First-in-human single-dose study of nizubaglustat, a dual inhibitor of ceramide glucosyltransferase and non-lysosomal glucosylceramidase: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses in healthy adults.

Nizubaglustat is a novel, orally available, brain penetrant, potent, and selective dual inhibitor of ceramide glucosyltranferase and non-lysosomal neutral glucosylceramidase (NLGase), which is currently under development for the treatment of subjects with neurological manifestations in primary and secondary gangliosidoses. The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics (PD) of single oral doses of nizubaglustat after single (1, 3, and 9 mg) and multiple oral doses (9 mg once per day (QD) over 14 days) in healthy adults. Nizubaglustat was rapidly absorbed and systemic exposure was dose-proportional. Steady-state was achieved after three days of QD multiple dosing with minimal accumulation. Renal clearance accounted for around 15% of nizubaglustat elimination. Following multiple dosing, plasma concentrations of glucosylceramide (GlcCer), lactosylceramide (LacCer), and monosialodihexosylganglioside (GM3) decreased to a nadir at Day 10. PD target engagement of GCS inhibition was shown by a median decrease from baseline of plasma concentrations of GlcCer, LacCer, and GM3 ganglioside by 70%, 50%, and 48%, respectively. NLGase inhibition was also manifested by increased concentrations of GlcCer in cerebrospinal fluid from Day 1 to Day 14. Nizubaglustat was safe and well-tolerated at all doses tested. Consistent with the high selectivity, and the absence of intestinal disaccharidases inhibition, no cases of diarrhea were reported. No decreased appetite or weight loss was noted. Only treatment-emergent adverse events with preferred terms belonging to the system organ class skin and subcutaneous disorders of mild intensity were reported as drug-related in the nizubaglustat arm, in line with the pharmacological mechanism targeting glucosylceramide metabolism. Taken together, these data support QD dosing of nizubaglustat and its ongoing development in patients with primary and secondary forms of gangliosidoses.

GM1-gangliosidosis: The caregivers' assessments of symptom impact and most important symptoms to treat.

GM1-gangliosidosis (GM1) is a rare neurodegenerative disorder leading to early mortality and causing progressive decline of physical skills and cerebral functioning. No approved treatment for GM1 exists. In this study-the first to explore priorities of parents of subjects with pediatric onset forms of GM1-we address a crucial gap by characterizing symptoms most critical to caregivers of children with GM1 to treat. Our two-part, mixed-methods approach began with focus groups, followed by interviews with a distinct set of parents. Interviews included a prioritization activity that used best-worst scaling. Quantitative data were analyzed descriptively. Qualitative data were analyzed using thematic analysis and rapid analysis process. Parents prioritized the symptoms they believed would increase their child's lifespan and improve their perceived quality of life (QoL); these symptoms focused on communicating wants/needs, preventing pain/discomfort, getting around and moving one's body, and enhancing eating/feeding. Although lifespan was highly valued, almost all parents would not desire a longer lifespan without acceptable child QoL. Parents indicated high caregiver burden and progressive reduction in QoL for children with GM1. This novel study of caregiver priorities identified important symptoms for endpoints' selection in patient-focused drug development in the context of high disease impact and unmet treatment needs.

Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study.

Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.

Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study.

We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naïve ('naïve') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of miglustat therapy. The median (range) hemoglobin concentration at miglustat initiation was 12.8 (10.2-16.4)g/dl in naïve patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at miglustat initiation were 101 (37-730)×10(9)/l in naïve patients and 173 (43-382)×10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145)×10(9)/l and -10 (-144-434)×10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naïve but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naïve patients treated with miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with miglustat in the current study is similar to previous studies.

Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study.

BACKGROUND: Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy. METHODS: Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count. RESULTS: Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3-765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (-1.1%; 95%CI -6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, -0.95 (-1.38, -0.53) g/dL and -44.1 (-57.6, -30.7) ×109/L, respectively. CONCLUSIONS: The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00319046.

Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension.

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-µg increments from 200 µg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 µg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.

Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial.

A randomized, controlled trial of miglustat indicated that miglustat (Zavesca) stabilized neurological disease over 12 months in adult and juvenile patients with Niemann-Pick disease type C (NP-C). We report data from a non-controlled, open-label extension to this initial randomized trial. All patients completing the randomized trial were allowed to continue treatment in a 12-month, non-controlled open-label extension. Those completing 12 months of extension therapy could continue further on miglustat in a 'continued extension' phase. From a total of 29 patients in the randomized phase (mean [+/-SD] age 24.6+/-9.1 ears; 52% female), 21 completed 12 months of therapy with miglustat (17 of whom received miglustat in the initial randomized phase, and four in the extension phase), and 15 patients (all from the miglustat-randomized group) completed 24 months on miglustat. Mean horizontal saccadic eye movement velocity (HSEM-alpha) indicated improvement in the 12-month miglustat group, and stabilization in the 24-month group; swallowing was improved or stable in 86% and in up to 93%, respectively. Ambulation was stabilized in both the 12- and 24-month groups. In an exploratory disease stability analysis of prospective data on key parameters of disease progression (HSEM-alpha, swallowing, ambulation and cognition), 13/19 (68%) patients receiving >or= 12 months' miglustat therapy had stable disease. Among all patients receiving >or= 1 dose of miglustat (n=28), the most frequent adverse events were diarrhoea, weight decrease, flatulence and tremor. Overall, these data suggest that long-term miglustat therapy stabilizes neurological disease and is well tolerated in adult and juvenile patients with NP-C.

Long-term miglustat therapy in children with Niemann-Pick disease type C.

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months' treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.

High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study.

Glucocorticoid (GC)-induced osteoporosis mostly affects trabecular bone of vertebrae. Only 30% of vertebral fractures are symptomatic, yet both clinical and radiological vertebral fractures have been associated with increased mortality and morbidity. The aims of this cross-sectional, outpatient-based study were to measure the prevalence of asymptomatic vertebral fractures in a large sample of post-menopausal women given GCs for different diseases; to compare prevalence of asymptomatic vertebral fractures according to disease, GC treatment and major risk factors; and to assess the quality of life in GC users with and without asymptomatic vertebral fractures. 551 patients referring to 39 centers as outpatients for their programmed follow-up and satisfying the inclusion criteria were included in the analysis. Each patient underwent structured medical interview (including dose and duration of GC therapy, major risk factors for osteoporosis, the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO) and a back function score questionnaire), thoraco-lumbar radiographs and subsequent morphometry; for 253 and 437 patients, respectively, lumbar spine bone mineral density (BMD) assessed by dual energy X-ray absorptiometry and calcaneal bone stiffness assessed by quantitative ultrasonometry were available. The prevalence of asymptomatic vertebral fractures resulted >37%, with >14% of patients having two or more asymptomatic vertebral fractures and was much higher than that found in epidemiological studies on healthy women. Distribution of asymptomatic vertebral fractures along the spine showed a bimodal pattern, with two peaks at T7 and T11. The prevalence of asymptomatic vertebral fractures clearly increased with age. Differences in prevalence among diseases were evidenced. When controlled for age, GC cumulative dose, duration of therapy and personal history of fractures, the adjusted prevalences were 30.77% for systemic lupus erythematosus, 33.78% for rheumatoid arthritis, 37.78% for asthma/chronic obstructive pulmonary disease, 43.20% for polymyalgia rheumatica and 43.36% for diseases grouped as "other vasculitides/connective tissue diseases". No significant association was found with GC cumulative dose and duration of therapy. Established risk factors for osteoporosis (except for age, years since menopause and personal history of fractures), lumbar spine BMD, calcaneal stiffness and QUALEFFO score were not associated with number and severity of asymptomatic vertebral fractures. Underlying disease is likely to contribute to the risk of fracture, but disease by itself could not be dissected from GC regimen. Vertebral fractures should be looked for carefully in all post-menopausal women receiving long-term systemic GCs since they can be asymptomatic and are scarcely predictable.

25(OH)D Serum levels decline with age earlier in women than in men and less efficiently prevent compensatory hyperparathyroidism in older adults.

BACKGROUND: Although a host of factors are known to influence 25-hydroxyvitamin D [25(OH)D] serum levels, few studies addressed the distinctive sex-specific influence of aging, and the age-specific relationship of parathyroid hormone (PTH) with 25(OH)D. The aims of this research were to evaluate changes of 25(OH)D and PTH levels with age in a large population-based sample of men and women and to test the hypothesis that 25(OH)D serum concentrations needed to offset age-associated hyperparathyroidism are significantly higher in older than in younger persons. METHODS: In 1107 participants of the InCHIANTI (Invecchiare in Chianti, i.e., Aging in the Chianti area) study, we collected information on dietary intake, daylight exposure, and disability, and measured renal function and serum 25(OH)D and PTH. RESULTS: In women, the age-related decline of 25(OH)D was already evident shortly after age 50, whereas in men it started only after age 70 and was substantially less steep. Age, daylight exposure, winter season, and disability were independent predictors of low 25(OH)D levels. For any given level of 25(OH)D, PTH levels were progressively and consistently higher in older than in younger participants. CONCLUSIONS: These findings suggest that the age-associated fall of serum 25(OH)D starts earlier in women than in men and that higher levels of 25(OH)D are required in older compared to younger persons to avoid the age-associated compensatory hyperparathyroidism.

The effect of age, weight, and lifestyle factors on calcaneal quantitative ultrasound: the ESOPO study.

Quantitative ultrasound (QUS) techniques have been shown to be as good as bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA), in predicting fracture risk: QUS technique could increase substantially the accessibility to a reliable bone osteoporosis risk evaluation, but little is know regarding the relationship of QUS to risk factors that have been found to predict DXA-BMD values and this is even more true in men. We studied 6,811 postmenopausal women 40 to 80 years of age and 4,981 men 60-80 years of age representative of the general population of all regions of Italy. All participants were questioned on lifestyle habits and on their medical history. After a physical examination "bone stiffness" (called here for simplicity, stiffness), which is derived from the values of broadband ultrasound attenuation (BUA) and speed of sounds (SoS) was measured by a heel QUS device (Achilles apparatus, Lunar, Madison, USA). The most common recognized determinants of bone mass (either categorical or continuous variables) were modeled with stiffness by multiple regression analysis or ANOVA. Stiffness was strongly related to age and weight. After adjusting for these variables, the women who had taken hormone replacement therapy for more than a year had significantly higher stiffness values. The difference versus nonusers remained significant for up to 20 years-since-menopause (YSM). This effect was so strong that for further analysis these women were excluded. By multivariate analysis, stiffness was then found to be significantly related to recalled body weight at 25 years of age, actual and past cigarettes smoked per day, and dairy calcium intake. Stiffness was also associated with a number of categorial factors adjusted for age, weight, and YSM: prior ovariectomy, history of more than 2 months confined to bed, outdoor physical activity, smoking, chronic use of any drug, and past corticosteroid use. All these categorial and continuous variables predicted stiffness equally in men and women. In conclusion, QUS bone measurements discriminate postmenopausal women according to past use of hormone replacement therapy. Risk factors usually associated to BMD as measured by DXA are also associated to calcaneal bone stiffness as measured by QUS, and most risk factors for osteoporosis usually observed in women are equally applicable to men.