Olesoxime for amyotrophic lateral sclerosis first line

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1 Olesoxime for amyotrophic lateral sclerosis first line May 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Olesoxime for amyotrophic lateral sclerosis first line Target group Amyotrophic lateral sclerosis (ALS) first line; in combination with riluzole. Background ALS is the commonest form of motor neurone disease (MND) 1, a fatal neurodegenerative disease characterised by progressive weakness of bulbar, limb, thoracic and abdominal muscles 1,2. The aetiology of ALS remains unknown, though it is hypothesised that neural degeneration is caused by excessive stimulation of glutamate receptors on neurones 3. Around 5% to 10% of cases have a familial form of the disease 4. ALS has an insidious onset and progresses relentlessly 1. Patients with ALS usually show a combination of signs of upper motor neurone (like spasticity, clonus) and lower motor neurone (like muscle weakness, atrophy and fasciculation) lesions without sensory involvement 1,2. Technology description Olesoxime (TRO19622) is a neuroprotectant which belongs to the cholesterol-oxime compound family of mitochondrial pore modulators. It has been shown to promote motor neurone survival and nerve regeneration through interactions with the mitochondrial permeability transition pore (mptp). Olesoxime is intended to be used in combination with riluzole for the treatment of patients with ALS. Olesoxime is administered orally at 330mg once daily in combination with riluzole at 50mg twice daily. Olesoxime is also in phase II clinical trials for the treatment of spinal muscular atrophy. Innovation and/or advantages Olesoxime belongs to a new drug class. If licensed, it may potentially improve survival and delay the need for mechanical ventilation and/or improve quality of life of patients with ALS. Developer Trophos SA. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to the white paper on genetics - Our Inheritance, Our Future (2003) and The National Service Framework for long term conditions (2005). Relevant guidance NICE technology appraisal. Guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease NICE clinical guideline. Motor neurone disease: the use of non-invasive ventilation in the management of motor neurone disease Royal College of Physicians. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care

3 Clinical need and burden of disease ALS accounts for 65% to 85% of all cases of MND 3. Lifetime risk of developing ALS is estimated to be around 1 per 300 7,a.The incidence and prevalence of MND in the UK ranges from 1.8 to 2.2 and 4.0 to 4.7 per 100,000 population respectively 1. Age specific incidence and mortality rates peak between 55 and 75 years 8. It is estimated that at any one time there are around 2,000 people affected with ALS in England and Wales 1. In England there were 2,695 admissions for MND (ICD G12.2), resulting in 29,738 bed days and 3,785 finished consultant episodes in Approximately 50% of patients with ALS die within 3 years of onset of symptoms, primarily from ventilatory failure 1. Diagnosis of ALS is often delayed and occasionally survival after diagnosis may be less than 6 months 4. In 2009, there were 1,789 deaths registered from MND (ICD G12.2) in England and Wales 10. Existing comparators and treatments Riluzole is the only drug currently licensed specifically for the treatment of ALS 1,3. The treatment of ALS consists mainly of supportive and palliative care provided by a range of health and social services, including physiotherapy, occupational therapy, speech therapy, mobility aids and district nursing 1,3. Symptomatic relief is provided by a range of pharmacological interventions 1,3. In later stages of the disease, interventions such as enteral feeding, ventilatory support (non-invasive/mechanical ventilation/tracheostomy) and domiciliary or hospice care may also be required 1,3. Efficacy and safety Trial MITOTARGET, NCT ; riluzole with olesoxime or placebo; phase II/III. NCT ; riluzole with olesoxime; phase II/III extension. Sponsor Trophos. Trophos. Status Ongoing. Ongoing. Source of Trial registry 11, manufacturer. 12 Trial registry, manufacturer. information Location EU (inc UK). EU (inc UK). Design Randomised, placebo-controlled. Uncontrolled, single arm. Participants and schedule n=470; adults; sporadic or familial ALS; clinically diagnosed according to modified EI Escorial criteria; ALS symptoms for 6 to 36 mths; slow vital capacity (SVC) 70% of predicted; treated with riluzole at 50mg twice daily for 30 days. Randomised to olesoxime at 330mg once daily or placebo, both with riluzole at 50mg twice daily. n=350 (planned); adults; sporadic or familial ALS; clinically diagnosed according to modified EI Escorial criteria; completed the trial NCT Participants continued with riluzole at 50mg twice daily in combination with olesoxime at 330mg once daily. Those in the placebo group crossed over to receive olesoxime in addition to riluzole. Follow-up Active treatment period 18 mths. Active treatment period maximum of 15 mths until availability of the key results of the trial NCT ; follow-up every 3 mths. Primary outcome Secondary outcomes Overall survival. Survival without the occurrence of tracheostomy, chronic invasive or noninvasive ventilation; physical functioning Safety. Survival time; physical functioning by 48- point ALS Functional Rating Scale- Revised; SVC. a Information from expert. 3

4 Expected reporting date by 48-point ALS Functional Rating Scale-Revised; SVC; manual muscle testing; quality of life by single-item McGill quality of life scale; safety. Study expected to complete August Study expected to complete March Estimated cost and cost impact The cost of olesoxime is not yet known. The treatment of ALS with riluzole at 50mg twice daily costs for a period of 28 days 13. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Reduction in associated morbidity or Improved quality of life for patients and/or carers. Quicker, earlier or more accurate diagnosis or identification of disease Services Increased use Service organisation Staff requirements Costs Decreased use: potential for delayed need for ventilatory support and gastrostomy. Increased unit cost compared to alternative New costs: additional add-on treatment Increased costs: more patients coming for treatment Savings: potential for delayed need for ventilatory support. Increased costs: capital investment needed Other issues Clinical uncertainty or other research question identified: What is the ideal time point in the course of the disease to begin treatment? Will olesoxime be considered for other MND subtypes? References 1 National Institute for Health and Clinical Excellence. Guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease. Technology appraisal TA20. London: NICE; January Bongioanni P, Reali C and Sogos V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2004; 3. Art. No: CD DOI: / CD pub2. 3 Stewart A, Sandercock J, Bryan S et al. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review. Health Technology Assessment 2001;5(2). 4 Leigh P N, Abrahams S, Al-Chalabi A et al. The management of motor neurone disease. Journal of Neurology Neurosurgery and Psychiatry 2003; 74 (Suppl IV): iv32-iv47. 5 National Institute for Health and Clinical Excellence. Motor neurone disease: the use of non-invasive ventilation in the management of motor neurone disease. Clinical guideline 105. London: NICE; July Turner-Stokes L, Skyes N and Silber Eli. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care. Clinical Medicine 2008; 8: Clare A, Johnston Biba R, Stanton Martin R et al. Amyotrophic lateral sclerosis in an urban setting: A population based study of inner city London. Journal of Neurology 2006; 253: Brettschneider J, Kurent J, Ludolph A et al. Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2008, 3. Art. No.: CD DOI: / CD pub2. 4

5 9 NHS. Hospital episode statistics. NHS England inpatient data. HES data Office for National Statistics. Mortality statistics-deaths registered in ClinicalTrials.gov. Safety and efficacy of TRO19622 as add-on therapy to riluzole versus placebo in treatment of patients suffering from amyotrophic lateral sclerosis (ALS) (MITOTARGET). Accessed 31 January ClinicalTrials.gov. Safety extension study of TRO19622 in ALS. Accessed 31 January British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0) Fax +44 (0)