olesoxime and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / antiinflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cholestenones; Dasatinib; Excitatory Amino Acid Antagonists; Humans; Mice; Mitochondria; Nerve Growth Factors; Neuroprotective Agents; Riluzole; Superoxide Dismutase-1; Treatment Outcome

Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are beginning to reveal possible principles governing the biology of motor neuron-selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cholestenones; Humans; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neuroprotective Agents

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Biomarkers, Pharmacological; Cholestenones; Disease Progression; Double-Blind Method; Drug Resistance; Female; Humans; Male; Metabolome; Metabolomics; Middle Aged; Placebos; Prognosis

To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole.. A double-blind, randomized, placebo-controlled, multicenter trial of 18 months' duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) ≥70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months' survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed.. At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan-Meier analysis was 67.5% (95% CI 61.0%-73.1%) in the placebo group and 69.4% (95% CI 63.0%-74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months' treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns.. Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Case-Control Studies; Cholestenones; Double-Blind Method; Europe; Female; Humans; International Cooperation; Kaplan-Meier Estimate; Male; Middle Aged; Neuroprotective Agents; Treatment Outcome

Patients with ALS may have insufficientenergy substrates, due to dysphagia and hypermetabolism, which adversely affects the prognosis. Hyperlipidaemia has been reported to be associated with ALS and to represent a significant prognostic factor for survival in ALS. The aim of this study was to examine the prevalence of dyslipidaemia among a cohort of patients with ALS and how the lipid profile of patients with ALS influenced the prognosis. This was a prospective observational cohort study comprising 512 ALS patients, recruited for the TRO19622 (Olesoxime) investigational medicinal product trial. Fasting serum concentrations of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured as part of routine monitoring in the trial. Seventy-three percent of the participants had hypercholesterolaemia (defined as total cholesterol ≥ 5.1 mmol/l) at the screening visit. The prevalence of hypercholesterolaemia decreased with time and was 64% at 18 months follow-up. On unadjusted analysis total cholesterol, LDL-C and LDL/HDL ratio had a statistically significant effect on survival (p = 0.015, 0.003 and 0.027, respectively). When adjusted for prognostic covariates, however, none of the lipid measures was found to have a statistically significant effect on survival. In conclusion, prognosis in ALS is not influenced by the lipid profile of patients.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Cholestenones; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Dyslipidemias; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Prevalence; Prognosis; Proportional Hazards Models; Prospective Studies

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.

Topics: Amyotrophic Lateral Sclerosis; Animals; Benzazepines; Cell Differentiation; Cell Survival; Cells, Cultured; Cholestenones; Embryonic Stem Cells; Glycogen Synthase Kinase 3; Humans; Indoles; Induced Pluripotent Stem Cells; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Motor Neurons; Mutation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Structure-Activity Relationship; Superoxide Dismutase; Superoxide Dismutase-1

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1(G93A) mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1(G93A) mice were randomized to receive olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that olesoxime initially reduced denervation from 60 to 30% compared to SOD1(G93A) mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1(G93A) mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether olesoxime could be beneficial for the treatment of ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Death; Cell Survival; Cells, Cultured; Cholestenones; Disease Models, Animal; Gliosis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Motor Neurons; Muscle Denervation

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.

Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Newborn; Binding, Competitive; Cell Enlargement; Cell Survival; Cells, Cultured; Cholestenones; Cytochromes c; Female; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Motor Neurons; Nerve Growth Factors; Nerve Regeneration; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, GABA; Sciatic Nerve; Superoxide Dismutase; Superoxide Dismutase-1; Survival Analysis; Voltage-Dependent Anion Channels