% "abnormal" tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD
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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
Plasma chitotriosidase activity versus CCL18 level for assessing type I Gaucher disease severity: protocol for a systematic review with meta-analysis of individual participant data.
BACKGROUND: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency in acid beta-glucosidase. GD exhibits a wide clinical spectrum of disease severity with an unpredictable natural course. Plasma chitotriosidase activity and CC chemokine ligand 18 (CCL18) have been exchangeably used for monitoring GD activity and response to enzyme replacement therapy in conjunction with clinical assessment. Yet, a large-scale head-to-head comparison of these two biomarkers is currently lacking. We propose a collaborative systematic review with meta-analysis of individual participant data (IPD) to compare the accuracy of plasma chitotriosidase activity and CCL18 in assessing type I (i.e., non-neuropathic) GD severity. METHODS: Eligible studies include cross-sectional, cohort, and randomized controlled studies recording both plasma chitotriosidase activity and CCL18 level at baseline and/or at follow-up in consecutive children or adult patients with type I GD. Pre-specified surrogate outcomes reflecting GD activity include liver and spleen volume, hemoglobin concentration, platelet count, and symptomatic bone events with imaging confirmation. Primary studies will be identified by searching Medline (1995 onwards), EMBASE (1995 onwards), and Cochrane Central Register of Controlled Trials (CENTRAL). Electronic search will be complemented by contacting research groups in order to identify unpublished relevant studies. Where possible, IPD will be extracted from published articles. Corresponding authors will be invited to collaborate by supplying IPD. The methodological quality of retrieved studies will be appraised for each study outcome, using a checklist adapted from the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The primary outcome will be a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, or platelet count <100 × 109/L. Effect size estimates for biomarker comparative accuracy in predicting outcomes will be reported as differences in areas under receiver operating characteristic curves along with 95% confidence intervals. Effect size estimates will be reported as (weighted) mean differences along with 95% confidence intervals for each biomarker according to outcomes. IPD meta-analysis will be conducted with both one- and two-stage approaches. DISCUSSION: Valid and precise accuracy estimates will be derived for CCL18 relative to plasma chitotriosidase activity in discriminating patients according to GD severity. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015 CRD42015027243
Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD
Development and validation of Gaucher disease type 1 (GD1)-specific patient-reported outcome measures (PROMs) for clinical monitoring and for clinical trials.
BACKGROUND: Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. RESULTS AND DISCUSSION: The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients' understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test-retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test-retest reliability. CONCLUSIONS: Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment
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