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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
IDrugs. Author manuscript; available in PMC 2011 March 16.
Published in final edited form as:
IDrugs. 2010 August; 13(8): 568–580.
PMCID: PMC3058503

Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis


Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are begsinning 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.


Amyotrophic lateral sclerosis (ALS) is a progressive and severely disabling fatal neurological disease characterized by initial muscle weakness followed by muscle atrophy, spasticity and eventual paralysis and death, typically within 3 to 5 years after onset of symptoms [1093240], [1093244]. The cause of the spasticity, paralysis and death is progressive degeneration and elimination of upper motor neurons (MNs) in the cerebral cortex, and lower MNs in the brainstem and spinal cord [1093240], [1093244]. Degeneration and loss of spinal and neocortical interneurons has also been noted in ALS [1093245], [1093247]. More than 5000 people are diagnosed with ALS each year in the US [1093231]. There are two forms of ALS: idiopathic (sporadic) and heritable (familial) [1093240], [1093244]. Most cases of ALS are sporadic with few known genetic contributions, except for missense mutations in TAR DNA binding protein [1093248]. Aging is a strong risk factor for ALS because the average age of onset is 55 years [1093231]. Familial forms of ALS (fALS) have autosomal dominant or autosomal recessive inheritance patterns and make up approximately 10% or less of all cases of ALS [1107246]. Mutations linked to ALS occur in the genes encoding SOD1 (ALS1), Alsin (ALS2), senataxin (ALS4), vesicle-associated membrane protein (synaptobrevin)-associated protein B (ALS8), dynactin, TAR DNA binding protein, and fused in sarcoma (ALS6) [1093249]. No effective treatments exist for ALS. Riluzole, a potent blocker of tetrodotoxin-sensitive sodium channels, is the only drug currently approved by the US FDA, but its effects are marginal or modest. Riluzole delays the onset of ventilator dependence or tracheostomy in some patients and may increase survival by approximately 3 to 5 months [1093244].

Therapeutic Olesoxime

Originator Trophos SA

Status Phase III Clinical

Indications Motor neuron disease, Multiple sclerosis, Parkinson’s disease, Peripheral neuropathy, Spinal muscular atrophy

Actions Analgesic, Antiparkinsonian, Apoptosis inhibitor, Neuroprotectant

Technologies Capsule formulation, Oral formulation, Small-molecule therapeutic

Synonym TRO-19622

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Experimental models of MN dysfunction and death, including axotomy models (axonal transection and avulsion), were used before the discovery of mutant genes linked to ALS and the generation of transgenic mice; these models are still used. Axotomy models have provided insights into the mitochondrial-based mechanisms of MN cell death after injury [1093281], [1093283]. The beneficial influences of trophic factors on injured MNs in preclinical animal and cell models provided potential opportunities for translation to ALS treatment. However, data from clinical trials of neurotrophins have been disappointing [1093244], and there are critical issues to be resolved regarding delivery problems, cell selectivity and side effects.

The developing understanding of mitochondrial biology over the past two decades may be relevant to ALS [1093283]. Mitochondria are multi-functional organelles [1093284], [1093292], which, in addition to their critical role in the production of ATP through the electron transport chain, have roles in intracellular calcium homeostasis, steroid, heme and iron-sulfur cluster synthesis, and programmed cell death [1093284], [1093292]. Mitochondria are also sites of formation of reactive oxygen species (ROS), including the superoxide anion (O2•−) and the highly reactive hydroxyl radical (OH) or its intermediates, and reactive nitrogen species, such as nitric oxide (NO) [1093292]. Thus, mitochondria have functions and properties that might confer an intrinsic susceptibility to subsets of long-lived post-mitotic cells, such as MNs, to aging and stress, including environmental toxins and genetic variations.

There is evidence for mitochondrial abnormalities in ALS, but definite causal relationships to pathogenesis are lacking. Studies of respiratory chain enzyme activities demonstrate increases in complex I, II and III activities in vulnerable and non-vulnerable brain regions in patients with mutant SOD1-fALS [1093294], but complex IV activity is decreased in the spinal cord ventral horn [1093295] and skeletal muscle [1093300] of sporadic ALS cases. In sporadic ALS skeletal muscle, reductions in the activity of respiratory chain complexes with subunits encoded by the mitochondrial genome are associated with decreased neuronal NO synthase levels [1093303]. However, no significant accumulation of the 5 kb common deletion in mitochondrial DNA has been demonstrated by single cell analysis of MNs from sporadic ALS cases [1093307]. Electron microscopy studies have demonstrated abnormalities in mitochondrial morphology in skeletal muscle, liver, spinal MNs and cortical upper MN regions in patients with ALS [1093310], [1093324]. Alterations in skeletal muscle mitochondria are progressive [1093325] and could be intrinsic to skeletal muscle [1093328], rather than caused merely by neurogenic atrophy, as frequently assumed. Skeletal muscle biopsies of patients with sporadic disease demonstrate ultrastructural changes that are indicative of elevated levels of calcium in MN synaptic terminals, with some mitochondria demonstrating an augmented calcium signal [1093329].

Excitotoxicity has been implicated in the pathogenesis of ALS [478891] and is another possible mechanism by which MNs may be damaged in cell and animal models of ALS [1093331]. Some patients with sporadic ALS have reduced levels of synaptosomal high-affinity glutamate uptake [478891] and the astroglial glutamate transporter excitatory amino acid transporter 2 (EAAT2) in the motor cortex and spinal cord [478890]. Reductions in levels of activity of EAAT2 in the spinal cord could increase the extracellular concentrations of glutamate at synapses on MNs [1093331]. However, the loss of glutamate transport occurs in other diseases [1093335] and, in some animal models of neuronal injury, loss of EAAT2 does not result in neurodegeneration, which might signify that astroglia are performing other functions unrelated to glutamate transport [1093336]. Nevertheless, MNs appear sensitive to glutamate excitotoxicity, perhaps because they have a low proportion of AMPA subtype glutamate receptor-2-edited or under-edited glutamate receptors on their surfaces, predisposing MNs to the risk of excess calcium entry and mitochondrial disturbances [1093337], [1093351].

Excess glutamate receptor activation in neurons can increase levels of intracellular calcium, augmented mitochondrial ROS production, bioenergetic failure, mitochondrial trafficking abnormalities and oxidative stress [1093353]. Markers of oxidative stress and ROS damage are elevated in ALS tissues [638230]. In human sporadic ALS, protein carbonyls are elevated in the motor cortex [1093355] and tyrosine nitration is increased in human ALS nervous tissues [318913], [1093357], [1093360]. Calcium-induced generation of ROS in brain mitochondria is mediated by mitochondrial permeability transition [1057796]. Motor neurons are particularly affected by inhibition of mitochondrial metabolism, which causes elevated cytosolic calcium levels and increased excitability [1093696].

Mitochondrial programmed cell death involving p53 appears to contribute to the selective degeneration of MNs in human sporadic ALS and fALS, albeit seemingly as a non-classical form differing from apoptosis [356003]. MNs appear to pass through sequential stages of degeneration involving chromatolysis (suggestive of initial axonal injury), somatodendritic attrition without extensive cytoplasmic vacuolation, and then nuclear DNA fragmentation, nuclear condensation and cell death. Motor neurons from individuals with sporadic ALS and fALS demonstrate the same patterns of degeneration [356003]. This human MN death is defined clearly by genomic DNA fragmentation (determined by DNA agarose gel electrophoresis and in situ DNA nick-end labeling) and cell loss, and is associated with accumulation of mitochondria, cytochrome c and cleaved caspase-3 [1093997]. The morphology of this cell death is distinct from classical apoptosis, despite the nuclear condensation [1093998], [1094007]. Nevertheless, the levels of the pro-apoptotic proteins Bax and Bak1 are increased in mitochondria-enriched fractions of selectively vulnerable motor regions (spinal cord anterior horn and motor cortex gray matter), but not in regions unaffected by the disease (somatosensory cortex gray matter) [356003]. In marked contrast, the anti-apoptotic Bcl-2 protein is severely depleted in mitochondria-enriched fractions of affected regions and is sequestered in the cytosol [356003].

Although these observations lacked direct specificity for MN events [356003], subsequent immunohistochemistry [1093997] and laser capture microdissection of MNs combined with mass spectroscopy-protein profiling have confirmed the presence of intact active caspase-3 in human ALS MNs [1094653]. Levels of p53 increase in vulnerable regions in individuals with ALS, and p53 accumulates specifically in MNs in human ALS [1094022]. This p53 is active functionally because it is phosphorylated at Ser392 and has increased DNA binding activity [1094007], [1094022]. p53 can mediate mitochondrial permeabilization and cell death independent of transcription through direct physical interaction with Bcl-2 family members [1094031].

Cell culture experiments revealed mitochondrial dysfunction in the presence of mutant SOD1 (mSOD1) [1094033], [1094034]. Expression of several human SOD1 mutants increases mitochondrial O2•− levels and causes toxicity in human neuroblastoma cells [1094033] and mouse NSC34 cells (a hybrid cell line with some MN-like characteristics, produced by fusion of MN-enriched embryonic mouse spinal cord cells with mouse neuroblastoma cells) [1094034]. These responses can be attenuated by overexpression of manganese SOD [1094036]. ALS-mSOD1 variants, compared with wild-type SOD1, preferentially associate with mitochondria in NSC34 cells and appear to form crosslinked oligomers that shift the mitochondrial glutathione/oxidized glutathione ratio towards oxidation [1094033].

Transgenic mice develop mitochondrial abnormalities in the presence of human mSOD1 [400332], [1094037], [1094039], [1094040], [1094042], [1094044], [1094045]. The MN degeneration observed in mice expressing high levels of Gly93Ala substituted mutant protein (G93Ahigh-mSOD1) in a non-tissue specific pattern throughout the body closely resembles a prolonged necrotic-like cell death process driven by chronic oxidative stress involving early mitochondrial damage, cellular swelling and dissolution [1093997], [1094046], [1094047], [1094048]. Biochemically, the death of MNs is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear DNA and mitochondrial DNA. The MN death is independent of activation of caspase-1 and -3, and also appears to be independent of capsase-8 and apoptosis-inducing factor activation within MNs. Indeed, caspase-dependent and p53-mediated apoptosis mechanisms might be blocked actively in G93Ahigh-mSOD1 mouse MNs, possibly by upregulation of inhibitors of apoptosis and changes in nuclear import of proteins [1094046]. Human SOD1 mutant proteins appear to gain a toxic property or function, rather than having diminished O2•− scavenging activity [1094065], [1094089], [1094092], and wild-type SOD1 can gain toxic properties through oxidative modification [1094097], [1094099]. A gain in aberrant oxidative chemistry may contribute to the mechanisms of mitochondriopathy in G93Ahigh-mSOD1 mice [1094046], [1094141], [1094388]. G93A–mSOD1 possesses enhanced free radical-generating capacity compared with wild-type enzyme [1094092] and can catalyze protein oxidation by hydroxyl-like intermediates and carbonate radicals [1094393]. G93Ahigh-mSOD1 mice have increased protein carbonyl formation in spinal cord tissue extracts at pre-symptomatic disease [1094428]. Protein carbonyl formation in mitochondrial membrane-enriched fractions of spinal cord is a robust signature of incipient disease [1094048], [1094429]. Nitrated and aggregated cytochrome c oxidase subunit-I and α-synuclein accumulate in G93Ahigh-mSOD1 mouse spinal cord [1094046]. Nitrated manganese SOD also accumulates in G93Ahigh-mSOD1 mouse spinal cord [1094048].

A new transgenic mouse model of ALS with expression of human SOD1 variants (mutant and wild-type) restricted to skeletal muscle (hSOD1mus) has revealed a critical role for skeletal muscle in ALS pathogenesis [1111761]. These mice develop ALS with a MN degeneration phenotype that, unlike the G93Ahigh-mSOD1 mouse, is similar structurally and biochemically to that observed in human ALS. Moreover, early in the course of disease, hSOD1mus transgenic mice display evidence for mitochondrial protein oxidative damage and nitration that coincides with damage to the neuromuscular junction [1111761]. The discovery of instigating molecular toxicities and disease progression determinants with skeletal muscle mitochondria could be very important for the development of new mitochondrial-directed therapies for the treatment of ALS.

Cyclophilin D (CypD; also known as cyclophilin F or peptidyl prolyl isomerase F) and the adenine nucleotide translocator (ANT; or solute carrier family 25) have been identified as targets of nitration in ALS mice [1094048]. CypD is believed to be a major regulator of the mitochondrial permeability transition pore (mPTP). Cyclophilin D nitration is increased in early- to mid-symptomatic stages, but declines to baseline levels by end-stage disease. The ANT was once believed to be a core component of the mPTP, but it is now known that it cannot fulfill this role [1094500]; nevertheless, the ANT has essential mitochondrial functions [1094432]. Nitration of ANT is notable particularly because it is found in pre-symptomatic and symptomatic stages, but not at end-stage disease or in transgenic mice expressing human wild-type SOD1 [1094048].

The ANT is believed to be important in the context of age-related neurodegenerative disease [1093281] because it undergoes carbonyl modification during aging in the housefly flight muscle [1094430] and rat brain [1094431]. In vitro experiments have demonstrated that NO and peroxynitrite (ONOO) can act directly on the ANT to induce mitochondrial permeabilization in a cyclosporine A-sensitive manner [1094432]. Oxidative stress enhances the binding of CypD to ANT [1094434]. Some SOD1 mutants are unstable and lose copper [1094435]; interestingly, copper interactions with ANT and thiol modification of ANT can cause mPTP opening [1094436], [1094437]. Together, these data may suggest that oxidative and nitrative damage to proteins, some of which are regulators of the mPTP, in ALS is targeted rather than stochastic and could affect the functioning of the mPTP. Thus, drugs that block these pathologic processes could be important new treatments for ALS.

G93Ahigh-mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate greater levels of O2•−, NO and ONOO than MNs in transgenic mice expressing human wild-type SOD1 [1094046]. MNs in hSOD1mus mice also accumulate mitochondria [1111761]. In G93Ahigh-mSOD1 mice this mitochondrial accumulation occurs at a time when MN cell body volume is increasing, which is suggestive of ongoing problems with ATP production or the plasma membrane sodium-potassium pump and cell volume control [1094046]. G93A–mSOD1 disturbs anterograde axonal transport of mitochondria in cultured primary embryonic MNs [1094438], making it possible that retrogradely transported mitochondria with toxic properties from the neuromuscular junction fail to be returned to distal processes [1094046], [1094439]. Mitochondria (with enhanced toxic potential) from distal axons and terminals could therefore have a 'Trojan horse' role in triggering degeneration of MNs in ALS via retrograde transport from diseased skeletal muscle [1094439], [1111761].

Recent electron microscopy studies have demonstrated that the outer mitochondrial membrane (OMM) remains relatively intact to permit formation of mega-mitochondria in MN cell bodies in G93Ahigh-mSOD1 mice [1094046], [1094047], [1094048]. Moreover, early in the disease of these mice, mitochondria in dendrites of the spinal cord ventral horn undergo extensive crista and matrix remodeling, while few mitochondria in MN cell bodies demonstrate major structural changes [1094048]. Another interpretation of ultrastructural data is that the mSOD1 causes mitochondrial degeneration by inducing OMM extension and leakage and intermembrane space expansion [1094044]. Mechanisms for this damage could be related to mSOD1 gaining access to the mitochondrial intermembrane space [1094044], [1094440] and the matrix [1094441], and inducing disturbances in oxidative phosphorylation [1094442] and antioxidant activity [1094046], [1094048]. This mitochondrial conformation noted using electron microscopy would favor the formation of the mPTP; indeed, there is evidence for increased contact sites between the OMM and inner mitochondrial membrane (IMM) in dendritic mitochondria in G93Ahigh-mSOD1 mice [1094048]. Another feature of MNs in young presymptomatic G93Ahigh-mSOD1 mice is apparent fission of ultrastructurally normal mitochondria in cell bodies and fragmentation of abnormal mitochondria [1094048]. It is not clear if the crista and matrix remodeling and the apparent fragmentation and fission mitochondria are related or independent events, and if these abnormalities interfere with mitochondrial trafficking. Nevertheless, morphological observations support the idea that mitochondria are critical to the pathobiology of mSOD1 toxicity to MNs in G93Ahigh-mSOD1 ALS mice [1093281].

Until recently the evidence for mitochondrial-based mechanisms of human and mouse ALS has been circumstantial, with direct, unequivocal causal relationships lacking. The mPTP was first implicated in ALS pathogenesis using pharmacological approaches. Cyclosporine A treatment of G93Ahigh-mSOD1 mice, delivered intracerebroventricularly or systemically to mice on a multiple drug resistance type 1a/b background, modestly improved outcome [1094483], [1094492], [1094493], but these studies are confounded by the immunosuppressant and other mPTP-independent actions of cyclosporine A through calcineurin inhibition. Pharmacological studies using CypD inhibitors that have no effects on calcineurin need to be undertaken in ALS mice.

A direct role for mitochondria in the mechanisms of ALS was determined by investigating the mPTP [1094048]. Mitochondrial permeability transition is a mitochondrial state in which the proton-motive force is disrupted reversibly or irreversibly. Conditions of mitochondrial calcium overload, excessive oxidative stress and decreased electrochemical gradient, ADP and ATP can favor mitochondrial permeability transition. This altered state of mitochondria involves the mPTP, which functions as a voltage, thiol and calcium sensor [1094496], [1094497], [1094498], [1094499], [1094500]. The mPTP is believed to be an IMM high-conductance channel or hemichannel. The opening of this channel leads to permeabilization of the IMM, to solutes ≤ 1500 Da [1111760]. The collective components of the mPTP are not known, but the voltage-gated anion channel (VDAC) in the OMM, the ANT in the IMM, and CypD in the matrix have been implicated in mPTP functioning, yet they are each dispensable for the process of mitochondrial permeability transition [1094497], [1094499], [1094500], [1094501], [1094927]. CypD is encoded by a single gene [1094497], [1094499] and, despite confusing nomenclature, there is only one isoform of CypD (EC, PPIF gene product) in humans and mice. The protein (approximately 20 kDa) encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase family, which catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerates the folding of proteins. CypD binds ANT1 [1094500]. Other components or modulators of the mPTP appear to be the mitochondrial phosphate carrier, hexokinase, creatine kinase, translocator protein 18 kDa (TSPO; or peripheral/mitochondrial benzodiazepine receptor) and members of the Bcl-2 family [1094497], [1094499], [1094500], [1094514], [1094515], [1111760].

During normal mitochondrial function, the OMM and IMM are separated by the intermembrane space, and the VDAC and the ANT do not interact [1094498], [1094927]. Permeability transition is activated by the formation of the mPTP: the IMM loses its integrity and the ANT changes conformation from its native state into a non-selective pore [1094500], [1094515]. This process is catalyzed by CypD that functions in protein cis-trans isomerization and chaperoning [1094497], [1094499], [1094515]. The molar concentration of CypD (in heart mitochondria) is much less (~ 5%) than ANT; thus, under normal conditions only a small fraction of the ANT can be in a complex with CypD [1094500], [1094515]. When this occurs, small ions and metabolites permeate freely across the IMM and oxidation of metabolites proceeds with electron flux not coupled to proton pumping, resulting in collapse of the electrochemical gradient, dissipation of ATP production, production of ROS, equilibration of ions between the matrix and cytosol, matrix volume increases, and mitochondrial swelling [1094498], [1094927].

The role of CypD in MN disease has been examined in ALS mice through gene ablation [1094048]. G93Ahigh-mSOD1 mice without CypD demonstrated markedly delayed disease onset and lived significantly longer than transgenic mice with CypD. The effect of CypD deletion was much more evident in females than in males. Female mice even demonstrated positive effects with haplo-deletion of CypD. Ppif gene ablation in transgenic mice with much lower levels of human mSOD1 expression and a slower disease progression (G93Alow-mSOD1 mice) resulted in significantly delayed disease onset and mice lived significantly longer than transgenic mice with CypD [1094048]. Thus, some form of mitochondrial pathobiology is occurring regardless of whether transgene expression of G93A–mSOD1 is high or low. Nevertheless, G93Ahigh-mSOD1 mice without CypD eventually develop MN disease and die. Other work on CypD null mice has demonstrated that high concentrations of calcium (2 mM) can still lead to mPTP activation without CypD and that cell deaths caused by Bid, Bax, DNA damage and TNFα are not affected [1094501]. The effects of CypD deficiency on MN cell mechanisms need to be examined in more detail, but the cell death phenotype might be switched or converted to another form with the attenuation of mitochondrial swelling. A switch in the cell death morphology and molecular mechanisms in MNs of mSOD1 mice without CypD is an outcome consistent with the cell death continuum concept [1093283].

Trophos SA is developing olesoxime (TRO-19622), a cholesterol-like neuroprotectant that targets putatively the mPTP, possibly preventing the release of apoptotic factors or occluding other cell death mechanisms, for the potential oral treatment of ALS, peripheral neuropathy and spinal muscular atrophy (SMA) [619434], [795507], [998571]. The company is also investigating the compound for the potential treatment of Huntington's and Parkinson's diseases and multiple sclerosis [619475], [875224], [910845], [972068], [972070]. Olesoxime has been granted Orphan Drug status for ALS in the US and the EU, and for SMA in the EU [647918], [688521].

Synthesis and SAR

Olesoxime (C27H45NO) has a molecular weight of 399.65 Da and is lipophilic. It exists as a stable mixture of syn- and anti-isomers of cholest-4-en-3-one oxime in the 3 position. In crystalline powder form, it is stable for more than 36 months under normal regulatory conditions. It can be synthesized by reacting cholest-4-en-3-one with hydroxylamine and sodium acetate [806418].

Olesoxime was identified from a 45,000-compound chemical library using medium-throughput screening of primary MNs in culture; it rescued cultured MNs from death induced by trophic factor deprivation [806418]. To identify potential molecular targets and mechanisms of action, olesoxime was screened on a panel of enzymes, receptors, channels and transporters. Out of 80 targets, only the progesterone receptor and TSPO demonstrated significant displacement of control binding. Olesoxime displacement of 0.2 nM [3H]PK-11195 binding to TSPO in rat heart membranes had an IC50 value of 30 to 50 µM (48 ± 2% inhibition of specific binding at 30 µM and 62 ± 11% at 50 µM). Follow-up experiments revealed that olesoxime did not interact functionally with the classical nuclear steroid receptor, but did interact with a specific neuroactive steroid binding site associated with mitochondria. The activity of olesoxime is believed to be caused by its binding of the TSPO and/or the VDAC [806418].

Preclinical development

In vitro

Exposure to olesoxime (ranging from 0.1 to 10 µM) at 1 h after plating significantly protected primary embryonic rat spinal MNs (that had been cultured for 3 days without brain-derived, ciliary and glia-derived neurotrophic factors) from cell death [806418]. At a concentration of 10 µM, olesoxime maintained survival of 74 ± 10% of the neurons supported by a combination of neurotrophic factors (brain-derived, ciliary and glia-derived neurotrophic factors). The mean EC50 value in this assay was 3.2 ± 0.2 µM. In addition to preserving MN cell bodies, olesoxime also promoted the outgrowth of neurites. At a concentration of 1 µM, which increased cell survival by only 38%, olesoxime increased overall neurite outgrowth per cell by 54% [806418].

The chemotherapeutic camptothecin causes DNA strand breaks and increases production of ROS. Co-treatment of cultural cortical neurons with camptothecin and olesoxime resulted in a dose-dependent increase in cell survival at 16 h and decreased levels of activated caspase-3 and -7. These effects were similar to those observed with brain-derived neurotrophic factor, although the neuroprotection with olesoxime was not associated with activation of ERK1/2 or PI3K [1040616].

In vivo dosing of microtubule-targeting agents is often restricted by development of peripheral neuropathy. In vitro, microtubule-targeting agents decreased neurite outgrowth in rat and human differentiated neuronal cells and triggered end binding protein (EB)1 and EB2 dissociation from the microtubules to the cytosol. EB distribution and neurite outgrowth was preserved with concomitant exposure to olesoxime [1040609].

The myelination promoting activities of olesoxime were tested in vitro in rodent central nervous system cell cultures. Olesoxime dose-dependently accelerated the differentiation of oligodendrocyte progenitor cells from neural progenitors. It also enhanced myelination in co-cultures of dorsal root ganglion neurons and oligodendrocyte progenitor cells [1082374].

In vivo

Olesoxime was tested in a neonatal rat model of MN degeneration induced by axotomy of the facial nerve. At 7 days after nerve axotomy, rats administered olesoxime (100 mg/kg po) for 5 days had significantly more surviving MNs compared with animals administered vehicle (29 ± 2 versus 20 ± 2%; p < 0.05) [806418].

To examine whether olesoxime could enhance regeneration of peripheral nerves, adult mice underwent sciatic nerve crush and were then administered olesoxime (0.3, 3 or 30 mg/kg sc) [806418]. Treatment resulted in a dose-dependent acceleration in regeneration beginning 2 weeks after injury and was significantly different for all doses compared with vehicle-treated mice by week 4 after injury. By week 6, mice administered olesoxime had recovered up to 80% of the neuromuscular function of sham-operated mice. Lesioned nerves from vehicle-treated mice demonstrated an overall reduction in axonal size compared with control mice. Olesoxime increased axonal cross-sectional area, with statistically significant differences compared with the vehicle group at the 30-mg/kg dose (mean axonal size = 7.6 ± 0.1 versus 6.0 ± 0.1 µm2; p < 0.05). At 4 weeks, all doses of olesoxime significantly reduced the number of 'poorly' militated fibers [806418].

The efficacy of olesoxime was also tested in a transgenic G93Ahigh-mSOD1 mouse model of ALS [806418]. Olesoxime (3 or 30 mg/kg sc, starting at post-natal day 60) improved motor performance, delayed disease onset and extended survival by 10%. There was a 15-day delay in the onset of decrease in body weight at the 3 mg/kg dose (p < 0.01) and a significant delay of approximately 11 days in decline in grid performance was observed at both doses (p < 0.01) [806418].

The neuroprotective and antinociceptive properties of olesoxime were investigated in a rat model of diabetic neuropathy induced by injection of streptozotocin (55 mg/kg) [732843], [911450], [1043542]. Neuropathy was monitored using electrophysiological measures and the tail-flick test; nociception was measured using thermal allodynia and thermal and mechanical hyperalgesia tests. At oral doses of 30 and 300 mg/kg/day starting 10 days after diabetes induction, olesoxime significantly relieved pain in diabetic rats (p ≤ 0.05) and the effects were comparable with those after administration of 3 mg/kg of morphine. Olesoxime also significantly reduced compound muscle action potential latency, a measure of motor nerve conduction. A single oral administration of olesoxime (10, 30 or 100 mg/kg) dose-dependently reversed diabetic allodynia, with statistically significant differences compared with vehicle-treated rats at the highest dose (p ≤ 0.05). After dosing for 5 days, all doses of olesoxime significantly reversed tactile allodynia and the effect was comparable with that of gabapentin (50 mg/kg bid) [732843], [911450].

The effects of olesoxime on paclitaxel-induced neuropathic pain were studied in rats administered paclitaxel (2 mg/kg ip) on days 0, 2, 4 and 6 [997562], [1064900]. Olesoxime was administered from either day −1 to 15 for prevention studies or for 5 consecutive days beginning on day 25 to determine effects on paclitaxel-induced pain behavior. Olesoxime (3 or 30 mg/kg/day po) significantly reduced paclitaxel-induced allodynia and hyperalgesia until day 40 (25 days after the last dose of olesoxime). It also reduced the loss of intraepidermal nerve fibers in rats exposed to paclitaxel: these were decreased by 46% in paclitaxel-treated rats and by 22 to 25% in rats that also received olesoxime. At doses of 10 or 100 mg/kg/day, olesoxime significantly reduced hyperalgesia and allodynia from the second day of administration. Although reversible, this analgesic effect was maintained for 10 days following the last administration of olesoxime [997562], [1064900].

In a similar study, olesoxime was assessed in a rat model of vincristine-induced (200 µg/kg iv, on days 1, 4, and 6) neuropathic pain [911450]. Olesoxime significantly decreased vincristine-induced allodynia 4 h after the first administration of the highest dose tested (100 mg/kg po; p < 0.001). Repeated treatment with 10, 30 and 100 mg/kg/day olesoxime significantly reduced vincristine-induced allodynia from day 11 to day 14 [911450].


Daily administration of olesoxime (3 or 30 mg/kg sc) to adult mice for more than 2 months was well tolerated without toxicity or adverse effects [806418]. Toxicity was not observed in animals exposed to doses 40-fold greater than the expected therapeutic dose for 4 weeks [619475]. At the time of publication, no further toxicity data were available.

Metabolism and pharmacokinetics

Olesoxime has been administered to rats and mice by oral gavage as a suspension in hydroxypropylmethylcellulose or vegetable oil, and by subcutaneous injection as a mixture of Cremophor EL/dimethyl sulfoxide/ethanol/ phosphate-buffered saline (5:5:10:80, respectively) [806418]. To determine bioavailability, adult mice received daily subcutaneous injections of olesoxime for 1 or 6 weeks at doses of 0.3, 3 and 30 mg/kg. Levels of olesoxime in plasma and brain were measured by high performance liquid chromatography with tandem mass spectroscopy detection. Plasma and brain olesoxime levels were dose-dependent, reached steady-state by 1 week and remained stable over the 6-week treatment period. Levels of olesoxime were approximately 1.25 and 0.5 µM in plasma and brain, respectively, at the 3-mg/kg/day dose [806418].

Pharmacokinetic studies in rats demonstrated that olesoxime had an elimination t1/2 value of approximately 24 h, leading to accumulation with steady-state levels in plasma achieved after three daily oral administrations [911450]. In the diabetic and vincristine-treated rats, repeated oral administration of a 10-mg/kg/day dose of olesoxime resulted in steady-state plasma concentrations of between 2 and 4.5 µM. Single-dose oral olesoxime at 100 mg/kg resulted in plasma concentrations between 14.2 and 37.5 µM in both models [911450].

In paclitaxel-treated rats, plasma levels after the first 10-mg/kg dose of olesoxime were 0.82 µM increasing to 1.39 µM after the fifth daily dose. For a 100-mg/kg dose, day 1 and day 5 plasma levels were 6.75 and 8.91 µM, respectively [1064900].

A phase I, randomized, double-blind, placebo-controlled, dose-escalation clinical trial assessed the pharmacokinetics of four doses of olesoxime (50, 150, 250 and 500 mg po, qd) administered for 11 consecutive days to healthy Caucasian volunteers (n = 48) [1043541]. The absorption and elimination of olesoxime were slow at all doses: the Tmax value was approximately 10 h and concentrations of olesoxime were measurable for up to 19 days after dosing. The mean t1/2 was comparable between doses at approximately 120 h. Dose increased in a ratio of 3, 5 and 10 (from 50 to 150, 250 and 500 mg, respectively), but day 1 Cmax increased in a ratio of 2.2, 4.4 and 10.2, and AUC0-τ increased in a ratio of 2.1, 4.6 and 10.8. At steady-state, which was reached on day 11 in all groups, Cmax increased with dose in a ratio of 2.1, 7.2 and 12.2, and AUC0-τ increased with a ratio of 2.0, 6.5 and 11.6. Mean accumulation ratios of Cmax and Ctrough observed between days 1 and 11 were approximately 4. Plasma pharmacokinetic profiles were similar between volunteers and across all doses: the coefficients of variation of Cmax and AUC0-τ were between 21 and 47% on day 11 [1043541].

The pharmacokinetics of olesoxime (dosed just before a meal), co-administered with riluzole for 1 month, were assessed in a phase Ib clinical trial in patients (n = 36) with ALS [846908], [1040613]. Median male and female Ctrough values were 512 and 742 ng/ml at a 125-mg dose of olesoxime, 979 and 1685 ng/ml at a 250-mg dose, and 2965 and 3310 ng/ml at a 500-mg dose; these values did not indicate a gender effect at any dose. The maximum Ctrough value was 5780 ng/ml and was observed on day 15 in the 500-mg dose group. Day 15 and day 30 olesoxime Ctrough values were similar, suggesting that steady-state was reached by day 15. Greater Ctrough plasma concentrations were observed in patients with ALS than in healthy volunteers, which may have been caused by co-administration with food or riluzole [846908], [1040613].

The pharmacokinetics of olesoxime were also assessed in a phase Ib trial in pediatric (n = 5) and adult (n = 3) patients with SMA. After a single dose of olesoxime (125 mg po), the Cmax and AUC values were comparable in children and adults after adjusting the dose to mg/kg; Tmax, t1/2 and total clearance were identical. Results after once-daily dosing were similar [997568].

Clinical development

Amyotrophic lateral sclerosis

A phase Ib, randomized, double-blind, placebo-controlled, 1-month clinical trial assessed olesoxime (125, 250 or 500 mg po, qd) in combination with riluzole (50 mg po, bid) in patients (n = 36) with a probable or definite diagnosis of ALS [846908], [1040613]. Target plasma concentrations, based on preclinical modeling, were obtained at the 250- and 500-mg doses. There was no change in the ALS functional rating scale and slow vital capacity assessments, but this was anticipated given the short duration of the trial [846908], [1040613].

At the time of publication, a phase II/III, randomized, double-blind, placebo-controlled, parallel-assignment, multicenter clinical trial ( identifier: NCT00868166; TRO19622 CL E Q 1015-1; MITOTARGET) was ongoing in patients (expected n = 470) with ALS. Patients were to receive either placebo or olesoxime (330 mg po, qd) as add-on therapy to riluzole (50 mg po, bid) for 18 months under double-blind conditions; open-label administration of olesoxime would then be permitted. The primary endpoint was the overall 18-month survival rate and the secondary endpoints included ALS functional rating scale, time-to-assisted ventilation, vital capacity, manual muscular testing and quality-of-life. The trial began in April 2009 and data were expected in mid-2011 [1006137].

Spinal muscular atrophy

A phase Ib, open-label clinical trial assessed olesoxime (125 mg po) in pediatric (aged 7 to 11 years; n = 5; 1 type Ib and 4 type II) and adult (n = 3; all type III) patients with SMA [835157], [997568]. Patients received single-dose olesoxime for pharmacokinetic assessments; this was followed by a 2-week washout period and then once-daily dosing for 10 days. Efficacy data were not reported, but the investigators reported difficulty in recruiting sufficient patients leading to the target number of 20 patients not being enrolled [997568].

A phase II, randomized, placebo-controlled, 24-month clinical trial was planned for the assessment of olesoxime in patients (n = 150) with SMA. The trial would use the compound muscle action potential physiological assessment at frequent timepoints, and would also collect pharmacokinetic data. At 1 year, a futility analysis would be conducted and, if clinical efficacy was demonstrated, all patients in the placebo group would then receive active treatment with olesoxime [1071528].

Peripheral neuropathy

At the time of publication, a phase IIa, randomized, double-blind, placebo-controlled, parallel-assignment clinical trial (NCT00876538; TRO19622 CL E Q 1204-1; CIPN) of olesoxime (330 mg po, qd for 6 weeks) was ongoing in patients (estimated n = 40) with chemotherapy-induced peripheral neuropathy. Patients would have the option to continue treatment for an additional 6 weeks. The primary endpoint was the percentage of responders, defined as patients with a minimum decrease of 50% in the maximum neuropathic pain dimension (either pain or dysesthesia) present at baseline. The trial began March 2009 and was due to finish in December 2009, although patients were still being recruited at the time of publication.

A phase IIa, randomized, double-blind, placebo-controlled, parallel-assignment, multicenter clinical trial (NCT00496457; TRO19622 CLEQ 1104-1) assessed olesoxime (125 mg po, qd for 6 weeks) in patients (estimated n = 180) with diabetic peripheral neuropathy. The primary endpoint was improvement in pain, measured by the Likert scale and other pain scales in a daily diary. This trial began in May 2007, but in December 2008, data were reported demonstrating that the primary endpoint of the trial had not been met. As a result of this, Trophos discontinued development of the drug for this indication [972068].

Non-alcoholic steatohepatitis

A phase II, randomized, double-blind, placebo-controlled, parallel-assignment clinical trial (NCT00666016; TRO19622 CL E Q 1159-1) assessed olesoxime (500 mg po, qd for 1 month) in patients (estimated n = 30) with non-alcoholic steatohepatitis. Safety, tolerability and short-term effects on circulating liver enzymes and biomarkers of oxidative stress and apoptosis were to be assessed. The primary endpoint was mean change in ALT assessed using an analysis of covariance. The secondary endpoint was sustained reduction in ALT to either 50% of baseline or a value less than or equal to the upper limit of normal. This trial began in April 2008, but was prematurely terminated in December 2008. Trophos stated that this was because of high variability in the baseline values for the primary endpoint [972068].

Side effects and contraindications

In the phase I clinical trial of olesoxime (50, 150, 250 and 500 mg po, qd for 11 days) in healthy volunteers, no serious adverse events were reported [1043541]. There were 69 treatment-emergent adverse events (TEAEs) reported, of which 18 were considered possibly related, 22 were considered unlikely to be related and 27 were judged unrelated to olesoxime. Of the possibly related TEAEs, two occurred after the 50-mg dose, two occurred after the 250-mg dose, seven occurred after the 500-mg dose and seven occurred after placebo. Most TEAEs were mild (48 events) or moderate (21 events) in intensity. The most frequently reported TEAEs were diarrhea (9 episodes), headache (7 episodes), constipation (4 episodes), pharyngitis (4 episodes) and back pain (4 episodes). TEAEs were not dose-related. There were no relevant changes in vital signs, ECG parameters, laboratory tests or physical examinations [1043541].

In the phase Ib clinical trial of olesoxime (125, 250 or 500 mg po, qd) plus riluzole (50 mg po, bid) in patients with ALS, all doses were well tolerated. There were 69 TEAEs reported, of which 2 were considered probably related, 13 possibly related, 21 unlikely to be related and 33 unrelated to olesoxime; the 2 considered probably related both occurred in the placebo group. Of the possibly related TEAEs, one occurred in the control group, six in the 125-mg group, three in the 250-mg group and three in the 500-mg group [846908], [1040613]. The TEAEs were mild (n = 55), moderate (n = 13) or severe (n = 2) in intensity. The most frequently reported TEAEs were asthenia (12 episodes, 9 after olesoxime), diarrhea (6 episodes, 4 after olesoxime), muscle spasms (4 episodes, 3 after olesoxime) and constipation (3 episodes, 1 after olesoxime). The frequency, severity and duration of TEAEs were not dose-related [1040613]. No relevant changes in vital signs, ECG parameters, laboratory tests or physical examinations were observed in any dose group [846908], [1040613].

No safety issues were reported during the phase Ib clinical trial of olesoxime (125 mg po) in pediatric and adult patients with SMA, or during the 1-month follow-up period [997568].

Patent summary

Olesoxime was first claimed by Trophos in WO-2004082581. At the time of publication, European or US equivalents had not been granted. However, the two French national filings, FR-02852246 and FR-02860159, have been granted and expire in March 2023 and September 2023, respectively. The equivalent Australian filing AU-2004222540 has also been granted and expires in March 2024.

The WO-2004082581 case was succeeded by WO-2006027454, which is the product case for related compounds, including the follow-up compound TRO-40303. This was followed by the three product cases WO-2007003767, WO-2007080270 and WO-2007074238. The WO-2007080270 case describes very closely related compounds and the other two describe pyrimidine and thiazole derivatives with similar actions. The product case WO-2008056059 is for follow-up compounds and WO-2008142231 is a formulation case. This was followed by a trio of new use cases, WO-2009044009, WO-2009044010 and WO-2009044011, all with the same priority and publication dates. The most recent application for olesoxime is WO-2009092892, claiming combinations with various anticancer agents.

Current opinion

The development of olesoxime as a potential treatment for ALS is a major step forward for the field of MN disease. The rationale for the use of olesoxime in ALS is reasonably strong and mechanism-based. The theory behind targeting mitochondria and, specifically, the mPTP is based firmly on cell and animal model basic research [1093997], [1094048], [1094435]. The specific targets of olesoxime have been suggested to be the TSPO and VDAC [806418]: TSPO is believed to be a modulator of the mPTP [1094500] and VDAC is believed to be a dispensable component of the mPTP [1094501], [1094927]. Another study using a different TSPO ligand (Ro5–4864) demonstrated protection against neonatal MN cell death induced by axotomy, but no positive effects were noted in G93Ahigh-mSOD1 mice [1094528], suggesting that olesoxime binding to VDAC is perhaps the more therapeutically relevant interaction for neuroprotection against pathologic mPTP opening in adult MNs. The properties of olesoxime are propitious for a neurotherapeutic compound: it can be administered as an oral capsule, it passes the blood-brain barrier and it is well tolerated. However, more data are needed on the actions and safety of this compound on injured or damaged biological systems.

More basic biological studies need to be undertaken to define the mechanisms of action of olesoxime at subcellular and molecular levels. First, the identification of olesoxime as a drug acting on mitochondria needs to be established firmly. There are three isoforms of VDAC and some are at the plasma membrane and endoplasmic reticulum as well as on the OMM [1094532], [1094536], [1094537]. If olesoxime does target mitochondria and does modulate the mPTP, then its actions on mitochondrial calcium retention need to be clarified [1058089]. Alternatively, olesoxime could indirectly act on the mPTP by modulating mithochondrial ROS products. Furthermore, the types of cells that olesoxime protects need to be identified. For example, in vivo olesoxime could be exerting protective actions directly on MNs or it could be acting on microglia, astrocytes, Schwann cells or skeletal muscle cells to indirectly protect MNs. Patients with ALS desperately need an effective treatment for their disease. The exploration of olesoxime as a new small-molecule therapy offers hope.

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Development status


The author is supported by grants from the US Public Health Service, NIH-NINDS (NS065895, NS052098) and NIH-NIA (AG016282).


Associated patent

Title Use of derivatives of cholest-4-en-3-one as medicaments, pharmaceutical compositions containing same, novel derivatives and preparation method thereof.

Assignee Trophos SA

Publication WO-2004082581 30-SEP-04

Inventors Bordet T, Drouot C, Buisson B.


•• of outstanding interest

• of special interest

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1094033. Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla EB, Rotilio G, Valentine JS, Carri MT. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. PROC NATL ACAD SCI USA. 2006;103(37):13860–13865. [PubMed]
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1094042. Higgins CMJ, Jung CW, Ding HL, Xu ZS. Mutant Cu, Zn Superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J NEUROSCI. 2002;22(6):1–6. [PubMed]
1094044. Higgins CMJ, Jung CW, Xu ZS. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC NEUROSCI. 2003;4 [PMC free article] [PubMed]
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1094442. Mattiazzi M, D'Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J BIOL CHEM. 2002;277(33):29626–29633. [PubMed]
1094483. Keep M, Elmer E, Fong KSK, Csiszar K. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. BRAIN RES. 2001;894(2):327–331. [PubMed]• First study to suggest that the mPTP is a potential target of therapy in ALS.
1094492. Karlsson J, Fong KSK, Hansson MJ, Elmer E, Csiszar K, Keep MF. Life span extension and reduced neuronal death after weekly intraventricular cyclosporine injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis. J NEUROSURG. 2004;101(1):128–137. [PubMed]
1094493. Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. J NEUROCHEM. 2004;88(4):821–826. [PubMed]
1094496. Hunter DR, Haworth RA, Southard JH. Relationship between configuration, function, and permeability in calcium-treated mitochondria. J BIOL CHEM. 1976;251(16):5069–5077. [PubMed]•• First description of mitochondrial permeability transition.
1094497. Crompton M. The mitochondrial permeability transition pore and its role in cell death. BIOCHEM J. 1999;341:233–249. [PubMed]
1094498. van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P. Mitochondrial intermembrane proteins in cell death. BIOCHEM BIOPHYS RES COMMUN. 2003;304(3):487–497. [PubMed]
1094499. Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, Forte MA. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 2006;273(10):2077–2099. [PubMed]•• Outstanding summary of the history and contemporary understanding of the mPTP.
1094500. Leung AWC, Halestrap AP. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. BIOCHIM BIOPHYS ACTA BIOENERG. 2008;1777(7–8):946–952. [PubMed]
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1094537. Yu WH, Wolfgang W, Forte M. Subcellular localization of human voltage-dependent anion channel isoforms. J BIOL CHEM. 1995;270(23):13998–14006. [PubMed]
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1094927. Rostovtseva TK, Tan WZ, Colombini M. On the role of VDAC in apoptosis: Fact and fiction. J BIOENERG BIOMEMBR. 2005;37(3):129–142. [PubMed]
1107246. Boukaftane Y, Khoris J, Moulard B, Salachas F, Meininger V, Malafosse A, Camu W, Rouleau GA. Identification of six novel SOD1 gene mutations in familial amyotrophic lateral sclerosis. CAN J NEUROL SCI. 1998;25(3):192–196. [PubMed]
1111760. Rasola A, Sciacovelli M, Pantic B, Bernardi P. Signal transduction to the permeability transition pore. FEBS LETT. 2010;584(10):1989–1996. [PubMed]•• This paper provides an excellent and up-to-date review of the definition, structure and function of the mPTP.
1111761. Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. HUM MOL GENET. 2010;19(11):2284–2302. [PubMed]• This paper describes the first study to demonstrate that skeletal muscle disease can cause ALS in mice.