New Drugs looking to the future NEW Developments

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

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

Antipsychotics What was new Phenothiazines Butyrophenones D 2 5 HT 2 Partial agonists CUt. LASS & CATIE NICE Guidance Depots High Dose Clozapine Atypicals Atypical Depot Metabolites

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

What is going to be new in the treatment of schizophrenia • More “New old drugs” – D 2 & 5 HT 2 – 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 10 a inhibitor

Aripiprazole depot ( Abilify maintena) • 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 Abilify maintena • Indication – schizophrenia “prevention of relapse” – 300 mg and 400 mg 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

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. j sp&mid=WC 0 b 01 ac 058001 d 124 • Key points from EU regulators – – – • • Leukopenia 3 X 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 400 mg monthly IM – Gluteal muscle Initial 14 consecutive days of concurrent oral aripiprazole or current oral antipsychotic

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 ( CYP 2 D 6 eg fluoxetine& CYP 3 A 4 eg & ketaconozole , HIV protease inhibitors) – –

Dosage adjustments - interactions

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 3 X greater than with oral ?

Don’t forget Alkermes • Aripiprazole lauroxil (ALKS 9070) • Depot made from new “Linke. Rx “ technology – Involves creating new molecules from existing compounds • Alks 9070 reformulated as aripiprazole lauroxil – prodrug for aripiprazole • P 3 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

New old depot - Paliperidone Jansssen-Cilag (Alkermes – nanoparticle technology) 9 OH 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? • • •

Bitopertin (RO 4917838, RG 1678) • Roche pharmaceuticals • New “new” drug • See http: //www. nhsc-healthhorizons. org. uk/files/downloads/1848/2235. 774408 e 0. Bitopertin_June 12. 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

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 10 mg, 20 mg 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 10 mg, 20 mg or placebo • Results expected 2013 & 2015 • Two phase 2 Randomised pbo controlled studies(n= 300 & n=323) – One 10, 30, 60 mg and Pbo & one 10, 30 mg 15 mg olanzapine or pbo • One published - 10 mg bitopertin superior to placebo • If approved - unlikely marketed before 2015 • January 2014 • 2 phase 3 studies failed to show Bitopertin effective in negative sysmptoms

RG 7203 • Roche • Phosphodiesterase 10 A inhibitor (PDE 10 inhibitor) • Therory – D 2 blockade increases c. AMP – PDE 10 inhibitors also increase c. AMP in striatum • Animal models suggest PDE 10 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+

Brexpiprazole OPC 34712 • • Otsuka & Lundbeck “Due to replace aripiprazole” ( patent exp 2014/2015) D 2 partial agonist & 5 HT 2 a 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

Cariprazine • • Forest labs Indication schizophrenia Preferential D 3, partial agonist at D 2 & D 3 Theory – D 3 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)

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

Iloperidone Dopamine D 2 and 5 HT 2 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 • •

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

New old drugs - Loxapine • Dibenzoxazepine • D 2/D 3 antagonist – higher affinity for D 3 than D 2 also 5 HT 2 antagonist • First reports of loxapine as antipsychotic France 1965 • Similar chemical structure to clozapine (dibenzodiazepine) • Half life following oral administration 4 -5 hours – T 1/2 major metabolite 8 -OHloxapine around 8 hours • Similar to other antipsychotics – More EPSE than “atypicals”

(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. pdf

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

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

Efficacy

Lurasidone • • Takeda pharmaceuticals D 2 and 5 HT 2/7 antagonist Indication Schizophrenia See NICE review – http: //www. nice. org. uk/mpc/evidencesummariesnewmedicines/ESNM 15. jsp • • FDA approved 2011 EU approval OCT 2012 Marketing 2014 Likely emphasis on cognitive effects of 5 HT 7 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 ( 20 mg ) for acute psychosis (completion 2014)

Lurasidone ( Latuda) • Regulators opinion – See http: //www. ema. europa. eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002713/WC 500164684. pdf – And http: //www. ema. europa. eu/ema/index. jsp? curl=pages/medicines/human/me dicines/002713/human_med_001737. jsp&mid=WC 0 b 01 ac 058001 d 124 • Take with food !

Pomaglumetad methioneil (mglu 2/3) ly 2140023 • 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

Zicronapine (LU 31 -130) • Lundbeck • D 1 D 2 and 5 HT 2 a antagonist • Phase 3 study completed Aug 2012 (n=160) zicronapine 7. 5 mg vs risperidone 5 mg • Phase 2 study looked at weekly dosing vs daily dosing (n=42) • If successful marketing unlikely before 2015

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

New drugs – lessons from the past 3 rd 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/AR 2006100201378. html

2006 -2014 • What’s changed?