Horizon Scanning Research September 2015 & Intelligence Centre

Pridopidine (Huntexil) for Huntington’s disease

LAY SUMMARY

Huntington’s disease is a genetic condition that usually occurs in adults. It affects the central nervous system by damaging nerve cells in the brain. This causes problems with eyesight, movement, speaking This briefing is and swallowing, and can also affect memory, moods and emotions. based on information There is no cure for Huntington’s disease, but there are treatments available at the time that can help control the symptoms. of research and a limited literature Pridopidine is a new drug which is given as a tablet to treat problems search. It is not with movement in people who have Huntington’s disease. Studies are intended to be a currently underway to see how well it works and whether it is safe for definitive statement patients to take. on the safety, efficacy or If pridopidine is licensed for use in the UK, it could offer a new effectiveness of the treatment option for patients with Huntington’s disease that may help health technology with movement problems. covered and should not be used for commercial NIHR HSRIC ID: 3555 purposes or commissioning 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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Huntington’s disease: ambulatory patients; for control of motor symptoms.

TECHNOLOGY

DESCRIPTION

Pridopidine (Huntexil; ACR-16; ASP-2314; FR-310826; TV-7820) is a small molecule piperidine, which acts to either enhance or inhibit dependent functions in the brain, depending on the initial level of activity. It inhibits dopamine activation of the D2 receptor and has a higher affinity for this receptor when dopamine is already bound to the receptor (activated receptor). However, it has no detectable agonist activity at this receptor. Pridopidine also strengthens glutamate function in the frontal cortex. Pridopidine is intended for the treatment of motor symptoms in Huntington’s disease through the regulation of dopamine levels. In a phase III clinical trial, pridopidine 45mg was administered orally, once daily in the morning before food for the first four weeks. Between weeks 5-26 pridopidine 45mg was administered orally twice daily, once in the morning before food and once early afternoon at least one hour after food1.

Pridopidine does not currently have Marketing Authorisation in the EU for any indication. It is not in late phase clinical trials for any other indication.

INNOVATION and/or ADVANTAGES

If licensed, pridopidine will offer a novel treatment option for patients with motor symptoms of Huntington’s disease, who currently have few effective therapies available.

DEVELOPER

Teva Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Huntington’s disease (HD) is an autosomal dominantly transmitted neurodegenerative disease of the central nervous system, which usually develops in adulthood2,3. HD is caused by a mutation of either one of an individual’s two copies of the huntingtin gene found on chromosome 43. Elongated CAG repeats of 36 repeats or more on the short arm of the chromosome lead to the production of an abnormally long version of the huntingtin protein, disrupting the normal function of nerve cells such as the basal ganglia and cerebral cortex; the longer the CAG repeat, the earlier the onset of disease3,4.

Early symptoms may include slight, uncontrollable muscular movements (chorea), stumbling and clumsiness, lack of concentration, short-term memory loss, depression, and mood

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changes including aggressive, obsessive-compulsive, or anti-social behaviour. On progression, patients may develop difficulty in speech and swallowing, unintended weight loss, involuntary movements, and rigidity, as well as emotional changes and dementia4,5. Involuntary motor symptoms in HD occur following an increased release of dopamine, however stiffness, staggering and difficulties speaking are common symptoms where there is inadequate dopamine release6. The gradual, increasing loss of independence associated with HD leads to the worsening of psychiatric symptoms such as low self-esteem and feelings of guilt, anxiety and apathy; all of which reduce patient quality of life and can in some cases result in suicide4.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Medical Genetics (All Ages). E01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

The prevalence of HD in the UK is rising; in 1990 the prevalence was estimated at 5.4 per 100,000 population, whereas in 2010 it had increased to 12.3 per 100,000 population. This equates to more than 5,700 people aged 21 years or older diagnosed with HD in 2010. This may be an underestimation as it is suggested that about twice as many people with the defective gene are not yet symptomatic7,8. Prevalence rates are similar for men and women (9.4 and 10.4 per 100,000 population, respectively)7.

Mean age of onset of disease symptoms is between 35 and 55 years with an average survival of 20 years. In 5-10% of cases, symptoms develop before the age of 204,8,9. The occurrence of psychiatric symptoms varies between 33% and 76% with completed suicide reported to be greater than 13% in HD9. During 2013, 212 deaths from HD were registered in England and Wales, excluding completed suicides10. In 2013-14, there were 261 hospital admissions for HD in England (ICD 10 G10), resulting in 12,566 bed days and 452 finished consultant episodes11.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• None identified.

Other Guidance

• European Huntington’s Disease Network Physiotherapy Working Group. Physiotherapy clinical guidelines for Huntington’s disease. 201212. • Agency for Healthcare Research and Quality. Evidence-based guidelines: pharmacologic treatment of chorea in Huntington disease: report of the Guideline Development Subcommittee of the American Academy of Neurology. 201213. • Huntington’s Disease Association. Standards of Care. 201114.

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CURRENT TREATMENT OPTIONS

At present, there is no cure for HD and disease progression cannot be slowed or reversed. Therapy for HD is aimed at controlling symptoms, often through a multidisciplinary team approach. Occupational therapy, physiotherapy, speech and language therapy, nutritional support, and counselling have all been recommended as non-pharmacological management options for the symptoms of HD15. The following pharmacological treatments may be considered for the treatment of common symptoms in HD15,16,17: • Depression – serotonin- and noradrenaline-reuptake inhibitors (e.g. , , paroxetine, and ), and electroconvulsive therapy (for patients with refractory depression). Mirtazapine may be considered in severe cases. • Anxiety – selective serotonin reuptake inhibitors, benzodiazepines, and . • Obsessive-compulsive behaviours – selective serotonin reuptake inhibitors such as citalopram or fluoxetine. • Behaviour and mood – selective serotonin reuptake inhibitors may be used at the higher recommended doses for early stage symptoms; anticonvulsants with mood stabilising properties such as valproic acid and carbamazepine, as well as , typical or atypical drugs, or benzodiazepines may also be considered. Atypical such as and may be considered more appropriate for patients with co-existent bradykinesia and rigidity. • Chorea – drugs which reduce chorea typically have adverse effects on mood, concentration, and coordination, all of which negatively affect functional ability in HD. Antipsychotics such as , , , olanzapine, sulpiride, or may be used. Tetrabenazine is a selective reversible vesicular monoamine transport inhibitor licensed in the UK for hyperkinetic motor disorders in HD. may help with chorea as well as benzodiazepines such as clonazepam and diazepam. • Predominant bradykinesia and rigidity – this may be difficult to treat, however levodopa/carbidopa may be tried as well as amantadine.

Pharmacological treatments for specific symptoms in HD may aggravate other existing symptoms. For example, although tetrabenazine in clinical trials has shown benefit in chorea, its use may cause depression and sedation. Therefore, it may be considered for patients who are intolerant to antipsychotics. The use of electroconvulsive therapy for depression however has shown positive response without aggravating other symptoms of HD15.

EFFICACY and SAFETY

Trial NCT00665223, MermaiHD, ACR16 C008; NCT00724048, HART, ACR16 C009; pridopidine (2 doses) vs placebo; phase pridopidine (3 doses) vs placebo; phase III. II/III. Sponsor Teva Pharmaceutical Industries. Teva Pharmaceutical Industries. Status Published. Published. Source of Publication18, trial registry1, manufacturer. Publication19, trial registry20, manufacturer. information Location EU (incl UK). USA and Canada. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=437; aged 30 years and older; HD n=227; aged 30 years and older; HD diagnosed with clinical features and a diagnosed with clinical features and a positive family history and/or presence of positive family history and/or presence of ≥36 CAG repeats in huntingtin gene; ≥36 CAG repeats in huntingtin gene; ambulatory; modified motor score (mMS) ambulatory; mMS ≥10; patients treated of ≥10; patients treated with specific with specific antipsychotics, antipsychotics, antidepressants or other antidepressants or other psychotic drugs

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psychotic drugs for ≥6 weeks and on a for ≥6 weeks and on a stable dose were stable dose were included. included. Schedule Randomised to oral pridopidine, 45mg per Randomised to oral pridopidine 10mg, day, or 90mg per day (45mg twice daily); 22.5mg, or 45mg; or placebo. Each dose or placebo, once daily for 4 weeks then was taken once daily between weeks 1-4, twice daily thereafter. then twice daily between weeks 5-26, equating to pridopidine total daily doses of 20mg, 45mg and 90mg, respectively. Follow-up Active treatment period 26 weeks, follow- Active treatment period 26 weeks, follow- up period up to 30 weeks. up period up to 30 weeks. Primary Change in mMS. UHDRS motor assessment. outcome Secondary Clinical global impression improvement CGI; safety. outcomes (CGI-I); Stroop word reading test; unified Huntington’s disease rating scale (UHDRS) behavioural assessment; hospital anxiety and depression scale (HADS); safety. Key results Mean changes from baseline for placebo, Mean changes from baseline for 20mg 45mg, and 90mg group, respectively: group vs placebo, 45mg group vs placebo, mMS, 0.22 points (95% CI -0.55 to 0.99), and 90mg group vs placebo, respectively: -0.14 (95% CI -0.90 to 0.63), and -0.77 mMS, -0.0 (95% CI -1.4 to 1.3) p=0.98, (95% CI -1.54 to 0.00); CGI-I, 4.02 points -1.2 (95% CI -2.5 to 0.2) p=0.08, and -1.2 (95% CI 3.86 to 4.19), 4.03 (95% CI 3.86 (95% CI -2.5 to 0.1) p=0.08; total motor to 4.19), and 4.00 (95% CI 3.84 to 4.16); score, -0.1 (95% CI -2.9 to 2.6) p=0.91, Stroop word reading test, -1.30 (95% CI -1.2 (95% CI -3.9 to 1.5) p=0.39, and -2.8 -3.31 to 0.71), -1.10 (95% CI -2.81 to (95% CI -5.4 to -0.1) p=0.04. 0.61), and -0.80 (95% CI -2.77 to 1.17); UHDRS, 0.12 (95% CI -2.13 to 2.37), -0.41 (95% CI -3.13 to 2.13), and -2.22 (95% CI -4.02 to -0.42); HADS, -0.10 (95% CI -1.13 to 0.93), -0.73 (95% CI -1.85 to 0.39), and 0.13 (95% CI -0.87 to 1.13). Adverse Any AE, for placebo group 64%, 45mg % of patients experiencing AEs, in placebo effects group 61%, and 90mg group 68%. AEs group, 62%; 20mg group, 50%; 45mg (AEs) included fall, chorea, diarrhoea, dizziness, group, 55%; 90mg group 74%. AEs nausea, nasopharyngitis, depression, included fall, nausea, headache, fatigue and insomnia. Serious AEs, for diarrhoea, depression, Huntington’s placebo group 8%, 45mg group 7%, and chorea, fatigue, nasopharyngitis and 90mg group 6%. 3 deaths were reported; excoriation. 9 serious AEs were reported 1 in placebo group from suicide (possibly in 6 subjects, including 1 subject in the related to study drug), 1 in the 45mg group placebo group (recurrent breast cancer), 2 (urosepsis), and 1 in 90mg group subjects in the 45mg group (suspected (subarachnoid haemorrhage). Deaths in seizure on 3 separate events, pridopidine groups were considered depression/suicidal ideation), and 3 unlikely to be related to study drug. subjects in the 90mg group (worsening bipolar disorder, left testicular torsion, adjustment disorder). All serious AEs, other than the first 2 of 3 seizures were considered to be unrelated to the study drug.

Trial NCT02006472, PRIDE-HD; NCT02494778, TV7820- NCT01306929, OPEN- TV7820-CNS-20002, 2013- CNS-20016, 2015-000904- HART, ACR16C015; 001888-23; pridopidine (4 24; pridopidine; phase II. pridopidine; phase II. doses) vs placebo; phase II.

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Sponsor Teva Branded Teva Branded Teva Branded Pharmaceutical Products, Pharmaceutical Products, Pharmaceutical Products, R&D Inc. R&D Inc. R&D Inc. Status Ongoing. Ongoing. Ongoing. Source of Trial registry21, Trial registry22, Trial registry23, information manufacturer. manufacturer. manufacturer. Location EU (incl UK), USA, Not reported. USA and Canada. Canada, Australia and Russia. Design Randomised, placebo- Uncontrolled, single-arm. Uncontrolled, single-arm. controlled. Participants n=400 (planned); aged 21 n=400 (planned); aged 21 n=116 (planned); years and older; diagnosis years and older; completed completed HART study of HD based on the PRIDE-HD study (NCT00724048) including presence of ≥36 CAG (NCT02006472) within the follow-up period, or the repeats; body weight ≥50kg last 6 months, including 2 PRIDE-HD study at screening; sum ≥25 week follow-up period; (NCT02006472) and has points on UHDRS-total body weight ≥50kg at remained on the drug motor score (TMS) and screening. during the on treatment UHDRS Independence part of the trial (after Score below 90%; successfully remaining on ambulatory. study drug through the HART study, subjects were re-evaluated for eligibility at a baseline visit using similar criteria to HART – most patients needed to have been on study drug prior to enrollment but some were on placebo). Schedule Randomised to oral Participants receive oral Participants receive oral pridopidine 45mg; or pridopidine 45mg, twice pridopidine 45mg, twice 67.5mg; or 90mg; or daily. daily. 112.5mg; or placebo; taken twice daily. Follow-up Active treatment period 26 Active treatment and Active treatment and weeks, follow up period 1 follow-up period 1 year. follow-up period 36 months. year. Primary UHDRS-TMS. AEs. AEs. outcome Secondary Modified physical Proportion of subjects who UHDRS. outcomes performance test; safety. prematurely discontinued from the study; proportion who discontinued due to AEs. Expected February 2016. September 2020. January 2020. reporting date

ESTIMATED COST and IMPACT

COST

The cost of pridopidine is not yet known.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other: increased independence therefore  No impact identified reduced burden on carers.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: reduced need to physiotherapy and other support services

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

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. A study of treatment with ACR16 in patients with Huntington’s disease (MermaiHD). www.clinicaltrials.gov/ct2/show/NCT00665223 Accessed 17 August 2015. 2 Myers RH. Huntington’s Disease Genetics. The Journal of the American Society for Experimental NeuroTherapeutics 2004;1(2):255-262. 3 Huntington’s Disease Association. What causes Huntington’s disease? http://hda.org.uk/hd/causes Accessed 17 August 2015. 4 Orphanet. Huntington disease. January 2011. http://www.orpha.net/consor/cgi- bin/Disease_Search.php?lng=EN&data_id=118&Disease_Disease_Search_diseaseGroup=huntin gton-s-disease&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group of diseases=Huntington-disease&title=Huntington-disease&search=Disease_Search_Simple Accessed 20 August 2015. 5 Huntington’s Disease Association. The early symptoms of Huntington’s disease. http://hda.org.uk/hd/symptoms Accessed 20 August 2015. 6 Huntington’s Outreach Project for Education, at Stanford. Drugs and Supplements, Miscellaneous Drugs. July 2011. http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/pridopidine-huntexil- acr-16/ Accessed 21 August 2015. 7 Evans SJW, Douglas I, Rawlins MD et al. Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. Journal of Neurology, Neurosurgery & Psychiatry 2013;84:1156-1160. 8 NHS Choices. Huntington’s disease. October 2014. www.nhs.uk/conditions/Huntingtons- disease/Pages/Introduction.aspx Accessed 20 August 2015. 9 Paulsen JS, Hoth KF, Nehl C et al. Critical periods of suicide risk in Huntington’s disease. American Journal of Psychiatry 2005;162:725-731. 10 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2013. www.ons.gov.uk

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11 Health and Social Care Information Centre, Hospital Episode Statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 12 Quinn L and Busse M. Physiotherapy clinical guidelines for Huntington’s disease. Neurodegenerative Disease Management 2012;2(1):21-31. 13 Armstrong MJ and Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2012;79(6):597-603. 14 Huntington’s Disease Association. Standards of Care. Liverpool: HAD; 2011. 15 BMJ Best Practice. Huntington’s disease: Treatment approach. Aug 2015. http://bestpractice.bmj.com/best-practice/monograph/513/treatment/step-by-step.html Accessed 24 August 2015. 16 NHS Choices. Huntington’s disease – treatment. October 2014. http://www.nhs.uk/conditions/Huntingtons-disease/pages/treatment.aspx Accessed 24 August 2015. 17 HDDW. Huntington’s disease drug works. https://hddrugworks.org/index.php?option=com_content&task=view&id=164 Accessed 24 August 2015. 18 de Yebenes JG, Landwehrmeyer B, Squitieri F et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurology 2011;10:1049-1057. 19 The Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Movement Disorders 2013;28(10):1407-1415. 20 ClinicalTrials.gov. A study of ACR16 for the treatment of patients with Huntington’s disease (HART). www.clinicaltrials.gov/ct2/show/NCT00724048 Accessed 21 August 2015. 21 ClinicalTrials.gov. A phase 2, to evaluating the safety and efficacy of pridopidine versus placebo for symptomatic treatment in patients with Huntington’s disease. www.clinicaltrials.gov/ct2/show/NCT02006472 Accessed 21 August 2015. 22 ClinicalTrials.gov. A study evaluating if pridopidine is safe, efficacious, and tolerable in patients with Huntington’s disease. www.clinicaltrials.gov/ct2/show/NCT02494778 Accessed 21 August 2015. 23 ClinicalTrials.gov. Open-label extension study of pridopidine (ACR16) in the symptomatic treatment of Huntington disease (OPEN-HART). www.clinicaltrials.gov/ct2/show/NCT01306929 Accessed 21 August 2015.

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