Plasma adiponectin is a potential biomarker for organ involvement in male Fabry disease patients.

Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in GLA. It manifests in hemizygous males and in many heterozygous females. Cardiovascular and renal involvement are frequent. Adiponectin is a circulating hormone that has been linked to numerous disease conditions including heart and kidney failure. In the present pilot study, we investigated plasma adiponectin levels in a cohort of 56 individuals with a genetic diagnosis of Fabry disease. Adiponectin levels did not differ between patients and controls. However, in male patients, significantly decreased adiponectin levels were associated with cardiovascular manifestation, while increased levels were associated with renal involvement. Similar trends in female patients did not reach statistical significance. Lyso-Gb3, a metabolite with good diagnostic/screening performance, was not indicative of organ involvement. In combination, adiponectin and Lyso-Gb3 may be of value for identification and stratification of Fabry patients. A potential additional relevance for prognosis and monitoring should be addressed by future studies in larger cohorts.

Children with type 1 Gaucher disease: Changing profiles in the 21st century.

Gaucher disease (GD) has phenotypic variability. Increased GD awareness especially among at-risk Ashkenazi Jews (AJ) and availability of non-invasive diagnosis induced trend to prenatal screening. We retrospectively assessed pediatric (<16years) Israeli AJ GD patients to ascertain demographics and phenotype at presentation and over-time because many were identified by large-scale screening. 55/67 patients born since 01/01/2000 are AJ with non-neuronopathic GD: 28 (50.9%) are N370S/N370S; 24 (43.6%) are N370S/other; 3 (3.5%) have no N370S allele. 30 (54.5%) diagnosed by screening; 10 (18.2%) with sibling diagnosed by screening. Of 19 (34.5%) receiving enzyme replacement therapy (ERT), 4/19 (21.1%) were by screening (N370S/N370S; N370S/L444P, N370S/84GG, N370S/IVS2+1); 15/19 (78.9%) diagnosed by symptoms and/or symptomatic sibling. 4/19 (21.1%) began ERT at age <2years; 9/19 (47.4%) at 3-5years; 6/19 (31.6%) at 6-12years. 49% presented with height/weight growth percentiles ≤25%, but group means were comparable up to 12years follow-up including 10 receiving ERT (8 for >5years). 22% presented with anemia, 20% with thrombocytopenia; at last follow-up 4% and 6%, respectively, remained cytopenic. We present a new demographic profile for pediatric GD because many identified by screening had/have few GD signs/symptoms. Nonetheless, early diagnosis is important, especially for non-N370S, non-mild genotypes.

Liver involvement in Gaucher disease - Review and clinical approach.

Gaucher disease (GD), one of the most prevalent lysosomal storage diseases, is associated with glucocerebroside accumulation in cells of the monocyte-macrophage system in various organs, including the liver. Evaluating and managing liver disease in patients with Gaucher disease may be challenging. While hepatic involvement is common in Gaucher disease, its severity, and clinical significance span a wide spectrum, ranging from sub-clinical involvement to liver cirrhosis with its associated complications including portal hypertension. Apart from liver involvement in Gaucher disease, patients with may also suffer from other comorbidities involving the liver. That Gaucher disease itself can mimic hepatic lesions, affect laboratory tests used to characterize liver disease, and may be associated with non-cirrhotic portal hypertension, complicates the diagnostic approach even more. Better understanding of liver involvement in Gaucher disease can spare patients unnecessary invasive testing, and assist physicians in decision making when evaluating patients with Gaucher disease suspected for significant liver disease. This review describes the various clinical manifestations, laboratory and imaging abnormalities that may be encountered when following patients with Gaucher disease for liver involvement. The mechanism for liver disease are discussed, as well as the possible hepato-protective effect of glucocerebroside, and the a diagnostic and treatment approaches.

Growth and final height of children with Gaucher disease: A 15-year follow-up at an Israeli Gaucher center.

BACKGROUND: It is held that enzyme replacement therapy (ERT) accelerates the growth rate in children with Gaucher disease, but its effect on final height has not been established with certainty. This study presents final heights of Gaucher patients followed up for 15years. METHODS: The study included 41 adults with non-neuronopathic Gaucher disease. The final height of the patients and age at puberty was compared to their mid-parental target height and to their siblings' heights. RESULTS: Mean final height standard deviation score (HSDS) in the patients was -0.22, but none of the patients was abnormally short (HSDS of less than -2.2). Mean age at menarche of the female patients (14.7years) was significantly delayed compared to that of their mothers (P=0.0005), and mean age at first shaving in the boys was 16years. CONCLUSION: Our study showed that the mean final height of Gaucher patients fell below the mean of the 2000 CDC growth charts, but the patients were not of short stature (height less than the 3rd percentile). ERT treatment did not significantly impact the mean final HSDS. The onset of puberty, as indicated by the age at menarche, was delayed in girls with Gaucher disease.

Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

Gaucher disease is an inherited metabolic disease characterized by ß-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.

Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials.

Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (ß-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD. A total of 22 treatment-naïve patients and 21 patients previously treated with imiglucerase (switch patients) were included in the analysis. Overall, demographics between the two groups were similar. Mean lyso-Gb1 concentrations were reduced by 302.2ng/mL from baseline to week 209 in treatment-naïve patients and by 57.3ng/mL from baseline to week 161 in switch patients, corresponding to relative reductions of 82.7% and 52.0%, respectively. In both the treatment-naïve and switch groups, baseline mean lyso-Gb1 was higher for patients with at least one N370S mutation (363.9ng/mL and 90.7ng/mL, respectively) than for patients with non-N370S mutations (184.6ng/mL and 28.3ng/mL, respectively). Moderate correlations between decreasing lyso-Gb1 levels and increasing platelet counts, and with decreasing spleen volumes, were observed at some time points in the treatment-naïve group but not in the switch group. These findings support the utility of lyso-Gb1 as a sensitive and reliable biomarker for GD, and suggest that quantitation of this biomarker could serve as an indicator of disease burden and response to treatment.

Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease.

The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical studies to eligible patients who received their initial infusions at a clinic. Patients who participated in the home therapy option and received at least 10% of their infusions at home (n=100) received a range of 11.6%-100% of their scheduled infusions at home (median 87.5%), excluding infusions received at the clinic during protocol-mandated visits. The length of time over which individual patients received home therapy ranged from 13days to 4.56years (median 0.57years). During the time that home therapy was available, 2904 of 3572 (81.3%) infusions were administered at home. Ten patients experienced 62 infusion-related adverse events (IRAEs) during 38 home infusions, with malaise, pain, hypertension, fatigue, and headache being reported most frequently. No notable differences were found between the type and severity of IRAEs experienced at home and those experienced at the clinic. Home infusions administered by trained and qualified medical personnel were successfully introduced into the velaglucerase alfa clinical development program, and fewer than 10% of patients experienced IRAEs in the home setting. Local labeling and practice guidelines should be consulted for administration of velaglucerase alfa infusions at home.

Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians.

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme ß-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD.

New Directions in Gaucher Disease.

In Gaucher disease (GD), mutant lysosomal acid ß-glucocerebrosidase fails to properly hydrolyze its substrate, glucosylceramide, which accumulates in the lysosomes. Due to its phenotypic heterogeneity, GD has been classified into type 1, non-neuronopathic, and types 2 and 3, the neuronopathic forms, based on the primary involvement of the central nervous system. Neuroinflammation and necroptotic death may appear in the neuronopathic forms of GD, whereas type 1 GD patients may develop Parkinson disease (PD), a prototype of protein misfolding disorders of the nervous system. PD is significantly more prevalent among GD carriers and patients than among the non-GD populations. It is apparent that the amount of mutant enzyme present in lysosomes depends on the amount of mutant enzyme recognized as correctly folded in the endoplasmic reticulum (ER) for physiologically correct transport through the Golgi apparatus to the lysosome. Mutant enzyme recognized as misfolded is retained in the ER, inducing the Unfolded Protein Response. In the current review, we present three discrete areas of interest: molecular and cellular mechanisms underlying the association between GD and PD; the clinical and genetic associations between GD and PD; and treatment options for GD. We also discuss the relevance of induced pleuripotent stem cells to the above associations.

The association between ABO blood group and obstetric hemorrhage.

UNLABELLED: Whether intra- and early post-partum hemorrhage is influenced by ABO blood groups remains unknown. Therefore, we compared women with O to non-O blood groups with regard to maternal post-partum hemorrhage and transfusion need. This retrospective study was conducted in a single tertiary center between 2005 and 2014. For the purpose of the study, parturients were categorized as O and non-O blood groups. Data included all deliveries but excluded patients with missing blood grouping or hemoglobin values, and/or stillbirth. Drop in hemoglobin was defined as hemoglobin concentration at admission for delivery minus lowest hemoglobin concentration post-delivery. Study outcomes were postpartum hemorrhage, hemoglobin drop >2-7 g/dL inclusive, and packed red blood cells transfusion. STATISTICS: descriptive, χ(2) (p < 0.05 significant) and multivariable regression models [odds ratio (OR), 95 % confidence interval (CI), p value]. 125,768 deliveries were included. After multivariable analysis, women with O blood type relative to women with non-O blood type had significantly higher odds of postpartum hemorrhage (OR 1.14; 95 % CI 1.05-1.23, p < 0.001), higher odds of statistically significant hemoglobin decreases of >2, 3, or 4 g/dL (OR 1.07; 95 % CI 1.04-1.11, p < 0.001, OR 1.08; 95 % CI 1.03-1.14, p = 0.002, OR 1.14; 95 % CI 1.05-1.23, p = 0.001; respectively), and higher odds, albeit not statistically significant of 5, 6, or 7 g/dL decreases in hemoglobin (OR 1.13; 95 % CI 1.00-1.29, p = 0.055, OR 1.05; 95 % CI 0.84-1.32, p = 0.66, OR 1.15; 95 % CI 0.79-1.68, p = 0.46; respectively), but no difference in blood products transfusion (OR 1.03; 95 % CI 0.92-1.16, p = 0.58). In conclusion, women with blood type O may be at greater risk of obstetrical hemorrhage.

Comparison of Bone Mineral Density by Dual-Energy X-Ray Absorptiometry and Bone Strength by Speed-of-Sound Ultrasonography in Adults With Gaucher Disease.

Patients with the lysosomal disorder Gaucher disease (GD) are at risk of osteoporosis and/or avascular necrosis, but to date, no adequate biomarkers are available to ascertain individual predilections. Bone mineral density by dual-energy X-ray absorptiometry (DXA) has traditionally been used to monitor trends. With the availability of a speed-of-sound (SOS) ultrasonography to assess bone strength/elasticity, we aimed to ascertain whether these modalities are complimentary or comparable so SOS, with no radiation risk, might be used more routinely as a potential biomarker. A prospective comparative study in adult GD patients undergoing routine follow-up of bone mineral density T- and Z-scores at forearm (FA), femoral neck, and lumbar spine, and SOS Z-scores at FA was initiated. Interpretation was by qualitative categorization of Z-scores. The kappa measure of agreement beyond chance was calculated between pairs of measurements and the McNemar test was then applied. This noninterventional trial (ClinicalTrials.gov Identifier: NCT02067247) was approved by the institutional ethics committee. There were 89 patients (ages 21-78 years, 61% female, 62% common Ashkenazi genotype, 18% splenectomized, and 18% with avascular necrosis/fractures). When comparing Z-scores at FA by DXA and SOS, only 39.3% correlated, while the remaining results were in disagreement; no trend was noted. Similarly, when comparing Z-scores at the femoral neck by DXA with those at FA by SOS, 44.9% of the results were in agreement; no trend was noted; and Z-scores at the lumbar spine by DXA with FA by SOS, 46% were in agreement and no trend was noted. DXA at the 3 sites did not track in the same direction or the same magnitude of difference with SOS at FA in adult patients with GD. Due to the fundamental differences between the 2 measurements and their clinical correlates, plus the lack of long-term follow-up to assess outcome, the potential added value of the measurements at the FA by SOS in patients with GD awaits further studies.

ASPECTS OF PATIENT REPORTED OUTCOMES IN RARE DISEASES: A DISCUSSION PAPER.

OBJECTIVES: A patient reported outcome (PRO) is "any report of the status of a patient's health condition that comes directly from the patient without interpretation of the patient's response by a clinician or anyone else" (USFDA 2009). PROs are discussed widely, and many regard the patients' perspective on treatment benefit as very valuable. Although many PROs have shown satisfactory measurement properties including reliability, validity, and responsiveness, there is great concern about risk of bias, that is, in clinical trials. METHODS: Differences in perspectives of PRO measurement in rare diseases are given arising from methodology, clinical, HTA, and patient advocacy views. RESULTS: PROs are playing an important role in dealing with treatment benefit especially in small sample size as occurring often in rare diseases. Challenges remain especially regarding lack of responsiveness of generic measures, limited capture of all patient relevant aspects, study design and high risk of bias. CONCLUSIONS: PROs seem a valuable instrument to detect patient relevant aspects in rare diseases. They should be seen in addition to other approved assessment methods as randomized controlled trials but not as their substitute.

13,845 home therapy infusions with velaglucerase alfa exemplify safety of velaglucerase alfa and increased compliance to every-other-week intravenous enzyme replacement therapy for Gaucher disease.

BACKGROUND: Lifelong intravenous (IV) enzyme replacement therapy (ERT) every other week for Gaucher disease is appreciated as decreasing quality of life in a palpable way. OBJECTIVE: To review the Israeli experience with the home therapy option for IV velaglucerase alfa (Shire, Lexington MA USA) infusions every-other-week in the clinical trial context, in the early access program (EAP) during a shortage with the standard commercial ERT, and currently with the commercially available drug (VPRIV, Shire). RESULTS: Among 24 patients participating in trials, 1654 infusions were at home; in the EAP and commercial setting, 12,191 infusions were performed at home for a total of 154 patients with 98.4% compliance. There were no incidents of serious adverse events. CONCLUSION: This is the first review of experience of 174 patients and 13,845 intravenous infusions of velaglucerase alfa for Gaucher in the home setting, underscoring its safety.

Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease.

Taliglucerase alfa is a plant cell-expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n=6) or 60U/kg (n=5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690.

Seven-year safety and efficacy with velaglucerase alfa for treatment-naïve adult patients with type 1 Gaucher disease.

Velaglucerase alfa is a human ß-glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7-year experience of the now-completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9-month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug-related adverse event or required premedication. No patient developed anti-drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and -42% (-53%, -31%) and -78% (-94%, -62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near-normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters.

Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials.

Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427.

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10-50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10(9) /L at baseline, were given at least one 15 U/kg-dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti-imiglucerase antibodies at baseline. This patient tested positive for anti-velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes.

The effects of maternal age and parity on maternal and neonatal outcome.

PURPOSE: Delayed childbearing is increasingly common; hence, concerns emerge regarding potential for additional risks of delivery at advanced maternal age (AMA; ≥35 years). In this study, we sought to assess impact of AMA and parity on maternal and perinatal outcomes. METHODS: In this retrospective single-center study (July 2005 to October 2011), we compared spontaneously-conceived singleton births of AMA mothers with spontaneously-conceived singletons of mothers aged 24-27 years. Maternal outcomes: incidence of diabetes, hypertension, and emergency cesarean sections (ECS). Neonatal outcomes: prematurity, birth weight, incidence of small or large for gestational age infants (SGA/LGA, respectively), low birth weight (LBW), and 5'-Apgar scores. Sub-groupings of maternal age were 35-38, 39-42, or 43-47 years; prematurity as <34 or <37 weeks; AMA parity as primiparous, 2-5 births, 6-9 births, or ≥10 births. Binary logistic regression was used for multivariate analyses. RESULTS: Of 24,579 eligible women, 11,243 were AMA (14.0% total singleton births) and 13,336 were aged 24-27 years (16.7% total singleton births) at delivery. There were no maternal or perinatal deaths. Incidence of maternal hypertension and diabetes was significantly greater in AMA, especially oldest AMA. AMA including primiparous had significantly more ECS than younger including primiparous controls, respectively, and were more likely to deliver LGA neonates. Primiparous AMA women did not have increased incidence of LGA babies but significantly increased incidence of SGA infants. CONCLUSION: AMA, especially primiparous, has more adverse maternal and neonatal outcomes than younger women; however, these did not include mortality. Consistent antenatal care may explain this.

Impact of velaglucerase alfa on bone marrow burden score in adult patients with type 1 Gaucher disease: 7-year follow-up.

BACKGROUND: Bone marrow infiltration by substrate-engorged "Gaucher" cells manifests early in Gaucher disease (GD). The impact of velaglucerase alfa on bone marrow burden (BMB) was evaluated as an exploratory assessment. METHODS: BMB scores were assessed using T1- and T2-weighted magnetic resonance images of the lumbar spine (LS) and femora among symptomatic GD patients who participated in the 9-month Phase I/II trial and long-term extension study for velaglucerase alfa. A post-hoc assessment of marrow involvement was performed. BMB scores per site are 0-8 (0/1=normal; 8=severe infiltration). RESULTS: The median LS-BMB score at baseline was 6 (n=12; range 3-8); at 9 months, compared with baseline, there was a median change of -2 (n=11; two-sided p-value=0.0078). LS-BMB scores continued to decrease through 5 years (n=8; median change from baseline -5 [p=0.0078], median score 1 [range 1-4]) and were subsequently sustained through 7 years (n=8). LS-BMB decreases of ≥2 points occurred in 6/11 patients at 9 months, and in all assessable patients (8/8) by 5 years. Long-term femoral BMB (F-BMB) assessment was possible for three patients; all experienced reductions of ≥2 points at 5 years with a total score (LS-BMB+F-BMB) decrease ≥4. CONCLUSIONS: This post hoc analysis suggests improvement in BMB scores through 5 years that was sustained through 7 years, despite dose reduction from 15 months. Prospective studies in a large cohort are needed to validate these findings.