sign in sign up
<<
Home , Asenapine

Asenapine (Saphris) for

January 2010

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

January 2010

Asenapine (Saphris) for schizophrenia

Target group • Schizophrenia: acute and maintenance treatment.

Technology description Asenapine (Saphris, Sycrest, Org-5222) belongs to pyrrolidino class of atypical . It has potent antagonist properties for and receptors. Asenapine is intended as a substitute for currently available atypical antipsychotics. Asenapine is administered sublingually at 5-10mg twice daily.

Asenapine is launched for the acute treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder in the USA. It is also in phase III clinical trials for manic episodes associated with bipolar I disorder in the EU and for treatment of psychosis in elderly patients in the USA.

Innovation and/or advantages If licensed, asenapine will be the first drug for this indication with a sublingual route of administration, although there are other licensed atypical antipsychotics agents with orodispersable formulation.

Developer Schering-Plough (a part of MSD).

Availability, launch or marketing dates, and licensing plans An application for a Marketing Authorisation has been filed with the EMEA.

NHS or Government priority area This topic is relevant to New Horizons: A Shared Vision for Mental Health (2009) and The National Service Framework for Mental Health: Modern Standards and Service Models (1999).

Relevant guidance • NICE technology appraisal in development. for the treatment of schizophrenia in people aged 15-17. Expected October 20101. • NICE technology appraisal. The clinical effectiveness and cost effectiveness of newer atypical drugs for schizophrenia. 20022. • NICE clinical guideline. Core interventions in the treatment and management of schizophrenia in primary and secondary care (update). 20093. • NICE clinical guideline. Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care. 20024. 5 • Clinical Knowledge Summaries. Schizophrenia – Management. 2009 . • American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 20046. 7 • SIGN. Psychosocial Interventions in the Management of Schizophrenia. 1998 .

Clinical need and burden of disease Schizophrenia is a psychiatric disorder that alters an individual’s perception, thoughts, affect and behaviour. Acute schizophrenia is marked by characteristic positive symptoms of hallucinations, delusions and behavioural disturbances such as agitation and distress. Following resolution of the acute phase, positive symptoms may diminish or disappear 2 January 2010

leaving negative symptoms which may include: poor self care, reduced motivation, reduced ability to experience pleasure, reduced production of thought, lack of emotional expression, reduced social functioning and, rarely, catatonia. This phase may last many years and is often interrupted by acute exacerbations or relapses3.

Schizophrenia is the most common form of psychotic disorder. The National Survey of Psychiatric Morbidity in the UK found a population prevalence of probable psychotic disorder of 5 per 1000 in the age group 16–74 years3. In England, in 2005-06 there were 24,349 finished consultant episodes with a diagnosis of schizophrenia (ICD10 F20) resulting in 20,334 admissions and 1,870,301 bed days8. Mortality among people with schizophrenia is approximately 50% above that of the general population, partly as a result of an increased incidence of suicide (about 10% die by suicide) and violent death, and partly as a result of an increased risk of a wide range of physical health problems3. In 2008 in England and Wales there were 7,519,687 prescription items dispensed in the community for antipsychotic drugs and antipsychotic depot injections with a net ingredient cost of £297,115,4759,10.

Existing comparators and treatments Treatment aims are to manage acute episodes, prevent relapse and to improve quality of life, with minimal adverse effects11. Drug treatment for schizophrenia is principally with antipsychotic agents. Current treatment options include12: • drugs (, aripiprazole, , , , , and ). • derivatives (, , , pericyazine, , , and ). • (). • (). • ( and ). • Substituted ().

Guidelines recommended that atypical antipsychotic drugs should be considered for the first line treatment of newly diagnosed schizophrenia and for managing an acute schizophrenic episode2.

Non-pharmaceutical treatments include: individual psycho-educational interventions, family interventions, cognitive behavioural therapy and assertive community treatment.

Efficacy and safety

Trial 41022, Hera 022, 41021, Hera 021, 41512, P05784, NCT00151424; asenapine, NCT00156117; asenapine, NCT00156091; phase III; olanzapine or placebo; olanzapine or placebo; extension. phase III. phase III. Sponsor Organon. Organon. Organon. Status Trial complete, Trial complete, Trial complete. unpublished. unpublished. Source of Trial registry13, Trial registry15, Trial registry16, review14. information manufacturer, review14. manufacturer, review14. Location USA, Ukraine and Russia. USA, Russia and Ukraine. Not known. Design Randomised, controlled. Randomised, controlled. Extension trial.

3 January 2010

Participants n=277; adults; acute n=417; adults; acute n=260; completed 41021, and schedule schizophrenia; PANSSa schizophrenia; PANSS NCT00156117. ≥60; PANSS positive score ≥60; PANSS positive Subjects receiving placebo subscale ≥4 in 2 or more subscale ≥4 in 2 or more received asenapine 5mg items; CGI-Sb ≥4; response items; CGI-S ≥4; response twice daily for week 1 then to an antipsychotic other to antipsychotic other than 5mg or 10mg twice daily. than clozapine. clozapine. Randomised to asenapine Randomised to asenapine 5mg or 10mg twice daily, 5mg or 10mg twice daily, olanzapine 10-20mg daily, olanzapine 15mg daily, or or placebo. placebo. Follow-up 6 weeks treatment. 6 weeks treatment. 1 yr. Primary PANSS. PANSS. Long-term safety, extra- outcomes pyramindal symptoms, maintenance of effect, QLSc, Q-LES-Qd, PETiTe. Secondary PANSS subscales, CGI-S, PANSS negative subscale. Neurocognition, cognitive outcomes CGI-If. functioning, weight, ECGs, CDSSg (depression). Key results Mean change from Mean change from Not known. baseline for total PANSS baseline for PANSS total asenapine, olanzapine and score, asenapine 5mg, placebo respectively (p asenapine 10mg, values vs placebo): -9.4 olanzapine 15mg and (p=0.84), -11.5 (p=0.50), placebo respectively: -9.9. -14.5, -13.4, -16.5, -11.1. No statistically significant differences vs placebo. Olanzapine superior to placebo. Adverse ≥1 AE asenapine, ≥1 AE asenapine 5mg, Not known. effects (AEs) olanzapine and placebo asenapine 10mg, respectively: 68.9%, olanzapine and placebo 63.0%, 60.2%. respectively: 71.2%, 73.5%, 71.6%, 70.0%.

Trial 41023, Hera 023, 41513, Hera, A7501012, RHEA, NCT00156104; asenapine NCT00156065; phase III; P05770, NCT00150176; vs haloperidol or placebo; extension. asenapine vs placebo; phase III. phase III. Sponsor Organon. Organon. Schering-Plough. Status Trial complete, Trial complete, Trial complete, unpublished. unpublished. unpublished. Source of Trial registry17, Trial registry18, review14. Trial registry19, information manufacturer, review14. manufacturer, review14. Location USA, Canada, Russia, Not known. USA and other countries. India and Romania. Design Randomised, controlled. Extension trial. Randomised, placebo controlled. a PANSS - Positive and Negative Syndrome Scale b CGI-S - Clinical Global Impressions scale - Severity c QLS - Quality of Life Scale d Q-LES-Q - Quality of Life Enjoyment and Satisfaction Questionnaire e PETiT - Personal Evaluation Of Transitions In Treatment f CGI-I - Clinical Global Impressions scale - Improvement g CDSS - Calgary Depression Scale for Schizophrenia 4 January 2010

Participants n=458; adults; acute n=187; completed 041023, n=386; adults; and schedule schizophrenia; PANSS NCT00156104. schizophrenia; ≥1 episode score ≥60; PANSS positive Subjects on placebo in in the previous 3 yrs; ≥1 yr subscale ≥4 in 2 or more study 041023 received continuous antipsychotics; items; CGI-S ≥4; response asenapine 5mg twice daily stable for ≥4 weeks. to antipsychotic other than for week 1 then asenapine Asenapine 5-10mg or clozapine. 5mg or 10mg twice daily. placebo. Randomised to asenapine 5mg, 10mg, haloperidol 4mg or placebo, all twice daily. Follow-up 6 weeks treatment. 1 year treatment. 56 weeks. Primary PANSS. Safety, maintenance of Time to relapse or outcomes effect, QoL, patient impending relapse. functionality.

Secondary PANSS negative subscale. Neurocognition and 5 dimensions of outcomes cognitive functioning, schizophrenia, CGI-S, weight, ECGs, CDSS depressive, suicidal (depression). thinking, cognition.

Key results Mean change in PANSS Not known. Relapse rate over 26 weeks total score (vs placebo): phase asenapine vs Asenapine 5mg (-16.2 vs placebo: 12.11% vs -10.7, p=0.0290); 47.37%. Relative risk of haloperidol 4mg (-15.4, relapse 0.26. -10.7, p=0.0342); asenapine 10mg (-14.9 vs -10.7, p=0.0680). Adverse ≥1 AE asenapine 5mg, Not known. ≥1 AE asenapine vs effects (AEs) asenapine 10mg, placebo: 55.2% vs 45.9%. haloperidol and placebo respectively: 64.8%, 75.5%, 75.7%, 72.4%.

Trial 25517, Actamesa, 25520, P05846, Actamesa- 25543, Aphrodite 1, NCT00212784; asenapine Ex, NCT00212771; phase P05817, NCT00212836; vs olanzapine; phase III. III; extension. asenapine vs olanzapine; phase III. Sponsor Organon, Pfizer. Organon. Schering-Plough. Status Trial complete, Trial complete, Trial complete, unpublished. unpublished. unpublished. Source of Trial registry20, Trial registry21, Trial registry22, information manufacturer, review14. manufacturer, review14. manufacturer. Location EU (inc UK) and other Not known. EU (inc UK), Australia, countries. Russia and South Africa. Design Randomised, controlled. Extension trial. Randomised, controlled. Participants n=1225; adults; n=440; completed 25517, n=444; schizophrenia with and schedule schizophrenia or NCT 00212784. predominant and persistent schizoaffective disorder; Continued with asenapine negative symptoms. PANSS score ≥60; PANSS 5-10mg twice daily or Asenapine 5 - 10mg twice positive subscale ≥4 in 2 or olanzapine 10-20mg daily. daily or olanzapine 5 - more items; CGI-S ≥4; 20mg daily. response to antipsychotic other than clozapine. Randomised to asenapine 5 January 2010

5-10mg twice daily or olanzapine 10-20mg daily. Follow-up 1 year. Up to an additional 72 6 months. weeks. Primary PANSS. PANSS. Negative Symptom outcome Assessment (NSA)-16 Total Score. Secondary PANSS subscales, PANSS PANSS subscales, PANSS - outcomes Marder factors, CGI-S, Marder factors, CGI-S, CGI-I. CGI-I. Key results Asenapine vs olanzapine: Asenapine vs olanzapine: No statistically significant mean change in total mean change total PANSS differences for asenapine PANSS -21.0 vs -27.5. -40.8 vs -39.5; mean 5-10mg vs olanzapine 5- % ≥20% reduction in total changes from endpoint of 20mg in NSA-16 total PANSS 66.5% vs 77.8%. 25517, 1.2 vs -1.5. score. % ≥30% reduction in total % ≥30% reduction in total PANSS 57.4% vs 68.0%. PANSS at week 76, 88.9% vs 89.0% and at week 124 93.9% vs 92.9%. Adverse ≥1 AE asenapine vs ≥1 AE asenapine vs ≥1 AE asenapine vs effects (AEs) olanzapine: 82.5%, 81.7%. olanzapine: 87.6% vs olanzapine: 74.7% vs 88.0%. 68.8%.

Trial 25544, Aphrodite 1-Ex, A7501013, P05771, A7501014, P05772, P05777, NCT00265343; Aphrodite 2, Aphrodite 2 Ex, phase III; extension. NCT00145496; asenapine NCT00174265; asenapine vs olanzapine; phase III. vs olanzapine, phase III; extension. Sponsor Schering-Plough. Organon, Pfizer. Organon. Status Trial complete, Trial complete, Trial complete, unpublished. unpublished. unpublished. Source of Trial registry23, Trial registry24, Trial registry25, information manufacturer. manufacturer. manufacturer. Location Not known. USA, Canada, Chile, Not known. Mexico and Brazil. Design Extension trial. Randomised, controlled. Extension trial. Participants n=306; completed 25543, n=264; adults; n=195; completed and schedule NCT00212836. schizophrenia with A7501013, NCT00145496. Asenapine 5-10mg twice persistent negative Asenapine 5-10 mg twice daily or olanzapine 5- symptoms. daily or olanzapine 5- 20mg once daily. Asenapine 5-10mg twice 20mg once daily. daily or olanzapine 5- 20mg once daily. Follow-up Additional 6 months. 6 months. Additional 6 months. Primary NSA-16. NSA-16. NSA-16. outcomes Secondary QLS, PANSS, CDSS, QLS, PANSS, CDSS, QLS, PANSS, CDSS CGI- outcomes CGI-S, CGI-I. CGI-S, CGI-I. S, CGI-I. Key results At 52 weeks difference in Not known. Not known. NSA total score between asenapine and olanzapine not significant (p=0.234). Expected - Not known. Not known. reporting date 6 January 2010

Adverse ≥1 AE asenapine vs Not known. Not known. effects (AEs) olanzapine: 85.1% vs 74.4%.

Estimated cost and cost impact The cost of asenapine is not yet known. The cost of some currently available treatments is as follows12:

Drug Dose Annual cost Olanzapine (Zyprexa; Eli Lilly) 5-20mg daily £570-£2,071 Risperidone (non-proprietary) 4-6mg daily £264-£418

Claimed or potential impact – speculative

Patients Reduced mortality or increased Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings:  Other: unknown relative cost.

References

1 National Institute for Health and Clinical Excellence. Aripiprazole for the treatment of schizophrenia in people aged 15-17. Technology appraisal in development. Expected October 2010. 2 National Institute for Health and Clinical Excellence. The clinical effectiveness and cost effectiveness of newer atypical antipsychotic drugs for schizophrenia. Technology appraisal TA43. London: NICE; June 2002. 3 National Institute for Health and Clinical Excellence. Core interventions in the treatment and management of schizophrenia in primary and secondary care (update). Clinical guideline CG82. London: NICE; March 2009. 4 National Institute for Health and Clinical Excellence. Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care. Clinical guideline CG01. London: NICE; December 2002. 5 Clinical Knowledge Summaries. Schizophrenia – Management. http://www.cks.nhs.uk/schizophrenia#390267001 Accessed 15 December 2009. 6 American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 2nd ed. Arlington (VA): American Psychiatric Association; February 2004. 7 Scottish Intercollegiate Guidelines Network. Psychosocial interventions in the management of schizophrenia. Publication No. 30. Edinburgh: SIGN; October 1998. 8 NHS. Hospital episode statistics. NHS England 2004-05. HES data 2006. www.hesonline.nhs.uk. 9 Health of Wales Information Service. Prescription Cost Analysis Wales 2008. 10 The NHS Information Centre. Prescription Cost Analysis England 2008. 11 Smith T, Weston C and Lieberman J. Schizophrenia (maintenance treatment). BMJ Clinical Evidence. 2009; 04:1007. 12 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2009. 13 ClinicalTrials.gov. Efficacy and safety of asenapine with placebo and olanzapine. http://clinicaltrials.gov/ct2/show/NCT00151424 Accessed 21 December 2009.

7 January 2010

14 Citrome L. Asenapine for schizophrenia and : a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. International Journal of Clinical Practice 2009; 63:1762–1784. 15 ClinicalTrials.gov. Efficacy and safety of asenapine with placebo and olanzapine. http://clinicaltrials.gov/ct2/show/NCT00156117 Accessed 08 January 2010. 16 ClinicalTrials.gov. Long-term efficacy and safety of asenapine using olanzapine as a positive control. http://clinicaltrials.gov/ct2/show/NCT00156091 Accessed 21 December 2009. 17 ClinicalTrials.gov. Efficacy and safety of asenapine with placebo and haloperidol. http://www.clinicaltrials.gov/ct2/show/NCT00156104 Accessed 21 December 2009. 18 ClinicalTrials.gov. Long-term efficacy and safety of asenapine using haloperidol as a positive control. http://www.clinicaltrials.gov/ct2/show/NCT00156065 Accessed 21 December 2009. 19 ClinicalTrials.gov. To determine long term efficacy and safety of asenapine in schizophrenic patient population. http://www.clinicaltrials.gov/ct2/show/NCT00150176 Accessed 21 December 2009. 20 ClinicalTrials.gov. Efficacy and safety of asenapine using an active control in subjects with schizophrenia or schizoaffective disorder. http://www.clinicaltrials.gov/ct2/show/NCT00212784 Accessed 21 December 2009. 21 ClinicalTrials.gov. Efficacy and safety of asenapine using an active control in subjects with schizophrenia or schizoaffective disorder. http://clinicaltrials.gov/ct2/show/NCT00212771 Accessed 21 December 2009. 22 ClinicalTrials.gov. Efficacy and safety of asenapine compared with olanzapine in patients with persistent negative symptoms of schizophrenia. http://clinicaltrials.gov/ct2/show/NCT00212836 Accessed 21 December 2009. 23 ClinicalTrials.gov. 6-month extension trial of asenapine with olanzapine in negative symptom patients who completed the first 6-month trial. http://clinicaltrials.gov/ct2/show/NCT00265343 Accessed 21 December 2009. 24 ClinicalTrials.gov. Efficacy and safety of asenapine compared with olanzapine in patients with persistent negative symptoms of schizophrenia. http://clinicaltrials.gov/ct2/show/NCT00145496 Accessed 21 December 2009. 25 ClinicalTrials.gov. 6-month extension trial of asenapine with olanzapine in negative symptom patients who completed the first 6- month trial. http://clinicaltrials.gov/ct2/show/NCT00174265 Accessed 21 December 2009.

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)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

8