Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype

Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m 2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m 2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFR were − 1.6 mL/min/1.73 m 2 overall and − 1.8 mL/min/1.73 m 2 and − 1.4 mL/min/1.73 m 2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFR were − 1.6 mL/min/1.73 m 2 overall and − 2.6 mL/min/1.73 m 2 and − 0.8 mL/min/1.73 m 2 in male and female patients, respectively. Mean annualized rate of change in eGFR in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m 2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFR change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m 2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes

BACKGROUND: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear. METHODS: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated. RESULTS: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations. CONCLUSIONS: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs

Assessment of plasma lyso-Gb(3)for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease

Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.Medical Biochemistr

Treatment of autosomal dominant hypocalcemia Type 1 with the calcilytic NPSP795 (SHP635)

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain‐of‐function mutations of the calcium‐sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to 4 distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration‐dependent manner up to 129% above baseline (p=0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol and little calcium supplementation. NPSP795 was generally safe and well‐tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half‐maximally activated (EC50) at lower concentrations of extracellular calcium (Ca2+o) compared to wild type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose‐dependent manner, and thus, serves as proof‐of‐concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype, or the response to calcilytics, suggesting that other parameters impact the response to the drug

Fibre-Related Dietary Patterns: Socioeconomic Barriers to Adequate Fibre Intake in Polish Adolescents. A Short Report

There is no complete explanation for the association between socioeconomic status (SES), fibre, and whole diet described by dietary patterns. The aim of this short report was to increase the understanding of adolescent dietary patterns related to fibre in their social context. A cross-sectional study was conducted involving 1176 adolescents aged 13–18 years from central and north-eastern Poland. The overall SES was composed of five single factors: place of residence, self-declared economic situation of family, self-declared economic situation of household, paternal and maternal education. The consumption frequency of nine dietary fibre sources was collected using Block’s questionnaire and was expressed in points. Fibre dietary patterns (DPs) were drawn by cluster analysis and odds ratios (ORs) adjusted for age, sex, and BMI were calculated. Three fibre-related DPs were identified: “High-fibre” (mean frequency of total fibre intake 22.7 points; range: 0–36), “Average-fibre” (17.7 points), “Low-fibre” (14.6 points). The “High-fibre” DP was characterized by a relatively higher frequency consumption of white bread, fruit, fruit or vegetable juices, potatoes, green salad and prepared vegetables, and a moderate frequency consumption of high-fibre or bran cereals and wholegrain bread compared to the “Low-fibre” DP. The “Average-fibre” DP was characterized by a relatively higher frequency consumption of wholegrain bread and high-fibre or bran cereals and a moderate frequency consumption of fruit, fruit or vegetable juices, green salad and prepared vegetables compared to the “Low-fibre” DP. Less likely to adhere to the “High-fibre” DP were adolescents with low SES (OR: 0.55, 95% CI: 0.39–0.77) or average SES (0.58, 95% CI: 0.41–0.81) in comparison with high SES (reference) as a result of elementary or secondary paternal or maternal education, rural residence, and lower household economic situation. Similar associations were found for the “Average-fibre” DP. Low and average socioeconomic status resulting from lower parents’ education, rural residence, and lower economic situation were inversely associated with achieving a relatively high fibre intake in Polish adolescents. Consuming single high-fibre foods was not sufficient to achieve a high-fibre diet in Polish adolescents. These data suggest that the consumption of a wide variety of dietary fibre sources—both relatively high-fibre and low-fibre foods—may help Polish adolescents in achieving a relatively high-fibre diet

Serum ‘Vitamin-Mineral’ Profiles: Associations with Postmenopausal Breast Cancer Risk Including Dietary Patterns and Supplementation. A Case-Control Study

Breast cancer is the most prevalent cancer in females worldwide. Studies evaluating the blood vitamins and minerals status in the breast cancer etiology are limited, and the results are inconclusive. This study analyzed the association between serum vitamin-mineral profiles (V-MPs) and breast cancer (BC) risk with including dietary patterns (DPs) and the use of supplements. This case-control study involved 420 women aged 40&ndash;79 years from north-eastern Poland, including 190 newly diagnosed breast cancer cases. The fasting serum concentrations of vitamins (folate, cobalamin, 25(OH) vitamin D) and minerals (iron, calcium, magnesium) were measured in 129 post-menopausal women, including 82 controls and 47 cases. Three V-MPs were derived with a Principal Component Analysis (PCA). A logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of the breast cancer risk associated with serum V-MPs and serum levels of single biomarkers. The risk of BC was lower by 88% (OR: 0.12; 95% Cl: 0.02&ndash;0.88; p &lt; 0.05) in the upper tertile of the serum &lsquo;Iron-Calcium&rsquo; profile compared to the bottom tertile, lower by 67% (OR: 0.33; 95% Cl: 0.11&ndash;0.97; p &lt; 0.05) at the level of serum 25(OH) vitamin D &ge;24.6 ng/mL and lower by 68% (OR: 0.32; 95% Cl: 0.11&ndash;0.91; p &lt; 0.05) at the level of serum calcium &ge;9.6 mg/dL. There was an inverse association of the serum &lsquo;Magnesium&rsquo; profile or serum level of iron with the risk of BC, which disappeared after adjustment for the set of confounders accounted for: age, body mass index (BMI), socioeconomic status, overall physical activity, smoking status, age at menarche, number of full-term pregnancies, oral contraceptive use, hormone-replacement therapy use, family history of breast cancer, vitamin/mineral supplement use, the molecular subtype of breast cancer, and dietary patterns. No significant association was found between BC risk and the serum &lsquo;Folate-Cobalamin-Vitamin D&rsquo; profile or serum folate, cobalamin or magnesium considered separately. These findings highlight that a higher-normal serum level of both iron and calcium, considered together as the serum profile, as well as a higher-normal serum level of calcium, considered separately, and a slightly below the normal range of serum vitamin D level may protect against breast cancer among postmenopausal women, independent of dietary patterns or the use of vitamin/mineral supplements. Therefore, the maintenance of the adequate status of vitamins and minerals and the regular monitoring of their blood markers should be included in breast cancer prevention

Associations of Mediterranean Diet and a Posteriori Derived Dietary Patterns with Breast and Lung Cancer Risk: A Case-Control Study

Lung cancer in men and breast cancer in women are the most commonly diagnosed cancers in Poland and worldwide. Results of studies involving dietary patterns (DPs) and breast or lung cancer risk in European countries outside the Mediterranean Sea region are limited and inconclusive. This study aimed to develop a ‘Polish-adapted Mediterranean Diet’ (‘Polish-aMED’) score, and then study the associations between the ‘Polish-aMED’ score and a posteriori-derived dietary patterns with breast or lung cancer risk in adult Poles. This pooled analysis of two case-control studies involved 560 subjects (280 men, 280 women) aged 40–75 years from Northeastern Poland. Diagnoses of breast cancer in 140 women and lung cancer in 140 men were found. The food frequency consumption of 21 selected food groups was collected using a 62-item Food Frequency Questionnaire (FFQ)-6. The ‘Polish-adapted Mediterranean Diet’ score which included eight items—vegetables, fruit, whole grain, fish, legumes, nuts and seeds—as well as the ratio of vegetable oils to animal fat and red and processed meat was developed (range: 0–8 points). Three DPs were identified in a Principal Component Analysis: ‘Prudent’, ‘Non-healthy’, ‘Dressings and sweetened-low-fat dairy’. In a multiple logistic regression analysis, two models were created: crude, and adjusted for age, sex, type of cancer, Body Mass Index (BMI), socioeconomic status (SES) index, overall physical activity, smoking status and alcohol abuse. The risk of breast or lung cancer was lower in the average (3–5 points) and high (6–8 points) levels of the ‘Polish-aMED’ score compared to the low (0–2 points) level by 51% (odds ratio (OR): 0.49; 95% confidence interval (Cl): 0.30–0.80; p &lt; 0.01; adjusted) and 63% (OR: 0.37; 95% Cl: 0.21–0.64; p &lt; 0.001; adjusted), respectively. In the middle and upper tertiles compared to the bottom tertile of the ‘Prudent’ DP, the risk of cancer was lower by 38–43% (crude) but was not significant after adjustment for confounders. In the upper compared to the bottom tertile of the ‘Non-healthy’ DP, the risk of cancer was higher by 65% (OR: 1.65; 95% Cl: 1.05–2.59; p &lt; 0.05; adjusted). In conclusion, the Polish adaptation of the Mediterranean diet could be considered for adults living in non-Mediterranean countries for the prevention of the breast or lung cancers. Future studies should explore the role of a traditional Mediterranean diet fitted to local dietary patterns of non-Mediterranean Europeans in cancer prevention