1. Sheffield Health & Social care NHS FT Trust
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

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? MARKETED 2014 Approved 2013 + Filed 2013 +
Phase 1…2020+
Phase
Phase
Filed
Approved
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 ( 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”
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
SPC and regulatory approval documents available for download
See
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 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 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
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) January 2014
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 & 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 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

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

16. Brexpiprazole OPC 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
EU approved Feb 2013
licensed for acute agitation in schizophrenia and bipolar disorder
Second dose allowed after 2 hours
See
Marketing plans Germany & Austria 2013
UK ( withdrawn from NICE TA 2013)
May 2013 Nice published “terminated appraisal”

23. How Loxapine Adasuve works

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
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
And
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 (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):

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."

32.
What’s changed?