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International Clinical Trials

On Target

With the population now living longer due to improvements in general healthcare and lifestyles, developed countries are expecting a considerable increase in healthcare costs related to dementia or other serious handicaps resulting from neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This is because, even though neurodegenerative diseases may have a genetic basis, age is the principle risk factor.

Despite the huge investment by pharmaceutical companies to find treatments that slow or stop neurodegeneration in diseases such as AD or PD, the only approved therapies for these, and less prevalent diseases, treat just the cognitive or motor symptoms by preserving, amplifying or modifying neurotransmitter levels produced by neurons affected in the disease. Examples are cholinesterase inhibitors for AD; dopamine substrates; agonists and degradation inhibitors for PD; tetrabenazine for Huntington’s disease (HD); and a potassium channel blocker, fampridine, for multiple sclerosis.

Although less prevalent neurodegenerative diseases have received smaller investment by pharma companies, those with a genetic basis or that have a particularly aggressive progression offer strategies for research and development. HD and genetic forms of PD and other familial neurodegenerative diseases provide molecular clues, as well as the potential to identify those likely to benefit from early neuroprotection therapies.

For Phase 2 proof-of-concept studies, a rapidly progressing neurodegenerative disease such as amyotrophic lateral sclerosis (ALS) might enable identification of a neuroprotective therapy in a shorter clinical trial, compared to slower progressing neurodegenerative diseases. Because of the significant future healthcare burden that neurodegenerative diseases represent, and the increasing reticence of pharma industries to enter this area, the European Commission (EC) has dedicated significant funds as part of its Framework Programme for Research and Technological Development to address this important group of healthcare needs.

Olesoxime Binding

A novel screening strategy based on using primary neurons isolated from the specific regions of the nervous system most affected in each neurodegenerative disease has been established: spinal motor neurons for motor neuron diseases, striatal neurons for HD and cortical neurons for AD. Each cellbased assay incorporated factors implicated in the disease, such as specific genetic mutations, lack of trophic factors and excitotoxicity.

The lead compound coming from this screening strategy, olesoxime (TRO19622), is one member of a family of cholesterol-oximes that target mitochondria and preserve mitochondrial function in stressed neurons and other cell types. Olesoxime binds to outer mitochondrial membrane proteins that regulate uptake of mitochondrial substrates, including those used to generate and transfer adenosine triphosphate (ATP) from the mitochondria to the cytoplasm. These same proteins are also implicated in oxidative stress and calcium-induced mitochondrial permeabilisation that then triggers programmed cell death (1,2).

By 2004, olesoxime had been found to be active in multiple models of motor neuron injury or degeneration and preclinical pharmacokinetic, and safety studies had been completed to start Phase 1 clinical trials in healthy volunteers. By 2007, all prerequisites for long-term clinical trials had been completed when the EC’s 7th Framework Programme issued a call for proposals focused on restorative approaches for therapy of neurodegenerative diseases. This call was focused on basic mechanisms of brain plasticity and brain repair in neurodegenerative diseases, with the aim of translating this knowledge into new neuroprotective or restorative therapeutic approaches.

MitoTarget Objectives

The MitoTarget project, a three-year collaborative project led by Trophos, was set up to deliver these objectives. Using olesoxime as a tool, the project investigated whether mitochondrial dysfunction – a characteristic of neurodegenerative diseases – could be addressed in a clinical trial in patients with ALS.

MitoTarget brought together an international collaboration of clinical investigators and basic scientists to complete this proof-of-concept clinical study. It involved examining mitochondrial function and dysfunction in a range of neurodegenerative diseases, continuing studies of the mechanism of action of olesoxime, and exploring its activity in preclinical models of neurodegenerative diseases with clear evidence of mitochondrial dysfunction.

The rationale for testing olesoxime in a clinical trial in ALS patients was based on preclinical studies showing that olesoxime prevented motor neuron death in vitro and slowed the disease process in a common model of ALS, the SOD1G93A mouse (1,3). On closer examination, olesoxime retarded neuromuscular junction breakdown, decreased motor neuron cell death and attenuated glial activation thought to be toxic to motor neurons in the spinal cord. In other models, olesoxime promoted myelin formation, all of which should be beneficial in neurodegenerative diseases (1,4).

ALS, also known as ‘Lou Gehrig’s disease’ or ‘maladie de Charcot’, is an extremely rapidly progressing neurodegenerative disease. Numerous clinical trials have been conducted in ALS patients with the hope that the rapid and fatal progression characteristic of the disease would facilitate detecting a drug’s neuroprotective effect. However, up to now only one drug, riluzole, has been approved for the treatment of ALS. The trial design leading to its approval was adopted for the MitoTarget trial, which was led by the same clinical group (5).

Trial Set-Up

The MitoTarget trial was a randomised, double-blind, placebo-controlled trial in 512 ALS patients who had been stably treated with riluzole (6). This trial was designed with the aim of detecting a 12 per cent increase in survival at 18 months over that observed in the placebo arm in previous clinical trials with xaliproden and pentoxifylline (62 per cent) – also led by the same principle investigator as the MitoTarget trial (7,8). Function, using the ALSFRS-R scale, muscle strength and respiratory capacity were also evaluated every three months (9). Particular attention was paid to function after nine months of treatment, when few deaths were expected, which can confound comparing results between the two treatment arms.

Fifteen clinical centres in France, Germany, Belgium, the UK and Spain, 14 of which were supported by the EC project grant, carried out the trial. Completing regulatory procedures in these countries ranged from two months in France to ten months in the UK, reflecting the diverse procedures necessary to initiate multi-centric trials in Europe, in contrast to the US, despite efforts to harmonise the process. Enrolment of all 512 patients was, nevertheless, completed in just ten months, with the first patient enrolled in May 2009 and the last patient completing the 18 month treatment period in September 2011. Rapid enrolment was essential since the trial had to be completed within the timeframe of the 36-month EC grant contract. To guarantee this, and to compensate for the slow regulatory approval in the UK, a centre in Spain was included, in addition to the 14 sites that received MitoTarget funding.

Project Results

The project as a whole was a three-year translational research programme aimed at better understanding the implication of mitochondrial dysfunction in neurodegenerative diseases. To achieve this, the project brought together leading European basic research teams based in the UK, Germany and France, each with focused expertise in HD, AD, ALS and hereditary spastic paraplegia, as well as aging. The array of preclinical models using cells and model organisms provided a unique opportunity to compare and contrast results. The work also prompted future research projects based on new or refined understanding of mitochondrial dysfunction and its place as cause or effect of neurodegeneration.

Perhaps unsurprisingly, the problem turned out to be even more complex than anticipated, and results opened more questions and avenues for future research. In short, while mitochondrial dysfunction is evident in most if not all cases of neurodegeneration, it is only one component. So, while targeting mitochondrial dysfunction has a place in the repertoire of therapies to treat or prevent neurodegeneration, it will probably need to be combined with other approaches, including symptomatic treatments. Although 18 months treatment with olesoxime did not show a significant beneficial effect over that of riluzole in ALS patients, the trial demonstrated that olesoxime is safe and well tolerated over a large exposure range. Some ALS patients who continued treatment at the end of the trial in an open label study were exposed for up to 33 months (10).

With evidence that olesoxime accelerated remyelination in models of multiple sclerosis, this safety data is supportive of future development of olesoxime in this indication. Future trials are being designed to test olesoxime as a complementary therapy to immunomodulatory treatments in order to prevent progressive neurodegeneration and promote repair in patients with various forms of multiple sclerosis.


1. Bordet T, Buisson B, Michaud M, Drouot C, Galéa P, Delaage P, Akentieva NP, Evers AS, Covey DF, Ostuni MA, Lacapère JJ, Massaad C, Schumacher M, Steidl EM, Maux D, Delaage M, Henderson CE and Pruss RM, Identification and characterisation of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis, J Pharmacol Exp Ther 322: pp709-720, 2007
2. Bordet, T, Berna, P, Abitbol, J-L and Pruss, RM, Olesoxime (TRO19622): a Novel Mitochondrial-Targeted Neuroprotective Compound, Pharmaceuticals 3: pp345-368, 2010
3. Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, Aebischer J, Latyszenok V, Gouarné C, Raoul C, Pruss RM, Bordet T, Pettmann B, Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model, Neuropharmacology 62: pp2,346-2,352, 2012
4. Magalon K, Zimmer C, Cayre, M, Khaldi J, Bourbon C, Robles I, Tardif G, Viola A, Pruss, RM, Bordet T and Durbec P, Olesoxime accelerates myelination and promotes repair in models of demyelination, Annals of Neurology 71: pp213-226, 2012
5. Lacomblez L, Bensimon G, Leigh PN, Guillet P and Meininger V, for the ALS/riluzole study group II, Dose-ranging study of riluzole in amyotrophic lateral sclerosis, Lancet 347: pp1,425-1,431, 1996
6. Visit:
7. Meininger V, Bensimon G, Bradley WR, Brooks B, Douillet P, Eisen AA, Lacomblez L, Leigh PN and Robberecht W, Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials, Amyotroph Lateral Scler Other Motor Neuron Disord 5: pp1-11, 2004
8. Meininger, V, Asselain B, Guillet P, Leigh PN, Ludolph A, Lacomblez L and Robberecht W, Pentoxifylline European Group, Pentoxifylline in ALS, A double-blind, randomised, multicenter, placebo-controlled trial, Neurology 66: pp88-92, 2006
9. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B and Nakanishi A, The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function, BDNF ALS Study Group (Phase III), J Neurol Sci 169: pp13-21, 1999
10. Visit:

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Dr Rebecca Pruss is Chief Scientific Officer at Trophos and is principle investigator on the EU MitoTarget and MitoCare projects. She has more than 25 years’ experience directing R&D in the pharmaceutical industry. Prior to joining Trophos in 2002, she was the head of exploratory research at Sanofi -Synthelabo, President and CEO at Synthélabo Biomoléculaire, and a senior scientist and project leader at Marion Merrell Dow. She received her PhD in biological chemistry from UCLA and has also served as Adjunct Professor in Cell Biology at the University of Cincinnati.

Dr Thierry Bordet is Head of CNS Pharmacology and HTS at Trophos. He obtained his PhD from the department of human genetics of the Institut Cochin, Paris. Joining Trophos in 2001, he developed a number of cell culture models of motor neurone disease for drug screening, which culminated in the identifi cation of olesoxime. He currently coordinates drug discovery programmes in neurodegeneration. Thierry also coordinated the basic research steering committee of the MitoTarget project and the MS-Repair project.

Julien Veys is Trophos’ Project and Strategic Partnership Manager. He has an MSc in biochemistry and an MSc in scientific and competitive information management. He joined Trophos in 2005, where he set up the information management process in the company before taking responsibility for grant applications and management. In 2008, he was declared Legal Entity Appointed Representative towards the EC for Trophos, coordinating and writing applications for the Framework project for Research and Technology, including the MitoTarget initiative.

Dr Jean-Louis Abitbol has held important scientific and managerial positions in the pharmaceutical industry for more than 20 years. Before joining Trophos as Chief Medical Officer, he was Executive Director at the clinical research department of Pierre Fabre Médicament. For most of his career, he was with Jouveinal/Parke-Davis/Pfizer holding positions. Jean-Louis has an MD and an MSc in Biomathematics and Human Physiology, and has extensive experience of all clinical research phases, with a particular emphasis on early clinical research and pharmacology. He is now head of R&D at HRA-Pharma.
Dr Rebecca Pruss
Dr Thierry Bordet
Julien Veys
Dr Jean-Louis Abitbol
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