Review article: The need for more efficient and patient-oriented drug development pathways in NASH-setting the scene for platform trials.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. METHODS: Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. RESULTS: Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. CONCLUSIONS: PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, 'proof-of-platform' at a smaller scale needs to be provided.

Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints.

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons.

Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.

Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with type 2 diabetes mellitus and obesity: A randomized dose-ranging study.

Weight loss has been shown to improve metabolic parameters and cardiovascular risk in people with type 2 diabetes mellitus (T2DM). This phase 2 study evaluated the safety and efficacy of JNJ-64565111, a dual agonist of GLP-1 and glucagon receptors, in individuals with T2DM and class II/III obesity. In this randomized, double-blind study, participants with T2DM (HbA1c 6.5%-9.5%), body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned (1:1:1:1) to placebo or JNJ-64565111 (5.0 mg, 7.4 mg or 10.0 mg). The primary endpoint was percent change from baseline in body weight at week 12. Of 195 dosed participants, 144 (73.8%) completed treatment. At week 12, placebo-subtracted body weight changes were -4.6%, -5.9% and -7.2% with JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg, respectively. All JNJ-64565111 doses were associated with no change in HbA1c and slight numerical elevation of fasting insulin. Numerical increases in fasting plasma glucose were observed with JNJ-64565111 5.0 mg and 7.4 mg. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher with JNJ-64565111 vs placebo. Overall, JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events, no HbA1c reductions, and increased fasting plasma glucose and fasting insulin.

Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition.

Objective- SGLT2 (sodium-glucose cotransporter 2) inhibition in humans leads to increased levels of LDL (low-density lipoprotein) cholesterol and decreased levels of plasma triglyceride. Recent studies, however, have shown this therapy to lower cardiovascular mortality. In this study, we aimed to determine how SGLT2 inhibition alters circulating lipoproteins. Approach and Results- We used a mouse model expressing human CETP (cholesteryl ester transfer protein) and human ApoB100 (apolipoprotein B100) to determine how SGLT2 inhibition alters plasma lipoprotein metabolism. The mice were fed a high-fat diet and then were made partially insulin deficient using streptozotocin. SGLT2 was inhibited using a specific antisense oligonucleotide or canagliflozin, a clinically available oral SGLT2 inhibitor. Inhibition of SGLT2 increased circulating levels of LDL cholesterol and reduced plasma triglyceride levels. SGLT2 inhibition was associated with increased LpL (lipoprotein lipase) activity in the postheparin plasma, decreased postprandial lipemia, and faster clearance of radiolabeled VLDL (very-LDL) from circulation. Additionally, SGLT2 inhibition delayed turnover of labeled LDL from circulation. Conclusions- Our studies in diabetic CETP-ApoB100 transgenic mice recapitulate many of the changes in circulating lipids found with SGLT2 inhibition therapy in humans and suggest that the increased LDL cholesterol found with this therapy is because of reduced clearance of LDL from the circulation and greater lipolysis of triglyceride-rich lipoproteins. Most prominent effects of SGLT2 inhibition in the current mouse model were seen with antisense oligonucleotides-mediated knockdown of SGLT2.

Pharmacokinetics and pharmacodynamics of canagliflozin in pediatric patients with type 2 diabetes.

OBJECTIVE: Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. METHODS: Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). RESULTS: There were dose-dependent increases in the PK of canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100 mg and to 69.1 (9.6) mg/dL with canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. CONCLUSIONS: In pediatric T2D patients, canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population.

BACKGROUND: Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described. METHODS: We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness. RESULTS: Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E': r = -0.65, P < .001, S': r = -0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r= 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E' and S' were observed only in subjects with CH (P < .005). CONCLUSIONS: A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. METHODS: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). RESULTS: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. CONCLUSION: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants.

Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2, is approved for the treatment of type-2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2-way crossover design: canagliflozin 300 mg/day was administered under fasted (Period-1) and fed (Period-2) conditions or vice versa. Study 2 was a 3-way crossover: participants were randomized to receive three single-doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10-14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47-112.93) and Cmax (ratio: 108.09; 90% CI: 103.45-112.95) were entirely within bioequivalence limits (80-125%). Plasma canagliflozin exposures were dose-proportional as the 90% CI of the slope of the regression line for dose-normalized AUC∞ and Cmax fell entirely within the prespecified limits of -0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well-tolerated.

Assessing function and endurance in adults with spinal and bulbar muscular atrophy: validity of the adult myopathy assessment tool.

Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA). Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Results. Lower AMAT scores were associated with longer disease duration (r = -0.29; P < 0.03) and lower serum androgen levels (r = 0.49-0.59; P < 0.001). The AMAT was significantly correlated with strength and functional status (r = 0.82-0.88; P < 0.001). The domains of the AMAT exhibited good internal consistency (Cronbach's α = 0.77-0.89; P < 0.001). Conclusions. The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifier NCT00303446.

Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: a placebo-controlled, exploratory study.

PURPOSE: To evaluate the activity of JNJ-26489112 in patients with photosensitive epilepsy and determine the doses that result in reduction or complete suppression of the intermittent photic stimulation (IPS) induced photoparoxysmal-EEG response (PPR). METHODS: In this multicenter, single-blind, within subject, placebo-controlled, sequential dose, exploratory study, 12 adult patients (3 men; 9 women) with idiopathic photosensitive epilepsy, with and without concomitant antiepileptic drug (AED) therapy, underwent standardized IPS under three eye conditions (open, during closure, and closed) for up to 12h after receiving a single oral dose of placebo on day 1, JNJ-26489112 on day 2, and a second dose of placebo on day 3. Based on review of the blinded EEG data, the standardized photosensitive range (SPR) (i.e., upper and lower frequencies of the IPS-induced PPR), was calculated for each eye condition at each time point. A positive response was defined as a reduction of the SPR in ≥3 out of 4 consecutive time points in ≥1 eye condition on either day 2 or 3 compared with baseline (day 1) while complete suppression was defined as disappearance of an IPS-induced PPR (i.e., SPR=0). For the first four patients (Cohort 1), JNJ-26489112 dose was 1000 mg, and the dose was escalated to a maximum of 3000 mg in subsequent cohorts. Blood and plasma samples were collected for pharmacokinetic evaluations along with measurements of concurrent AED concentrations. Safety was also assessed. RESULTS: The majority of patients showed a positive response on day 2 following JNJ-26489112 administration: 3/4 patients (1000 mg dose), 3/4 patients (2000 mg dose), and 2/3 patients (3000 mg). There was an apparent dose-dependent effect observed in patients who exhibited complete suppression of the SPR: 0/4 patients (1000 mg dose), 1/4 patient (2000 mg dose), and 2/3 patients (3000 mg dose). The median tmax of JNJ-26489112 (range: 3.73-5.04 h) in plasma was similar across all 3 dose groups and plasma exposure of JNJ-26489112 increased proportionally with dose; approximate mean Cmax of 16, 28, and 42 µg/mL for the 1000-, 2000-, and 3000 mg cohorts, respectively. Concentrations of other AEDs did not appear to be affected by co-administration of JNJ-26489112. JNJ-26489112 was generally well-tolerated with the most frequent adverse events (>10%) reported being mild headache, dizziness, and nausea. CONCLUSION: Single oral doses of JNJ-26489112 were well-tolerated and the pharmacodynamic effects appeared to be dose-related in patients with idiopathic, photosensitive epilepsy.

Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database.

The aim of this cross-sectional study was to analyse disease progression in Friedreich's ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich's ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ≤14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich's ataxia.

Impaired mitochondrial function in psychiatric disorders.

Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as 'neurochemical diseases', it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. Enhancing mitochondrial function could represent an important avenue for the development of novel therapeutics and also presents an opportunity for a potentially more efficient drug-development process.

Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. METHODS: We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov, NCT00303446. FINDINGS: 50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (-0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI -5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, -3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3%vs -3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events. INTERPRETATION: Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials.

Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.

Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia.

OBJECTIVE: To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity. DESIGN: Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress. SETTING: Exercise physiology laboratory in a single clinical research center. PARTICIPANTS: Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA. INTERVENTION: Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months. MAIN OUTCOME MEASURES: Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment. RESULTS: Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo. CONCLUSIONS: Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology.

The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.

Clinical features of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.

Standard and modified statistical MUNE evaluations in spinal-bulbar muscular atrophy.

Motor unit number estimation (MUNE), a technique used in amyotrophic lateral sclerosis (ALS) clinical trials to quantitatively assess motor neuron loss, should also be valuable in assessing progression in spinal bulbar muscular atrophy (SBMA), an x-linked neuronopathy. In ALS, instability of single motor units (SMUP) prompted Shefner et al.6(6) to modify the statistical MUNE method to exclude SMUPs < or = 40 microV. It is unknown if there is similar SMUP instability in the more chronic degenerative disease of SBMA. In this study the standard parameter of excluding SMUP < 10 microV was compared with the exclusion of SMUP < 40 microV in the calculation of the statistical MUNE. The mean statistical MUNE, using the standard method and the Shefner et al. method, was 60 +/- 21 to 47 +/- 23, respectively. Similar to ALS, SBMA showed an increased proportion (17%) of individual SMUPs < or = 40 microV compared to normal controls. In conclusion, excluding SMUPs < or = 40 microV from the statistical MUNE calculations is appropriate for SBMA subjects because their SMUP, characteristics are similar to ALS. Exclusion of the low-amplitude SMUPs reduces the calculated MUNE.

Clinical experience with high-dose idebenone in Friedreich ataxia.

Several reports in the literature describe the effects of low-dose (5 mg/kg/day) idebenone in significantly reducing cardiac hypertrophy in patients with Friedreich ataxia. However, the effects of idebenone on neurological function have not been reliably determined in these studies; when neurological parameters were reported, results were often inconclusive, usually because of subject heterogeneity and lack of adequate statistical power. In two of these studies, some patients showed beneficial effects of idebenone on their cardiomyopathy only when the dose was increased, prompting the systematic investigation of higher doses of idebenone. Following a phase 1 dose escalation study, a phase 2 tolerability and efficacy trial with low, intermediate, and high doses of idebenone was conducted. The results suggested that treatment with intermediate- and high-dose idebenone had beneficial effects on neurological symptoms. On the basis of these results, two phase 3 trials have been initiated, one in the United States with young ambulatory patients and one in Europe without limits on age and disease severity.