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

The cognitive profile of type 1 Gaucher disease patients

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain.This work was supported by Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. This study was set up under the auspices of the European Working Group on Gaucher Disease (EWGGD). MB received financial support from Actelion to conduct her activities related to this study. MB, CEMH, INvS and AM have received consultancy fees from Actelion for participation in clinical trial programs and other projects, and CEMH, INvS and AM have received speaker fees for participation in scientific congresses and sponsored events. MB and CEMH donate all fees to the Gaucher Stichting, a national foundation that supports research in the field of lysosomal storage disorders. Consulting fees for INvS are donated to the Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders. DH has received consultancy fees from Actelion for participation in clinical trials, grants for local laboratory projects, and speaker fees for participation in scientific congresses and sponsored events. KEM, PG and LM have received speaker fees from Actelion for participation in sponsored events. PG received consultancy fees for participation in local clinical projects. LM received a travel grant from Actelion and was financially supported by TÁMOP 4.2.1./B-09/1/KONV-2010-0007 and TÁMOP 4.2.2-08/1-2008-0015. CN got speaker fees for participation in scientific meetings. KAW was sole shareholder of Cognitive Drug Research Ltd. Cognitive Drug Research Ltd supplied the CDR System for the study and received financial support from Actelion. KAW is currently an employee of United BioSource Corporation (UBC) that owns the CDR System since August 2009. CL is an employee of Actelion Pharmaceuticals Ltd. MP and MM report no conflicts of interest

The cognitive profile of type 1 Gaucher disease patients

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain

Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement

Introduction With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). Methods To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. Results After five years of iterative work a document with the ideal criteria for a PTCOE is presented. Conclusions Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Granulopoiesis during acute Toxoplasma gondii infection in mice

There is little evidence for the role of granulocytes in the host defence against the protozoan parasite Toxoplasma gondii. Thus, the purpose of this study was to assess the involvement of granulocytes during acute murine infection with the parasite virulent RH strain. Since, all infected animals succumb to infection in a dose-dependent period of time, the effect of two parasite doses, 2x10(2) and 2x10(6), on granulocytis cell compartments in the bone marrow and peripheral blood up to 2 or 6 days post infection, respectively, was investigated. The data obtained revealed that granulocytic cells at various stages of differentiation and maturation were affected by T.gondii infection regardless of the dose applied. The observed oscillating changes in the number of cells in granulocytic proliferative and nonproliferative compartments imply that parallel with T.gondii-induced damage to granulocytic cells, a process of stimulated production of granulocytes occurred. Although some differences in the kinetics of cellular changes and in the extent of cell damage were found similar reactivity patterns of granulocytic cells were seen following infection with both doses. Our results demonstrated significant changes in granulopoiesis during T.gondii infection, suggesting a possible contribution of granulocytes to parasite control

Interleukine-17-induced inhibitory effect on late stage murine erythroid bone marrow progenitors

Recent studies have shown that the T cell-derived cytokine, interleukin-17 (IL-17), stimulates hematopoiesis, specifically granulopoiesis inducing expansion of committed and immature progenitors in bone marrow. Our previous results pointed to its role in erythropoiesis too, demonstrating significant stimulation of BFU-E and suppression of CFU-E growth in the bone marrow from normal mice. As different sensitivities of erythroid and myeloid progenitor cells to nitric oxide (NO) were found, we considered the possibility that the observed effects of IL-17 were mediated by NO. The effects of recombinant mouse IL-17, NO donor (sodium nitroprusside - SNP) and two NO synthases inhibitors (L-NAME and aminoguanidine) on erythroid progenitor cells growth, as well as the ability of IL-17 to induce nitric oxide production in murine bone marrow cells, were examined. In addition, we tested whether the inhibition of CFU-E colony formation by IL-17 could be corrected by erythropoietin (Epo), the principal regulator of erythropoiesis. We demonstrated that IL-17 can stimulate low level production of NO in murine bone marrow cells. Exogenously added NO inhibited CFU-E colony formation, whereas both L-NAME and aminoguanidine reversed the CFU-E suppression by IL-17 in a dose-dependent manner. The inhibition of CFU-E by IL-17 was also corrected by exposure to higher levels of Epo. The data obtained demonstrated that at least some of the IL-17 effects in bone marrow related to the inhibition of CFU-E, were mediated by NO generation. The fact that Epo also overcomes the inhibitory effect of IL-17 on CFU-E suggests the need for further research on their mutual relationship and co-signalling