Horizon Scanning Research July 2016 & Intelligence Centre

Cariprazine (Vraylar) for schizophrenia in adults

LAY SUMMARY

Schizophrenia is a long term mental health condition that causes changes in the perception of reality. The disease can be distressing and interrupt normal social interaction, with symptoms including hallucinations, confusion, lack of motivation and blunt emotions.

This briefing is based on Cariprazine is a new drug taken to treat the symptoms of information schizophrenia. Cariprazine works by changing the body’s response to available at the time dopamine: a naturally occurring brain chemical used for controlled of research and a movement and motivation. limited literature search. It is not Cariprazine is currently being studied to see how well it works and intended to be a whether it is safe to use in people with schizophrenia. If cariprazine is definitive statement licensed for use in the UK, it will offer a new treatment for adults with on the safety, schizophrenia. efficacy or effectiveness of the health technology NIHR HSRIC ID: 4385 covered and should not be used for commercial 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

• Schizophrenia: in adults.

TECHNOLOGY

DESCRIPTION

Cariprazine (Vraylar; cariprazine prolonged release; MP-214; RGH-188) is an atypical antipsychotic, dopamine D2 and D3 partial agonist, acting as a dopamine system stabiliser through preferential D3 receptor binding. In a phase III trial cariprazine was administered orally at 3-9mg once daily for 6 weeks1.

Cariprazine does not currently have Marketing Authorisation in the EU for any indication.

Cariprazine is currently in phase III trials for depression and bipolar I disorder2,3.

INNOVATION and/or ADVANTAGES

If licensed, cariprazine will offer an additional treatment option for schizophrenia.

DEVELOPER

Gedeon Richter.

AVAILABILITY, LAUNCH OR MARKETING

Cariprazine launched in the USA for schizophrenia in March 2016. The company submitted a Marketing Authorisation Application to the EMA in Q1 20164.

PATIENT GROUP

BACKGROUND

Schizophrenia is a long term mental health condition that usually emerges gradually in an affected individual’s 20s, but may come about suddenly at other times in life. Schizophrenia is characterised by psychotic symptoms: those related to the perception of reality. Symptoms are divided into ‘negative’ and ‘positive’. Negative symptoms are those that are deficient compared to normal experience, for example social withdrawal, lack of motivation, blunted affect and poverty of speech. Positive symptoms are those added to normal experiences – speech, confusion, false beliefs and hallucinations (auditory, visual, tactile, gustatory or olfactory)5.

CLINICAL NEED and BURDEN OF DISEASE

Schizophrenia is a major psychiatric disorder, or cluster of disorders, in which a person’s perception, thoughts, mood and behaviour are significantly altered. Over a lifetime, about 1% of the population will develop schizophrenia6. In 2014 it was estimated that 220,000 people in England and Wales received a diagnosis of schizophrenia7. In 2014-15, there were 16,792 admissions due to schizophrenia in England, resulting in 1,986,495 bed days and

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25,258 finished consultant episodes (ICD10 F20)8; in 2014, 108 deaths from schizophrenia were registered in England and Wales9.

The population likely to be eligible to receive cariprazine for schizophrenia could not easily be estimated from available routine published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years (TA213). January 2011. • NICE technology appraisal. The clinical effectiveness and cost effectiveness of newer atypical antipsychotic drugs for schizophrenia (TA43). June 2002. • NICE clinical guideline. Psychosis and schizophrenia in adults: prevention and management (CG178). February 2014. • NICE quality standard. Psychosis and schizophrenia in adults (QS80). February 2015.

NHS England Policies and Guidance

• NHS England. 2014/15 NHS Standard Contract for High Secure Mental Health Services (Adults). C02/S/a. • NHS England. 2014/15 NHS Standard Contract for Medium And Low Secure Mental Health Services (Adults). C03/S/a.

Other Guidance

• NHS Clinical Knowledge Summary. Psychosis and schizophrenia. February 201510.

CURRENT TREATMENT OPTIONS

As a complex mental health condition, schizophrenia requires personalised care. Antipsychotic drugs are the primary treatment of schizophrenia, but are often used in conjunction with a care programme including psychological and social interventions. Early detection and intervention is important for avoiding adverse outcomes, such as periods of untreated psychosis and acute hospital admissions. Choice of antipsychotic is made according to clinician and patient preference when considering benefits, known side effects and health risks of each medication6,11.

Antipsychotics can be divided into first and second generation drugs. First generation antipsychotics are characterised by primarily dopamine D2 receptor antagonism, while second generation ‘atypical’ antipsychotics act on a range of receptors at variable affinity. There are currently 15 first generation and 8 second generation antipsychotics listed as available for use in the BNF12.

In summary the treatment options for schizophrenia include: • Personalised care programme – including the assessment of needs, development of a care plan, appointment of relevant care coordinator (social worker or nurse), which is regularly reviewed.

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• First generation antipsychotics – e.g. chlorpromazine, fluphenazine, prochlorperazine, haloperidol. • Second generation (atypical) antipsychotics – e.g. aripiprazole, amisulpride, olanzapine, quetiapine, risperidone. • Individual cognitive behavioural therapy (CBT) – helping the patient to recognise and avoid acting on delusional thoughts. • Family therapy – information, discussion and support for patients and family members. • Crisis resolution teams – for the intervention of acute episodes in the community, without requiring hospital treatment. • Voluntary / compulsory detention – admission to hospital for the protection of the patient and others. • Arts therapy – encouraging creative expression, shown to alleviate negative symptoms of schizophrenia.

EFFICACY and SAFETY

Trial NCT01412060; cariprazine vs placebo; phase III. Sponsor Forest laboratories. Status Completed. Source of Trial registry1, publication13. information Location EU (not UK), USA, and other countries. Design Randomised, placebo-controlled. Participants n=765 (open label phase), n=200 (double-blind phase); aged 18-60 years; schizophrenia as confirmed by diagnostic and statistical manual of mental disorders 4, text revision (DSM-IV-TR) diagnosed >1 year before first visit; positive and negative syndrome scale (PANSS) ≥70 and ≤120 at visit 1 and 2. Schedule Randomised to cariprazine 3-9mg oral once daily; or placebo once daily. Follow-up Active treatment for 92 weeks. Primary Time from baseline to first symptom relapse between week 17 and 92. outcomes Secondary Not reported. outcomes Key results Time to relapse was reported to be significantly increased in the cariprazine treated group. 25 (24.8%), 47 (47.5%) relapse in cariprazine and placebo group respectively. 55% reduction in risk of relapse vs. placebo (hazard ratio 0.45, 95% CI 0.28, 0.73 p=0.0010). Adverse Akathisia, insomnia, headache, restlessness, extrapyramidal disorder, nausea, effects (AEs) dyspepsia, weight gain, constipation, anxiety, tremor.

ESTIMATED COST and IMPACT

COST

The cost of cariprazine is not yet known. The cost of other selected drugs for schizophrenia are outlined in the following table:

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Drug Dose Cost12 Aripiprazole tablets (Actavis) 15mg once daily £6.35 (28 days) Quetiapine tablets (Actavis) 150mg twice daily £2.51 (30 days) Haloperidol tablets (Teva UK) 3mg three times daily £14.10 (28 days) Haloperidol decanoate depot 300mg every 4 weeks £15.16 (28 days) injection (Jansen-Cilag)

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing 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 randomized, double-blind, placebo-controlled, parallel-group study of cariprazine (RGH-188) in the prevention of relapse in patients with schizophrenia. www.clinicaltrials.gov/ct2/show/NCT01412060 Accessed 21 June 2016. 2 ClinicalTrials.gov. Study on the efficacy, safety, and tolerability of cariprazine relative to placebo in patients with bipolar depression. https://clinicaltrials.gov/ct2/show/study/NCT02670551 Accessed 20 July 2016. 3 ClinicalTrials.gov. An efficacy, safety and tolerability as an adjunctive treatment to antidepressant therapy (ADT) in patients with major depressive disorder. https://clinicaltrials.gov/ct2/show/study/NCT01715805 Accessed 20 July 2016. 4 Gedeon Richter press release. EMA started the evaluation of Richter’s marketing authorisation application for cariprazine for the treatment of schizophrenia. https://www.richter.hu/en- US/pressroom/press-release/Pages/press-releases/pr160329.aspx Accessed 20 July 2016. 5 Tandon R, Gaebel W, Barch D et al., Definition and description of schizophrenia in the DSM-5, Schizophrenia Research. 2013; http://dx.doi.org/ 10.1016/j.schres.2013.05.028 6 National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline CG178. London: NICE; February 2014. 7 National Institute for Health and Care Excellence. Costing statement: Costing statement: psychosis and schizophrenia in adults: treatment and management-Implementing the NICE guideline on Psychosis and schizophrenia in adults. Clinical guideline CG178. London: NICE; February 2014.

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8 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 9 Office for National Statistics. Deaths registered in England and Wales (series DR) – 2014. www.ons.gov.uk 10 NICE Clinical Knowledge Summary. Psychosis and schizophrenia. February 2015. http://cks.nice.org.uk/psychosis-and-schizophrenia Accessed 21 June 2016. 11 NHS Choices. Schizophrenia. www.nhs.uk/Conditions/Schizophrenia/Pages/Introduction.aspx accessed 21 June 2016. 12 Joint Formulary Committee. British National Formulary. BNF June 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com 13 Durgam S, Early W, Li R et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a double-blind, placebo-controlled trial. 28th congress of the European college of neuropsychopharmacology (ECNP) August-September 2015.

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