Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data.

BACKGROUND: The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT). METHODS: In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers' maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients' age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods. RESULTS: 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively. CONCLUSIONS: PROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www. CLINICALTRIALS: gov/search?term=NCT03729362 .

Efficacy and safety of migalastat in a Japanese population: a subgroup analysis of the ATTRACT study.

BACKGROUND: Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. METHODS: Patients were randomly assigned to receive migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. RESULTS: Data from 7 Japanese patients (migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. CONCLUSION: Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to migalastat according to the dosage and administration approved in other countries. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT01218659 and NCT02194985.

Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study.

PURPOSE: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. METHODS: Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). RESULTS: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with migalastat was -0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were -16.7 (18.64) g/m2, -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (-0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients. CONCLUSION: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial.

BACKGROUND: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. METHODS: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). RESULTS: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). CONCLUSIONS: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease. TRIAL REGISTRATION: NCT00925301 ; June 19, 2009.

Low frequency of Fabry disease in patients with common heart disease.

PURPOSE: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease. METHODS: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing. RESULTS: We tested 2,256 consecutive patients: 852 women (median age 65 years (19-95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5'UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5'UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81-77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease. CONCLUSION: This population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment.

OBJECTIVE: Deficiency of α-galactosidase A (αGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease. METHODS AND ANALYSIS: We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods. RESULTS: Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury. CONCLUSION: Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. TRIAL REGISTRATION NUMBER: NCT00925301; Pre-results.

A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease.

Fabry disease is caused by mutations in the gene (GLA) that encodes α-galactosidase A (α-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes α-Gal A, increasing total cellular levels and activity for some mutant forms (defined as "responsive"). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of α-Gal A that are responsive to AT1001. Concentration-dependent increases in α-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of α-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 α-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 µM) were generally consistent with observed increases in α-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of α-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms.

Evaluating plant-soil feedback together with competition in a serpentine grassland.

Plants can alter biotic and abiotic soil characteristics in ways that feedback to change the performance of that same plant species relative to co-occurring plants. Most evidence for this plant-soil feedback comes from greenhouse studies of potted plants, and consequently, little is known about the importance of feedback in relation to other biological processes known to structure plant communities, such as plant-plant competition. In a field experiment with three C4 grasses, negative feedback was expressed through reduced survival and shoot biomass when seedlings were planted within existing clumps of conspecifics compared with clumps of heterospecifics. However, the combined effects of feedback and competition were species-specific. Only Andropogon gerardii exhibited feedback when competition with the clumps was allowed. For Sorghastrum nutans, strong interspecific competition eliminated the feedback expressed in the absence of competition, and Schizachyrium scoparium showed no feedback at all. That arbuscular mycorrhizal (AM) fungi may play a role in the feedback was indicated by higher AM root colonization with conspecific plant neighbours. We suggest that feedback and competition should not be viewed as entirely separate processes and that their importance in structuring plant communities cannot be judged in isolation from each other.

Separate effects of human visitation and touch on plant growth and herbivory in an old-field community.

Although animal scientists have long been aware that methods used to measure an experimental system can affect the subject of measurement, similar confounding effects of commonly used field methods have only recently been acknowledged by plant ecologists. Here we demonstrate significant effects of weekly visitation (walking up to a focal plant) and handling (taking morphological measures) on plant growth and herbivory in an old-field community. Of the three species examined, Apocynum cannabinum was the most severely affected by our treatments. For Apocynum, weekly visitations resulted in a positive relationship between initial and final size, which did not occur in the unvisited plants. Visitation also increased leaf herbivory, resulting in a reduced leaf:stem biomass ratio. Handling the plants nearly doubled the proportion of individuals with a stem borer emergence hole. Growth of the other species in this study, Potentilla recta and Erigeron philadelphicus, was altered by either visitation or visitation plus handling. Visiting plants in order to observe them and touching them as one would when making morphological measurements can have important biological consequences. We suggest that plant ecologists treat repeated entry into a natural system as a research method, subject to the same scrutiny and justification as all other experimental methods.