Asenapine (Saphris) for schizophrenia 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 tetracyclic class of atypical antipsychotics. It has potent antagonist properties for dopamine serotonin and adrenergic 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. Aripiprazole 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 antipsychotic 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: • Atypical antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone and zotepine). • Phenothiazine derivatives (chlorpromazine, levomepromazine, promazine, pericyazine, pipotiazine, fluphenazine, perphenazine and trifluoperazine). • Butyrophenones (haloperidol). • Diphenylbutylpiperidines (pimozide). • Thioxanthenes (flupentixol and zuclopenthixol). • Substituted benzamides (sulpiride). 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.