Peter Pratt Chief Pharmacist Sheffield Health & Social care NHS FT Trust

1. New Drugs – looking to the future “NEW” Developments in the pharmacological treatment of schizophrenia Peter Pratt Chief Pharmacist Sheffield Health & Social care NHS FT Trust peter.pratt@shsc.nhs.uk

2. Disclosure statement • NHS salary • no other income sources • No external influence on content – views are entirely personal • No financial – or other benefits accepted from pharmaceutical industry, agents or other sources • Member NICE GDG violence • Former member several other NICE GDG

3. Antipsychotics What was new Phenothiazines Butyrophenones Depots D2 High Dose Clozapine D2 5HT2 Atypicals Partial agonists Atypical Depot CUtLASS & CATIE NICE Guidance Metabolites

4. What is coming up? Phase 1…2020+ Phase 2 2017+ Phase 3 2015+ Filed 2013 + Approved 2013 + MARKETED 2014

5. What is going to be new in the treatment of schizophrenia • More “New old drugs” • D2 & 5HT2 • Prodrugs • Existing (old) drugs • New formulations • New indications • New and Old drugs • Combinations • New ” new drugs” • Glyceine transport inhibitor (glutamate modulator) • Nicotinic agonist • May be new drugs (Phase 1) • Phosphodiesterase 10a inhibitor

6. Aripiprazole depot ( Abilifymaintena) • Otsuka &Lundbeck (BMS partnership ended 2013) • Partial dopamine agonist – available as tablets (and immediate action injection) • New formulation – monthly depot • Dry powder – reconstituted suspension before administration • March 2013 FDA approved Abilifymaintena • Indication – schizophrenia “prevention of relapse” • 300mg and 400mg vials in kit form • EU approval ( late 2013) • Marketed UK 2014… as we speak • Further phase 3 studies ( completion due 2014) investigating depot use as acute treatment • 30/4/2015 Licenced by FDA (In USA) for use in ACUTE phase

7. Aripiprazole Depot • Lundbeck/Otsuka • Marketing See http://www.lundbeck.com/upload/abilify/files/marketing/global_branding/design_manual/Abilify_Maintena_Global_Brand_Plan_2013.pdf# • SPC and regulatory approval documents available for download • See http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002755/human_med_001711.jsp&mid=WC0b01ac058001d124 • Key points from EU regulators • Leukopenia 3X greater than with oral ( requires post monitoring survellance) • increased weight (48/534, 9.0%) • akathisia (42/534, 7.9%) • insomnia (31/534, 5.8%) • and injection site pain (27/534, 5.1%). • with oral aripiprazole prior to initiating • Starting dose 400mg monthly IM – Gluteal muscle • Initial 14 consecutive days of concurrent oral aripiprazole or current oral antipsychotic

8. Aripiprazole depoit SPC (ABILIFY MAINTENA) • Tells you what you need to know eg • For aripiprazole naïve patients • Tolerability with oral aripiprazole must occur prior to ABILIFY MAINTENA. • Starting and maintenance dose is 400 mg. • Titration of the dosenot required. • It should be administered once monthly • Continue oral aripiprazole 14 consecutive days concentrations during initiation of therapy. • Dose adjustements needed if drug interactions ( CYP2D6 eg fluoxetine& CYP3A4 eg & ketaconozole , HIV protease inhibitors)

9. Dosage adjustments - interactions

10. Risks & Benefits • Benefits – reduced risk of relapse • Aripiprazole depot reduced relapse ( cf placebo) • 15% Aripiprazole depot relapsed at 1 year • 85% Placebo relapsed at 1 year • Aripiprazole depot reduced exacerbation • 10% Aripiprazole depot symptom exacerbation • 40% Placebo symptom exacerbation • Harms - risk of akathisia • Akathisia – most commonly reported s/e (8% patients), weight gain & insomnia • Leukopenia 3X greater than with oral ?

11. Don’t forget Alkermes • Aripiprazole lauroxil (ALKS 9070) • Depot made from new “LinkeRx “ technology • Involves creating new molecules from existing compounds • Alks 9070 reformulated as aripiprazole lauroxil • prodrug for aripiprazole • P3 Clinical trials to asses release of aripiprazole from ALKS 9070 due completion mid 2014 • Company claims aripiprazole safety & efficacy already established – only need to establish kinetic profile • Possible market 2015 ++ Cheep? “generic “atypical depot”” • ? UK/EU plans

12. New old depot - Paliperidone • Jansssen-Cilag (Alkermes – nanoparticle technology) • 9OH risperidone • Proposed indication schizophrenia • 3 monthly long acting injection • 2 Phase 3 study non inferiority with paliperidone monthly (n=1800) • Results expected 2014 • If successful regulatory submission unlikely before 2015… • Pre release marketing have you heard?

13. Bitopertin(RO4917838, RG1678) • Roche pharmaceuticals • New “new” drug • See http://www.nhsc-healthhorizons.org.uk/files/downloads/1848/2235.774408e0.Bitopertin_June12.pdf • New “new “ approach – biomarkers – Treatment individualisation • Roche comitement to development of biomarker for all “new compounds” • Discovered in phase II validated in phase III studies • Glycine transporter inhibitor • Prevent reuptake of glycine - Increase glycine levels • Glycine acts alongside glutamate as agonist at NMDA receptor • Theory – NMDA receptor dysfunction may be implicated in pathogenesis of schz. • Bitopertin modulates glutamate activity by increased glycine in synaptic cleft which in turn improves NMDA receptor functioning

14. Bitopertin • Indication (s) • As combination treatment with existing antipsychotics for “inadequate response” • Three Phase 3 Randomised pbo controlled studies (n=1800 )patients taking antipsychotics cf 10mg,20mg or placebo • Results expected 2015 • If approved - unlikely marketed before 2016 • As combination with existing antipsychotics for “Persistent negative symptoms” • Three phase 3 studies (n=1890) patients taking antipsychotics cf 10mg,20mg or placebo • Results expected 2013 & 2015 • Two phase 2 Randomised pbo controlled studies(n= 300 & n=323) • One 10,30,60mg and Pbo & one 10,30mg 15mg olanzapine or pbo • One published - 10mg bitopertin superior to placebo • If approved - unlikely marketed before 2015 • January 2014 • 2 phase 3 studies failed to show Bitopertin effective in negative sysmptoms

15. RG7203 • Roche • Phosphodiesterase 10A inhibitor (PDE 10 inhibitor) • Therory • D2 blockade increases cAMP • PDE 10 inhibitors also increase cAMP in striatum • Animal models suggest PDE10 inhibition may improve +ve and –ve symptoms • May also improve cognition • 2013 One phase 1 double blind, dose escalating placebo controlled study(n=92) in progress • If successful - Marketing 2020+

16. BrexpiprazoleOPC 34712 • Otsuka & Lundbeck • “Due to replace aripiprazole” ( patent exp 2014/2015) • D2 partial agonist & 5HT2a antagonist • Indication acute schizophrenia • Three Phase 3 studies ( 1 open label n=140,1 dose range n=660, 1 double blind placebo with quetiapine n=465. • Results expected mid 2013 – late 2015 • If successful marketing unlikely before 2016 • ?? UK marketing plans

17. Cariprazine • Forest labs • Indication schizophrenia • Preferential D3, partial agonist at D2 & D3 • Theory • D3 selectivity may improve cognition and reduce likelihood of EPSE • 6 phase 3 trails N>3000 patients, including placebo controlled and aripiprazole comparison • Main side effect reported Akathisia, EPS, dyspepsia, vomiting, (weight gain& metabolic effects also reported) • Outcome from FDA submission expected late 2014 • Unsure if EU/UK submission – • Appears effective but unsure about tolerability • (US stock investors caution about tolerability)

18. Nicotinic alpha -7 agonist • Envivo pharmaceuticals EVP 6124 • Targacept pharmaceuticals TC-5619 • Indication schizophrenia ( also investigated in Alzheimer's disease) • Enhances synaptic transmission in brain & acts as co agonist with ach • Theory • Nicotinic ACH - important for cognition • Alpha 7 agonists enhance cognition without the addictive effects of nicotine • EVP 6124 • Adverse effects (Phase 2 studies) • Less than 4% nasopharyngitis, nausea and headache • Two Phase 3 (n=700) studies looking at combination with atypical antipsychotics just started • Unlikely to be submitted for approval before 2016 • TC-5619 • AZ – withdrawn option to licence ( Targacept exclusive rights) • 2014 phase 2 studies failed to show effect as add on in negative sysmptoms

19. Iloperidone • Dopamine D2 and 5HT2 antagonist • Vanda pharmaceuticals • Oral iloperidone launched in US 2010 • Novartis discontinued development of long acting version Oct 2012 • EMA recommended non approval (oral) due to weak evidence of efficacy against placebo & risks of cardiac problems (QT prolongation) • March 2013 Vanda withdrawn EU licence application

20. Lisdexampfetamine • Shire pharmaceuticals • Already licensed by Shire pharmaceuticals for ADHD where inadequate response to methylphenidate • Proposed Indication • Augmentation in schizophrenia for negative symptoms • Phase 3 ( US) • Prodrug consists of lysine linked to dexamfetamine – • Activation occurs by splitting lysine in red blood cells – therefore independent of route of administration – • Theory • Leads to longer duration of action & reduced likelihood of misuse • Reality • Lots of INTERNET tips how to split lysine prior to administration • E.g PROTEASE BUT Don’t try this at home

21. New old drugs - Loxapine • Dibenzoxazepine • D2/D3 antagonist – higher affinity for D3 than D2 also 5HT2 antagonist • First reports of loxapine as antipsychotic France 1965 • Similar chemical structure to clozapine (dibenzodiazepine) • Half life following oral administration 4-5hours • T1/2 major metabolite 8-OHloxapine around 8 hours • Similar to other antipsychotics • More EPSE than “atypicals”

22. (Loxapine adasuve) - Alexza pharmaceuticals • Vaporised Loxapine • US FDA approval Dec 2012 • Single dose only (no repeat within 24 hours) • See http://www.adasuve.com/ • EU approved Feb 2013 • licensed for acute agitation in schizophrenia and bipolar disorder • Second dose allowed after 2 hours • See http://www.adasuve.com/index-eu.php • Marketing plans Germany & Austria 2013 • UK 2014 ( withdrawn from NICE TA 2013) • May 2013 Nice published “terminated appraisal” • http://www.nice.org.uk/nicemedia/live/14172/63900/63900.pdf

23. How Loxapine Adasuve works http://www.alexza.com/products/the-staccato-system/staccato-animation

24. Undesirable effects • Less likely to be effective in patients taking antipsychotics • Based on two Phase 3 and one Phase 2 short-term (24-hour) placebo-controlled clinical trials • Agitation associated with schizophrenia (n=524) (including 27 patients with schizoaffective disorder) • Agitation associated with bipolar disorder, ADASUVE 4.5 mg (n=265 ) or ADASUVE 9.1 mg (n=259 ). • Bronchospasm Serious adverse reaction, • Uncommon • Common in subjects with active airways disease, • Very common: (≥ 1/10); • Dysgeusia, • Common (≥ 1/100 to < 1/10 • Sedation/somnolence and dizziness (dizziness was more common after placebo treatment than loxapine treatment). • throat irritation • Dry mouth • Fatigue • Uncommon: (≥ 1/1,000 to < 1/100); • dystonia, dyskinesia, oculogyration, tremor, akathisia/restlessness • hypotension

25. Efficacy

26. Lurasidone • Takeda pharmaceuticals • D2 and 5HT2/7 antagonist • Indication Schizophrenia • See NICE review • http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM15.jsp • FDA approved 2011 • EU approval OCT 2012 • Marketing 2014 • Likely emphasis on cognitive effects of 5HT7 antagonism • Non inferior to Quetiapine XL • Low incidence of wt gain & metabolic effects • Two published studies • Akathisia and parkinsonism were more commonly seen with lurasidone, and weight gain and dry mouth were more commonly seen with olanzapine. (Meltzer 2011) • Nausea, vomiting and akathisia. More common with lurasidone – more constipation and weight gain reported with risperidone (Citrome 2012) • Phase 3 studies on going • eg n= 400 low dose ( 20mg ) for acute psychosis (completion 2014)

27. Lurasidone ( Latuda) • Regulators opinion • See http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002713/WC500164684.pdf • And http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002713/human_med_001737.jsp&mid=WC0b01ac058001d124 • Take with food !

28. Pomaglumetad methioneil (mglu2/3)ly2140023 • Glutamate agonist • Lilly discontinued studies – drug as single agent as the drug did not show any benefits over placebo • Trial as add on to atypical also failed to show benefit

29. Zicronapine (LU 31-130) • Lundbeck • D1 D2 and 5HT2a antagonist • Phase 3 study completed Aug 2012 (n=160) zicronapine 7.5mg vs risperidone 5mg • Phase 2 study looked at weekly dosing vs daily dosing (n=42) • If successful marketing unlikely before 2015

30. Drug Treatments beyond 2020 • See Miyamoto et al Alternative pharmacologic targets for the treatment of schizophrenia: results from phase I and II trials.   Current Opinion in Psychiatry.  2013, 26(2):158-165

31. New drugs – lessons from the past 3rd Oct 2006 "The claims of superiority for the [newer drugs] were greatly exaggerated," wrote Columbia University psychiatrist Jeffrey Lieberman. "This may have been encouraged by an overly expectant community of clinicians and patients eager to believe in the power of new medications. At the same time, the aggressive marketing of these drugs may have contributed to this enhanced perception of their effectiveness in the absence of empirical information." Peter Jones, a psychiatrist at the University of Cambridge in England who led the study, searched yesterday for the right word to describe what had happened to his colleagues. " 'Duped' is not right," he said. "We were beguiled." http://www.washingtonpost.com/wp-dyn/content/article/2006/10/02/AR2006100201378.html

32. 2006 -2014 • What’s changed?