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Bitopertin for schizophrenia

Source agency:
NIHR-HSC
Date of Submission:
31/05/2012
Date of Printing:
01/08/2014
Disclaimer:
This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:
Bitopertin (GLYT-1; RO-4917838; RG1678)
Technology - description:
Bitopertin (GLYT-1; RO-4917838; RG1678) is a glycine transporter type 1 (GlyT1) inhibitor that increases levels of the neurotransmitter glycine by inhibiting its reuptake from the synaptic cleft(1). Glycine acts as a required co-agonist along with glutamate at N-methyl-D-aspartate (NMDA) receptors. Dysfunction of NMDA receptors may play a key role in the pathogenesis of schizophrenia and modulation of glutamatergic signalling via increased concentrations of glycine in the synaptic cleft may help potentiate NMDA receptor function and improve the symptoms of schizophrenia(2). Bitopertin is administered orally at 10mg or 20mg once daily for 56 weeks.
Company or developer:
Roche Products Ltd.
Reason for database entry:
If licensed, bitopertin would represent the first in a new class of treatments for this patient group.

Technology - stage in early warning process:
Assessment in progress
Technology - stage of development:
Investigational - phase III
Licensing, reimbursement and other approval:
No information available.
Technology - type(s):
Drug
Technology - use(s):
Therapeutic

Patient Indication & Setting

Patient indications:
Schizophrenia: primary, persistent negative symptoms; sub-optimally controlled positive symptoms – in combination with antipsychotics.
Disease description and associated mortality and morbidity:
Schizophrenia is a major psychiatric disorder, or cluster of disorders, characterised by psychotic symptoms that alter a person's perceptions, thoughts, affect, and behaviour(3). Although the combination of symptoms and experiences associated with schizophrenia are unique to the individual, there is typically a prodromal period which may occur 1-2 years before the onset of psychotic symptoms. This is followed by an acute episode marked by characteristic positive symptoms, including hallucinations, delusions and disorders of thought and emotion(4). Following resolution of the acute phase, usually as a result of medical intervention, positive symptoms subside and patients can experience a range of negative symptoms such as social withdrawal, self-neglect, lack of motivation, anhedonia and poverty of speech(3). This phase can often last for many years and may be interrupted by recurrent acute exacerbations or relapses(3). Persistent negative symptoms of schizophrenia are not well managed by currently available treatments(5).
Number of Patients:
Schizophrenia is one of the most common forms of psychotic disorder with a lifetime risk of approximately 1%(3). The 2007 National Survey of Adult Psychiatric Morbidity in England found the overall population prevalence of psychotic disorder (including schizophrenia) to be 0.4% (0.3% men, 0.5% women)(6). In both men and women the highest prevalence was observed in those aged 35 to 44 years (0.7% and 1.1% respectively). There was no change in the overall prevalence of probable psychosis between the 2000 and 2007 surveys(6). In 2010-11 there were 16,807 admissions for schizophrenia resulting in 2,403,719 bed days and 24,848 finished consultant episodes (ICD10 F20)(7). While it estimated that around three quarters of patients with schizophrenia will suffer recurrent relapse and continued disability, longer-term studies suggest that there is a moderately good long-term outcome in over half of patients with schizophrenia, with a smaller proportion having extended periods of remission without further relapses(8).
Technology - specialities(s):
Mental health, addiction & learning difficulties
Technology - setting(s):
Community and primary care, General hospital and ambulatory care, Specialist hospital
Setting - further information:
No further information available.

Impact

Alternative and/or complementary technology:
Additive or complementary technology
Current Technology:
The aims of treatment in schizophrenia are to manage acute episodes, prevent relapse and improve quality of life, with minimal adverse effects . Current pharmacological treatments include(3,9,10):
•Typical (first-generation) antipsychotics:
oPhenothiazines – chlorpromazine, levomepromazine, promazine, pericyazine, pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine.
oButyrophenones – benperidol, haloperidol.
oThioxanthines – flupentixol, zuclopentixol.
oDiphenylbutylpiperidines – pimozide.
oSubstituted benzamides – sulpiride.

•Atypical (second-generation) antipsychotics – amisulpiride, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone and zotepine.

•Antipsychotic depot injections – flupentixol, fluphenazine, haloperidol, olanzapine, paliperidone, pipotiazine palmitate, risperidone, zuclopenthixol.

Non-pharmacological treatments include: individual psycho-educational interventions, family interventions and cognitive behavioural therapy.
Health Impact:
No information available.
Diffusion:
No information available.
Cost, infrastructure and economic consequences:
No information available.
Ethical, social, legal, political and cultural impact:
No information available.

Evidence & Policy

Clinical evidence and safety:
Trial: NCT01235559, WN25305, 2010-020718-26; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(11).
Location: EU, USA, Bulgaria, China and Japan.
Design: Randomised, placebo-controlled.
Participants and schedule: n=600 (planned); adults ≥ 18 years; schizophrenia; antipsychotic treatment stable for 8 weeks prior to screening period; patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Follow-up: Active treatment period 52 weeks; 2 year follow-up thereafter.
Primary outcomes: Positive symptoms factor score assessed by Positive and Negative Syndrome Scale (PANSS); safety.
Secondary outcomes: Symptom domains of schizophrenia using PANSS; Clinical Global Impression – Improvement (CGI-I) symptoms scale; Clinical Global Impression – Severity (CGI-S) symptoms scale; safety.
Expected reporting date: Estimated study completion date May 2015.

Trial: NCT01235585, WN25306, 2010-020616-11; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(12).
Locatin: EU, USA, Canada and other countries.
Design: Randomised, placebo-controlled.
Participants and schedule: n=600 (planned); adults ≥ 18 years; schizophrenia; antipsychotic treatment stable for 8 weeks prior to screening period; patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Follow-up: Active treatment period 52 weeks; 2 year follow-up thereafter.
Primary outcomes: Positive symptoms factor score assessed by PANSS; safety.
Secondary outcomes: Symptom domains of schizophrenia using PANSS; CGI-I symptoms scale; CGI-S symptoms scale; safety.
Expected reporting date: Estimated study completion date May 2015.

Trial: NCT01235520, NN25307, 2010-020696-23; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(13).
Locations: EU (inc UK), USA and other countries.
Design: Randomised, placebo-controlled.
Participants and schedule: n=600 (planned); adults ≥ 18 years; schizophrenia; antipsychotic treatment stable for 8 weeks prior to screening period; patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Follow-up: Active treatment period 52 weeks; 2 year follow-up thereafter.
Primary outcomes: Positive symptoms factor score assessed by PANSS; safety.
Secondary outcomes: Symptom domains of schizophrenia using PANSS; CGI-I symptoms scale; CGI-S symptoms scale; safety.
Expected reporting date: Estimated study completion date May 2015.


Trial: NCT01192880, WN25308, 2010-020470-42; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(14) .
Locations: EU, USA, Bulgaria, China and Japan.
Design: Randomised, placebo-controlled.
Participants and schedule: n=630 (planned); adults ≥ 18 years; schizophrenia of paranoid, disorganized, residual, undifferentiated or catatonic subtype; predominant negative symptoms; with the exception of clozapine, patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Follow-up: Active treatment period 52 weeks; 2 year follow-up thereafter.
Primary outcomes: Efficacy at 24 weeks (PANSS negative symptoms factor score [NSFS]); safety.
Secondary outcomes: Efficacy at 24 weeks (Personal and Social Performance [PSP] total score).
Expected reporting date:Estimated study completion sate Apr 2015.

Trial: NCT01192906, WN25309, 2010-020467-21; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(15).
Locations: EU, USA, Canada and other counties.
Design: Randomised, placebo-controlled.
Participants and schedule: n=630 (planned); adults ≥ 18 years; schizophrenia of paranoid, disorganized, residual, undifferentiated or catatonic subtype; predominant negative symptoms; with the exception of clozapine, patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Follow-up: Active treatment period 52 weeks; 2 year follow-up thereafter.
Primary outcomes:Efficacy at 24 weeks (PANSS NSFS); safety.
Secondary outcomes: Efficacy at 24 weeks(PSP total score).
Expected reporting date: Estimated study completion date Mar 2013.

Trial: NCT01192867, NN25310; bitopertin vs placebo; phase III.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(16).
EU (inc UK), USA and other countries.
Randomised, placebo-controlled.
n=630 (planned); adults ≥ 18 years; schizophrenia of paranoid, disorganized, residual, undifferentiated or catatonic subtype; predominant negative symptoms; with the exception of clozapine, patients continue on any available marketed atypical or typical antipsychotics (maximum of two antipsychotics).
Randomised to once daily bitopertin 10mg or 20mg, or placebo.
Active treatment period 52 weeks; 2 year follow-up thereafter.
Efficacy at 24 weeks (PANSS NSFS); safety.
Efficacy at 24 weeks (PSP total score).
Estimated study completion date Nov 2013.

Trial: NCT01234779, WN25333, 2010-021984-33; phase II; bitopertin vs olanzapine or placebo.
Sponsor: Hoffmann-La Roche.
Status: Ongoing.
Source of information: Trial registry(17).
Location: USA, EU and other countries.
Design: Randomised, placebo and active-controlled.
Participants and schedule :n=300 (planned); 18-65 years; schizophrenia; acute exacerbation within prior 8 weeks; no other antipsychotic medication.
Randomised to once daily bitopertin 10mg or 30mg, olanzapine 15mg or placebo.
Follow-up: Active treatment period 4 weeks.
Primary outcomes: PANNS; safety.
Secondary outcomes: Clinical response, defined as at least 30% or 50% improvement in PANSS total score; change in symptoms as measured by PANSS; CGI-S symptoms scale; Clinical Global Impressions - Change (CGI-C) symptoms scale; Nurses' Observation Scale For Inpatient Evaluation (NOSIE); time to readiness for discharge from inpatient unit as assessed by the Readiness For Hospital Discharge Questionnaire (RDQ).
Expected reporting date: Estimated study completion date Dec 2012.

Trial: NCT00616798, NN20372; phase II; bitopertin vs placebo.
Spnsor: Hoffmann-La Roche.
Status: Complete and published in abstract.
Source of information: Poster(18).
Locations: EU, USA and other countries.
Design: Randomised, placebo-controlled.
Participants and schedule: n=323 (planned); 18-60 years; schizophrenia; medically and psychiatrically stable over previous month without symptom exacerbation within prior 3 months; currently taking no more than 2 antipsychotic drugs.
Randomised to once daily bitopertin 10mg, 30mg or 60mg or placebo.
Follow-up: Active treatment period 8 weeks; 4 week follow-up thereafter.
Primary outcome: Mean change in PANNS NSFS.
Secondary outcomes: Total change in PANNS NSFS; CGI-I in negative symptoms; PSP score.
Key results: For bitopertin 10mg, 30mg, 60mg or placebo respectively (+SE, p-value vs placebo), response rate in intention to treat population for 10mg vs placebo respectively, 58% vs 44% (p=0.077); response rate for 10mg, 30mg and placebo respectively, 65% (p=0.013), 60% (p=0.088) and 43% [per-protocol population]; mean change from baseline in NSFS at week 8, -6.45 + 0.52 (p=0.071),
-6.40 + 0.54 (p=0.090), -5.03 + 0.54 (p=0.93), -5.11 + 0.53 [intention to treat population]; CGI-I in negative symptoms, 10mg statistically significantly superior to placebo (p=0.025) [per-protocol population]; mean change in PSP score for 10mg group vs placebo respectively, 8.76 + 1.15 vs 5.96 + 1.31 (p=0.072) [per-protocol population].
Adeverse events (AEs): For bitopertin 10mg, 30mg, 60mg and placebo respectively:
somnolence, 6 (7%), 4 (5%), 8 (5%), 2 (3%); dizziness, 1 (1%), 3(4%), 9 (12%), 2 (3%); headache, 2 (2%), 2 (2%), 7 (9%), 1 (1%); nasopharyngitis, 4 (5%), 0, 2 (3%), 6 (8%).
Economic evaluation:
No futher infomation available.
Ongoing research:
None.
Ongoing or planned HTA:
No further information available.
Web link:
 
References and sources:
1) Bray NJ, Leweke FM, Kapur S et al. The neurobiology of schizophrenia: new leads and avenues for treatment. Current Opinion in Neurobiology 2010;20(6):810-815.
2) Yang CR and Svensson KA. Allosteric modultation of NMDA receptor via elevation of brain glycine and D-serine: the therapeutic potentials for schizophrenia. Pharmacology and Therapeutics 2008;120(3):317-332.
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. Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years. Technology appraisal TA213. London: NICE; January 2011.
5) Knapp M, McCrone P and Leeuwenkamp O. Associations between negative symptoms, service use patterns, and costs in patients with schizophrenia in five European countries. Clinical Neuropsychiatry 2008;5(4):195-205.
6) The Information Centre. Adult psychiatry morbidity in England, 2007 - Results of a household survey http://www.ic.nhs.uk/webfiles/publications/mental%20health/other%20mental%20health%20publications/Adult%20psychiatric%20morbidity%2007/APMS%2007%20%28FINAL%29%20Standard.pdf Accessed 25 April 2012.
7) NHS Hospital episode statistics. NHS England 2010-2011 HES data. 2011. www.hesonline.nhs.uk
8) National Institute for Health and Clinical Excellence. NHS Evidence. Schizophrenia Annual Evidence Update 2010 http://www.library.nhs.uk.
9) NHS Clinical Knowledge Summaries. Schizophrenia – Management. Version 1.1. July 2009. http://www.cks.nhs.uk/schizophrenia/management/quick_answers/scenario_new_or_suspected_schizophrenia#-390311 Accessed 25 April 2012.
10) British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 63. London: BMJ Group and RPS Publishing, March 2012.
11) ClinicalTrials.gov. A study of RO4917838 in patients with sub-optimally controlled symptoms of schizophrenia (WN25305). http://clinicaltrials.gov/ct2/show/NCT01235559?term=RO4917838&rank=13 Accessed 25 April 2012.
12) ClinicalTrials.gov. A study of RO4917838 in patients with sub-optimally controlled symptoms of schizophrenia (WN25306). http://clinicaltrials.gov/ct2/show/NCT01235585?term=RO4917838&rank=15 Accessed 25 April 2012.
13) ClinicalTrials.gov. A study of RO4917838 in patients with sub-optimally controlled symptoms of schizophrenia (NN25307). http://clinicaltrials.gov/ct2/show/NCT01235520?term=RO4917838&rank=14 Accessed 25 April 2012.
14) ClinicalTrials.gov. A study of RO4917838 in patients with persistent, predominant negative symptoms of schizophrenia (WN25308). http://clinicaltrials.gov/ct2/show/NCT01192880?term=RO4917838&rank=11 Accessed 26 April 2012.
15) ClinicalTrials.gov. A study of RO4917838 in patients with persistent predominant negative symptoms of schizophrenia (WN25309). http://clinicaltrials.gov/ct2/show/NCT01192906?term=RO4917838&rank=10 Accessed 26 April 2012.
16) ClinicalTraisl.gov. A study of RO4917838 in patients with persistent predominant negative symptoms of schizophrenia (NN25310). http://clinicaltrials.gov/ct2/show/NCT01192867?term=RO4917838&rank=12 Accessed 26 April 2012
17) ClinicalTrials.gov. A study of RO4917838 in patients with acute exacerbation of schizophrenia. http://clinicaltrials.gov/ct2/show/NCT01234779?term=RO4917838&rank=8 Accessed 26 April 2012.
18) Umbricht D, Martin-Facklam M, Pizzagalli F et al. Glycine transporter type 1 (GlyT1) inhibitor RG1678: results of the proof-of-concept study for the treatment of negative symptoms in schizophrenia (Poster). The International College of Neuropsychopharmacoloy (CINP). 28th CINP World Congress of Neuropsychopharmacology 2012. No: S28.
Notes: