Summary Background Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist ...that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. Methods We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov , number NCT01283594. Findings Of 420 randomised patients (mean age 63·3 SD 8·3 years; mean duration of Parkinson's disease 8·7 4·7 years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (−1·1 h, 95% CI −1·8 to −0·5; p=0·0006), the tozadenant 120 mg twice-daily group (−1·1 h, −1·8 to −0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (−1·2 h, −1·9 to −0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven 8% of 84 patients in the placebo group, 13 16% of 82 in the 120 mg twice-daily group, and 17 20% of 85 in the 180 mg twice-daily group), nausea (three 4%, 9 11%, and ten 12%), and dizziness (one 1%, four 5%, and 11 13%). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 20% of 84 patients). Interpretation Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. Funding Biotie Therapies.
Leriglitazone is a unique peroxisome proliferator‐activated receptor‐gamma (PPARγ) agonist that crosses the blood–brain barrier in humans and clinical trials have shown evidence of efficacy in ...neurodegenerative diseases. At clinical doses which are well‐tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti‐inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose‐exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8‐mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration‐time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.
X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive ...spinal cord axonopathy adrenomyeloneuropathy (AMN) to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop ...life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL SD 20%) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 81% of 77 patients receiving leriglitazone and 34 87% of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean SD change from baseline leriglitazone: –27·7 41·4 m; placebo: –30·3 60·5 m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 70% of 77 vs nine 23% of 39 patients, respectively) and peripheral oedema (49 64% of 77 vs seven 18% of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six 5% of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
The objective of this study is to evaluate the safety and efficacy of tozadenant as an adjunct to levodopa in PD patients with wearing-off fluctuations and determine dosages for phase 3 trials. ...Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist. This was an international, 12-week, double-blind, phase 2 trial in which patients on stable dosages of levodopa with at least 2.5 hr of OFF time/day were randomized to tozadenant 60, 120, 180 or 240mg BID, or matching placebo. Primary outcome measure was change from baseline to Week 12 in hr/day spent in the OFF state. A mixed-model repeated-measures ANCOVA was used for analyses with a prespecified hierarchical step-down approach to test multiple dose groups. Tozadenant, at a daily dosage of 120 or 180 mg BID, was generally well tolerated and demonstrated efficacy in reducing OFF time and improving motor signs without significantly increasing troublesome dyskinesia. These two dosages can be considered for future trials.
Background and Objectives Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator–activated receptor γ agonist that ...crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study. Methods In this double-blind, randomized controlled trial, eligible participants (age 12–60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2–6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio. Results Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares LS mean change standard error (SE): leriglitazone, −0.39 0.55 mm2; placebo, 0.08 0.72 mm2; p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change SE: leriglitazone, 0.10 1.33 ppb; placebo, 4.86 1.84 ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change SE: leriglitazone, 0.03 0.02; placebo, −0.02 0.03; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%). Discussion The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA. Trial Registration Information ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1. Classification of Evidence This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.
There is increasing interest on the part of investigators and the public at large in finding ways to study and improve treatments for the seriously mentally ill without exposing such individuals to ...unnecessary risks. One group of particular interest in this regard are patients suffering from acute mania. We set out to define "exit" criteria or novel clinical endpoints that might help to assess the efficacy of antimanic compounds. We sought a method that would be safer, more economical, and less sensitive to nonspecific factors in the clinical environment while still allowing unambiguous assessment of efficacy.
From a pool of subjects being screened for or already participating in intervention studies, we retrospectively identified 76 admissions of patients with a manic or mixed episode according to DSM-IV. We fit a mixed-effects regression model to all available data obtained using the Bech-Rafaelsen Mania Scale from admission to day 28 of treatment. Using the estimated model coefficients, we obtained empirical Bayes (EB) estimates of each subject's trend coefficients based on (1) all available data and (2) data through day 11 of treatment for mania.
We found a high correlation (r = .67) between EB estimates of final response at day 28 and actual day 28 scores on the Bech-Rafaelsen scale based on scores through day 11. When subjects were categorized as full, partial, or nonresponders according to their final Bech-Rafaelsen score, we were able to show that only 2 of the 23 predicted nonresponders became full responders, 27 of the 31 predicted full responders became full responders, and 16 of the 22 predicted partial responders became partial or full responders.
We conclude on the basis of this chart review study that it should be possible to define exit criteria for trials assessing the efficacy of antimanic compounds on the basis of relatively short duration exposure to experimental treatment.
Lesions at the volar aspect of the forearm may lead to isolated paralysis of the anterior interosseous nerve, which is a purely motor branch of the median nerve. The same syndrome may result from ...circumscribed damage at the level of the upper arm. Two patients are reported with the typical anterior interosseous nerve syndrome following supracondylar lesions of the median nerve and the literature is reviewed. In most cases this syndrome is a complication of supracondylar fractures of the humerus in children. A simple clinical test for the diagnosis, the pinch test, and the typical electromyographic findings are described. Whereas electroneurography has been considered to provide little help in diagnosis, a significantly lower nerve conduction velocity was found in the median nerve between the medial intermuscular spatium and the cubital fossa compared to the normal arm, and a prolonged response latency of the pronator quadratus of the injured arm following stimulation of the median nerve in the intermuscular medial spatium and the cubital fossa.
