Horizon Scanning Centre September 2012

EPI-743 for – first line

SUMMARY NIHR HSC ID: 5867

EPI-743 is intended to be used as first line therapy for the treatment of inherited mitochondrial respiratory-chain disease; including, but not limited to , Leber’s hereditary optic neuropathy, and the neurodegenerative disorder Friedreich’s . If licensed, it would provide a new treatment option for this patient group, who currently have no effective This briefing is therapeutic options. EPI-743 is a catalytic, 2-electron transfer NADPH based on quinine oxidoreductase (NQ01) cofactor that synchronises the energy information generation in mitochondria with the need to counter cellular redox stress.

available at the time Mitochondrial disorders affect around 1 in 8,500 individuals, however they of research and a are thought to be greatly under-diagnosed and the true prevalence is difficult limited literature to determine. There is also thought to be a high rate of misdiagnosis due to search. It is not the wide range and varying severity of the symptoms experienced. intended to be a Mitochondrial disease can go undetected for many years. An estimated 60% definitive statement of cases display an episodic course with relatively stable periods punctuated on the safety, by abrupt degeneration that may coincide with an infection or other stress to efficacy or mitochondrial function effectiveness of the health technology There is currently no established treatment for mitochondrial disorders, and covered and should the clinical management of individuals is largely supportive, with the aim of not be used for providing prognostic information and genetic counselling. EPI-743 is commercial currently in small phase I and II clinical trials and case-series, studying the purposes or change in Newcastle Paediatric Mitochondrial Disease scores against commissioning placebo. without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk

NIHR Horizon Scanning Centre

TARGET GROUP

• Inherited mitochondrial respiratory-chain disease; including, but not limited to Leigh syndrome, Leber’s hereditary optic neuropathy, and the neurodegenerative disorder Friedreich’s Ataxia – first line.

TECHNOLOGY

DESCRIPTION

EPI-743 is a catalytic, 2-electron transfer NADPH quinine oxidoreductase (NQ01) cofactor1 that synchronises the energy generation in mitochondria with the need to counter cellular redox stress2,3. EPI-743 is intended for first line use of inherited mitochondrial respiratory- chain disease; including, but not limited to Leigh syndrome, Leber’s hereditary optic neuropathy (LHON), and the neurodegenerative disorder Friedreich’s Ataxia.It is administered orally, three times a day, at a variable dose according to the patients’ age and weight.

INNOVATION and/or ADVANTAGES

If licensed, EPI-743 would provide a new treatment option for this patient group, who currently have no effective therapeutic options.

DEVELOPER

Edison Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

In small phase I and II clinical trials and case-series.

PATIENT GROUP

BACKGROUND

Mitochondrial disorders are a diverse group of conditions that often involve the , are usually progressive, and often cause significant disability and premature death4. The mitochondria are complex, ubiquitous, intracellular that perform an essential role in a number of cellular processes. They contain involved in cellular metabolism, are involved in many cell death pathways, and play a pivotal role in the final common pathway of aerobic metabolism - oxidative phosphorylation (OXPHOS). OXPHOS results in the generation of (ATP)1. The diversity of mitochondrial disease is influenced by their complex genetics and environmental influences. Genetic leading to mitochondrial disease can affect either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)5. However, mtDNA has a rate of about ten times that of nDNA6, and identical mtDNA mutations may not produce identical diseases7.

Despite their diversity as a group, there are common characteristics of mitochondrial diseases. In particular, they are typically progressive and multi-systemic, most often affecting

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organs that have high energy demands such as the nervous system; skeletal and cardiac muscle; and the liver and kidneys1. manifestations include , , , ataxia, intellectual disabilities, global delay and brain malformations1. Sensory and peripheral nerves can also be affected, leading to deafness, blindness, or neuropathy1. However, the onset and time course of mitochondrial diseases are variable, with some occurring early and progressing rapidly while others only occurring after many months, years or even decades of life2.

LHON, is caused by single-point mutations occurring in mtDNA, and mainly affects young male patients. In most patients affected, LHON leads to persistent bilateral blindness8. Leigh syndrome, which usually develops in infancy or childhood9, is caused by a mutation in nuclear or mitochondrial DNA and results in rapid and death10. Friedreich’s Ataxia is caused by mutations in the gene for the protein frataxin, which may play a role in regulating the levels of iron within the mitochondria11. It usually begins in childhood and leads to impaired muscle coordination (known as ataxia) that worsens over time, along with clinically significant cardiomyopathy and loss of visual function12.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • The National Service Framework for Long-Term Conditions (2005). • The National Service Framework for Child Health and Maternity (2004).

CLINICAL NEED and BURDEN OF DISEASE

Mitochondrial disorders are estimated to affect around 1 in 8,500 individuals13, however they are thought to be greatly under-diagnosed and the true prevalence is difficult to determine14. There is also thought to be a high rate of misdiagnosis due to the wide range and varying severity of the symptoms experienced15. LHON, is the most common ophthalmologic mitochondrial disease with a prevalence of 1 in 50,0006; the incidence of blindness due to LHON is believed to be 1 in 14,000 males16. Leigh syndrome or Leigh-like disease has an incidence of 1 in 77,0007, and Friedreich’s Ataxia has a prevalence of 1.8 per 100,000 in the UK17.

Mitochondrial disease can go undetected for many years, and an estimated 60% of cases display an episodic course with relatively stable periods punctuated by abrupt degeneration that may coincide with stress to mitochondrial function11. In an estimated 72% of such cases, deterioration was associated with a naturally acquired infection2. It has been estimated that at least 3,500 women in the UK, carry a potentially symptomatic level of mtDNA mutation, but this is likely to be an underestimate18.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

None identified.

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Other Guidance

• Nuffield Council on Bioethics. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review 201219. • Newcastle Mitochondrial Disease Guidelines. Respiratory involvement in adult management: screening and initial management 201120. • Newcastle Mitochondrial Disease Guidelines. Pregnancy in mitochondrial disease 201121. • Newcastle Mitochondrial Disease Guidelines. Ocular involvement in adult mitochondrial disease: screening and initial management 201122. • Newcastle Mitochondrial Disease Guidelines. in adult mitochondrial disease: investigation and management 201023. • Newcastle Mitochondrial Disease Guidelines. Cardiac involvement in adult mitochondrial disease: screening and initial management 201024. • Clinical Molecular Genetics Society. Practice guidelines for the molecular diagnosis of mitochondrial diseases 200825.

EXISTING COMPARATORS and TREATMENTS

There is currently no established treatment for mitochondrial disorders, and the clinical management of individuals is largely supportive, with the aim of providing prognostic information and genetic counselling. Treatments used to modify the underlying disease process fall into three groups: pharmacological and nutritional agents, modification of macronutrient composition in the diet (dietary supplementation with vitamins and co-factors) and exercise therapy. A number of different pharmacological treatments and nutritional supplements have been used in individuals with mitochondrial disease, with varying reports of success. These include1,6,26: • Antioxidants such as co- Q10, idebenone, vitamin C, vitamin E and menadione. • Agents that specifically improve such as dichloroacetate and dimethylglycine, which is a component of pangamic acid (vitamin B15). • Agents that correct secondary biochemical deficiencies such as carnitine and creatine. • Respiratory chain co-factors such as nicotinamide, , riboflavin, succinate, and co-enzyme Q10. • Hormones including growth hormone and corticosteroids.

EFFICACY and SAFETY

Trial NCT01642056, 120161, 12-HG-0161; NCT01370447, EPI-2009-1; EPI-743. EPI-743 vs placebo; phase I/II. Sponsor National Human Research Edison Pharmaceuticals Inc. Institute (NHGRI). Status Ongoing. Ongoing. Source of Trial registry27. Trial registry28 and publication1. information Location USA. USA. Design Randomised, placebo-controlled,. Non-randomised, open-label, case-series. Participants n=20 (planned); children aged 2–11 n=14; patients aged 1 year and older; years; neuromuscular disease with a inherited mitochondrial respiratory chain component of impaired energy or disease; within 90 days of end-of-life oxidation/reduction. hospice/terminal care. Schedule Participants receive EPI-743, oral, or Participants receive EPI-743, oral, 50mg, placebo, three times daily for 6 months twice daily for 14 days then escalate to followed by a 1-month wash out period. 100mg, twice daily on day 15 and

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Participants who receive EPI-743 in the increase to three times daily on day 29. first 6 months then receive placebo and those who receive placebo receive EPI- 743 for 6 months. Follow-up Active treatment period for 13 months. Active treatment period for 12 weeks. Primary NPMDS scorea. Brain redox assessmentb, change in outcome/s neuromuscular function, adverse effects, change in NPMDS score. Secondary Safety. Safety. outcome/s Key results - Improvement in NPMDS score frome baseline, p=0.004; increased whole brain HMPAO uptake, p=0.0186. Adverse - Common AEs (related to patients effects (AEs) underlying disease) include choreoathestosis; gastrointestinal dysmobility; seizures; persistent ; -like episodes. Expected Primary completion date reported as April - reporting 2015. date

COST and IMPACT

ESTIMATED COST

The cost of EPI-743 is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services: Shorter length of stay, reduced referrals.

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs: reduced use of secondary care/specialist services.

 None identified a Newcastle Paediatric Mitochondrial Disease Scores: a validated scale to assess the clinical severity of mitochondrial disease. b Obtained using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging.

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Other Issues

 Clinical uncertainty or other research question  None identified identified: Expert opinion suggests that evidence for the effectiveness of EPI-743 is still limited, but it does appear to have therapeutic potential.

REFERENCES

1 Enns GM, Kinsman SL, Perlman SL et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-74. Molecular Genetics and Metabolism 2012;105:91-102. 2 Sies H. Oxidative stress: oxidants and antioxidants. Experimental Physiology 1997;82:291-295. 3 Catarina M, Hirano Q and Hirano M. Coenzyme Q and mitochondrial disease. Developmental disabilities research reviews 2012;16:183-188. 4 Chinnery PF, Majamaa K, Turnbull D et al. Treatment for mitochondrial disorders (review). Cochrane Database of Systematic Reviews 2012, Issue 4. Article No: CD004426. 5 National Institute of Neurological Disorders and Stroke. Mitochondrial : Potential relationships to autism? 2008 http://www.ninds.nih.gov/news_and_events/proceedings/20090629_mitochondrial.htm 6 Yakes FM, and Van Houten. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress 1997. Proceedings of the National Academy of Sciences 94:514-9. 7 United Mitochondrial Disease Foundation. What is Mitochondrial Disease? http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934627 Accessed 31 July 2012. 8 Alfredo A, Sadun MD, Carlos FC et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber Hereditary Optic Neuropathy. Archives of 2012;69(3):331- 338. 9 United Mitochondrial Disease Foundation. Types of mitochondrial disease; Leigh disease or syndrome. http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934629#Leigh's Accessed 6 Aug 2012. 10 National Instititue of Neurological Disorders and Stroke. NINDS Leigh’s disease information page. Last update Dec 16 2011. http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm Accessed 6 Aug 2012. 11 Muscular Dystrophy Association. Friedreich’s Ataxia; Causes/Inheritance. http://mda.org/disease/friedreichs-ataxia/causes-inheritance Accessed 6 Aug 2012. 12 National Institute of Neurological Disorders and Stroke. Friedreich’s Ataxia fact sheet. http://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm Accessed 6 Aug 2012. 13 Chinnery P F. Mitochondrial Disorders overview. GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1224/ Accessed 24 July 2012. 14 United Mitochondrial Disease Foundation. Mitochondrial disease fact sheet. http://www.umdf.org/atf/cf/%7B858ACD34-ECC3-472A-8794-39B92E103561%7D/fact_sheet.pdf Accessed 25 July 2012. 15 Schaefer AM, Taylor RW, Turnbull DM et al. The epidemiology of mitochondrial disorders-past, present and future. Biochimica et Biophysica Acta (BBA) – Bioenergetics 2004;1659:115-20. 16 Patient.co.uk. Professional reference, Leber’s Optic Atrophy. http://www.patient.co.uk/doctor/Leber's-Optic-Atrophy.htm Accessed 6 Aug 2012. 17 Patient.co.uk Professional reference, Friedreich’s ataxia. http://www.patient.co.uk/doctor/Friedreich's-Ataxia-(FRDA).htm Accessed 6 Aug 2012. 18 Brown DT, Herbert M, Lamb VK et al. Transmission of mitochondrial DNA disorders: possibilities for the future The Lancet 2006;368:87-9. 19 Nuffield Council on Bioethics. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. London: NuffieldBioethics; June 2012.

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20 Newcastle Mitochondrial Disease Guidelines. The Rare Mitochondrial Disease Service for Adults and Children. Respiratory involvement in adult management: screening and initial management. Newcastle: RMD; Jan 2011. 21 Newcastle Mitochondrial Disease Guidelines. The Rare Mitochondrial Disease Service for Adults and Children. Pregnancy in mitochondrial disease. Newcastle: RMD; June 2011. 22 Newcastle Mitochondrial Disease Guidelines. The Rare Mitochondrial Disease Service for Adults and Children. Ocular involvement in adult mitochondrial disease: screening and initial management Newcastle: RMD; June 2011. 23 Newcastle Mitochondrial Disease Guidelines. The Rare Mitochondrial Disease Service for Adults and Children. Epilepsy in adult mitochondrial disease: investigation and management. Newcastle: RMD; Aug 2011. 24 Newcastle Mitochondrial Disease Guidelines. The Rare Mitochondrial Disease Service for Adults and Children. Cardiac involvement in adult mitochondrial disease: screening and initial management. Newcastle: RMD; Jan 2011. 25 Clinical Molecular Genetics Society. Practice guidelines for the molecular diagnosis of mitochondrial diseases. London: CMGS; July 2008. 26 Dimauro S, Hirano M and Schon EA. Approaches to the treatment of mitochondrial disease. Muscle and nerve 2006;34:265-283. 27 ClinicalTrials.gov. Therapeutic Trial of EPI-743 in patients with disorders of energy utilization or oxidation-reduction. http://clinicaltrials.gov/ct2/show/NCT01642056?term=epi-743&rank=2 Accessed 30 July 2012. 28 ClinicalTrials.gov. Emergency use protocol for EPI-743 in acutely ill patients with inherited mitochondrial respiratory chain disease within 90 days of end-of-life care. http://clinicaltrials.gov/ct2/show/NCT01370447?term=epi-743&rank=1 Accessed 30 July 2012.

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