Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients ...with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001–012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16–74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 MM); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 EM). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 MM, n = 31; Group 2 EM, n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.
ABSTRACT
Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double‐blind, placebo‐controlled trial of ...ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6‐minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6‐minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand‐held myometry. Results: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. Conclusion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. Muscle Nerve 48: 343–356, 2013
Friedreich's ataxia (FA) is a life-threatening autosomal recessive disorder characterized by neurological and cardiac dysfunction. Arrhythmias and heart failure are the main cause of premature death. ...From prior studies in murine models of FA, adeno-associated virus encoding the normal human frataxin gene (AAVrh.10hFXN) effectively treated the cardiac manifestations of the disease. However, the therapeutic dose window is limited by high level of human frataxin (hFXN) gene expression associated with toxicity. As a therapeutic goal, since FA heterozygotes have no clinical manifestations of FA, we estimated the level of frataxin (FXN) necessary to convert the heart of a homozygote to that of a heterozygote. In noncardiac cells, FA heterozygotes have 30-80% of normal FXN levels (17.7-47.2 ng/mg, average 32.5 ng/mg) and FA homozygotes 2-30% normal levels (1.2-17.7 ng/mg, average 9.4 ng/mg). Therefore, an AAV vector would need to augment endogenous in an FA homozygote by >8.3 ng/mg. To determine the required dose of AAVrh.10hFXN, we administered 1.8 × 10
, 5.7 × 10
, or 1.8 × 10
gc/kg of AAVrh.10hFXN intravenously (IV) to muscle creatine kinase (mck)-Cre conditional knockout
mice, a cardiac and skeletal FXN knockout model. The minimally effective dose was 5.7 × 10
gc/kg, resulting in cardiac hFXN levels of 6.1 ± 4.2 ng/mg and a mild (
< 0.01 compared with phosphate-buffered saline controls) improvement in mortality. A dose of 1.8 × 10
gc/kg resulted in cardiac hFXN levels of 33.7 ± 6.4 ng/mg, a significant improvement in ejection fraction and fractional shortening (
< 0.05, both comparisons) and a 21.5% improvement in mortality (
< 0.001). To determine if the significantly effective dose of 1.8 × 10
gc/kg could achieve human FA heterozygote levels in a large animal, this dose was administered IV to nonhuman primates. After 12 weeks, the vector-expressed FXN in the heart was 17.8 ± 4.9 ng/mg, comparable to the target human levels. These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA.
Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype.
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).
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/1.73m2 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.
Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.
ABSTRACT
Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into ...reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6‐minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6‐minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013
Purpose
Fabry disease is a rare multisystemic disorder caused by functional deficiency of the lysosomal enzyme alpha-galactosidase A. Gastrointestinal (GI) signs and symptoms are among the earliest ...clinical manifestations in patients with Fabry disease but are often nonspecific, misdiagnosed, and untreated. No instruments have been developed specifically to assess GI signs and symptoms in Fabry disease. The
FAB
ry disease
P
atient-
R
eported
O
utcome-
G
astro
I
ntestinal (FABPRO-GI) was developed to address this unmet need and is intended for use in clinical trials (24-h FABPRO-GI) and real-world settings (7-day FABPRO-GI).
Methods
Findings from a literature review, expert advisory meetings, and patient concept elicitation interviews (CEIs) were summarized into conceptual models. These conceptual models were used to develop preliminary versions of the 24-h and 7-day FABPRO-GI. Cognitive debriefing interviews (CDIs) were conducted with additional patients to assess content validity, including understandability, relevance, and comprehensiveness of the preliminary versions of the 24-h and 7-day FABPRO-GI.
Results
Literature review (
n
= 17 articles), expert advisory meetings (
n
= 5), and patient CEIs (
n
= 17) identified mostly overlapping Fabry disease-related GI signs and symptoms, including abdominal cramps, bloating, and diarrhea, and informed development of the preliminary 24-h and 7-day FABPRO-GI. CDIs (
n
= 15) provided evidence of content validity and informed revisions of the 24-h and 7-day FABPRO-GI.
Conclusion
With evidence of content validity, the 24-h and 7-day FABPRO-GI are the first Fabry disease-specific patient-reported outcomes to assess GI signs and symptoms in patients with Fabry disease with potential for use in clinical trials and real-world settings, respectively.
Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate ...a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins.
This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint.
Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated.
Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD.
ClinicalTrials.gov NCT00264888.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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
(α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease.
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.
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.
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.
Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed ...to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis.
This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s FEV1 ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.
Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% 95% CI -0.8 to 6.3; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 95% CI 0.57-1.05; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% -4.0 to 2.1 vs -6.4% -9.8 to -3.7; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events 0.9-1.9 vs 2.18 events 1.6-2.7; rate ratio 0.60 0.42-0.86; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.
Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin.
PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
Abstract
Background
Chronic wounds are a fundamental issue for patients with epidermolysis bullosa (EB). Herein, we assess the natural history of wound closure in patients with EB who were randomly ...assigned to the vehicle-control arm of the multicenter, randomized, double-blind, phase 3 ESSENCE (NCT02384460) trial.
Methods
ESSENCE was designed to assess the efficacy and safety of a topical cream formulation of 6% allantoin (SD-101 6%) vs vehicle (SD-101 0%) in patients ≥1 month old who had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10–50 cm
2
present for ≥21 days. Time to complete target wound closure and the proportion of patients with target wound closure over time were analyzed overall and by parameters including patient age and baseline body surface area index (BSAi) of total wound burden (< 5% and ≥ 5%). Changes in BSAi of lesional skin, pain, and itching were also assessed.
Results
The vehicle-control arm included 87 patients. Mean (standard deviation SD) time to target wound closure within 3 months was 53.6 (28.6) days, with a range of 14 to 142 days. The proportion of patients with target wound closure increased over time from 7.1% at day 14 to 53.6% at month 3. Mean (SD) changes from baseline in BSAi of total wound burden and BSAi of lesional skin at month 3 were −2.3% (6.3) and −5.0% (13.5) of total body coverage, respectively. Reductions in pain and itching were observed at day 7 and maintained for 3 months. Faster healing times and a greater proportion of patients with wound closure were observed in patients aged 1 month to < 2 years; those with wounds < 30 days old, and in those with BSAi of total body wound burden < 5%.
Conclusions
Treatment response observed in the vehicle-control arm of the ESSENCE study was unexpectedly high and may have been due to unforeseen benefits of vehicle or enhanced wound care provided by the clinical trial staff. These observations will help inform the study design of future trials in patients with EB.
Trial registration
ClinicalTrials.gov
,
NCT02384460
; Date of registration: February 13, 2015; First participant enrollment: March 11, 2015.
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