Presentation on theme: "Sheffield Health & Social care NHS FT Trust"— Presentation transcript:
1Sheffield Health & Social care NHS FT Trust New Drugs – looking to the future “NEW” Developments in the pharmacological treatment of schizophreniaPeter PrattChief PharmacistSheffield Health & Social care NHS FT Trust
2Disclosure statement NHS salary no other income sourcesNo external influence on content – views are entirely personalNo financial – or other benefits accepted from pharmaceutical industry, agents or other sourcesMember NICE GDG violenceFormer member several other NICE GDG
3Antipsychotics What was new PhenothiazinesButyrophenonesDepotsD2High DoseClozapineD2 5HT2AtypicalsPartial agonistsAtypical DepotCUtLASS & CATIENICE GuidanceMetabolites
5What is going to be new in the treatment of schizophrenia More “New old drugs”D2 & 5HT2ProdrugsExisting (old) drugsNew formulationsNew indicationsNew and Old drugsCombinationsNew ” new drugs”Glyceine transport inhibitor (glutamate modulator)Nicotinic agonistMay be new drugs (Phase 1)Phosphodiesterase 10a inhibitor
6Aripiprazole depot ( Abilify maintena) Otsuka &Lundbeck (BMS partnership ended 2013)Partial dopamine agonist – available as tablets (and immediate action injection)New formulation – monthly depotDry powder – reconstituted suspension before administrationMarch 2013 FDA approved Abilify maintenaIndication – schizophrenia “prevention of relapse”300mg and 400mg vials in kit formEU approval ( late 2013)Marketed UK 2014… as we speakFurther phase 3 studies ( completion due 2014) investigating depot use as acute treatment30/4/2015 Licenced by FDA (In USA) for use in ACUTE phase
7Aripiprazole Depot Lundbeck/Otsuka Marketing SeeSPC and regulatory approval documents available for downloadSeeKey points from EU regulatorsLeukopenia 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 initiatingStarting dose 400mg monthly IM – Gluteal muscleInitial 14 consecutive days of concurrent oral aripiprazole or current oral antipsychotic
8Aripiprazole depoit SPC (ABILIFY MAINTENA) Tells you what you need to know egFor aripiprazole naïve patientsTolerability 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 monthlyContinue 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)
10Risks & Benefits Benefits – reduced risk of relapse Aripiprazole depot reduced relapse ( cf placebo)15% Aripiprazole depot relapsed at 1 year85% Placebo relapsed at 1 yearAripiprazole depot reduced exacerbation10% Aripiprazole depot symptom exacerbation40% Placebo symptom exacerbationHarms - risk of akathisiaAkathisia – most commonly reported s/e (8% patients), weight gain & insomniaLeukopenia 3X greater than with oral ?
11Don’t forget Alkermes Aripiprazole lauroxil (ALKS 9070) Depot made from new “LinkeRx “ technologyInvolves creating new molecules from existing compoundsAlks reformulated as aripiprazole lauroxilprodrug for aripiprazoleP3 Clinical trials to asses release of aripiprazole from ALKS 9070 due completion mid 2014Company claims aripiprazole safety & efficacy already established – only need to establish kinetic profilePossible market Cheep? “generic “atypical depot””? UK/EU plans
12New old depot - Paliperidone Jansssen-Cilag (Alkermes – nanoparticle technology)9OH risperidoneProposed indication schizophrenia3 monthly long acting injection2 Phase 3 study non inferiority with paliperidone monthly (n=1800)Results expected 2014If successful regulatory submission unlikely before 2015…Pre release marketing have you heard?
13Bitopertin (RO4917838, RG1678) Roche pharmaceuticals New “new” drug SeeNew “new “ approach – biomarkers – Treatment individualisationRoche comitement to development of biomarker for all “new compounds”Discovered in phase II validated in phase III studiesGlycine transporter inhibitorPrevent reuptake of glycine - Increase glycine levelsGlycine acts alongside glutamate as agonist at NMDA receptorTheory – 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
14Bitopertin 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 placeboResults expected 2015If approved - unlikely marketed before 2016As combination with existing antipsychotics for “Persistent negative symptoms”Three phase 3 studies (n=1890) patients taking antipsychotics cf 10mg,20mg or placeboResults expected & 2015Two phase 2 Randomised pbo controlled studies(n= 300 & n=323)One 10,30,60mg and Pbo & one 10,30mg 15mg olanzapine or pboOne published mg bitopertin superior to placeboIf approved - unlikely marketed before 2015January 20142 phase 3 studies failed to show Bitopertin effective in negative sysmptoms
15RG7203 Roche Phosphodiesterase 10A inhibitor (PDE 10 inhibitor) TheroryD2 blockade increases cAMPPDE 10 inhibitors also increase cAMP in striatumAnimal models suggest PDE10 inhibition may improve +ve and –ve symptomsMay also improve cognition2013 One phase 1 double blind, dose escalating placebo controlled study(n=92) in progressIf successful - Marketing
16Brexpiprazole OPC 34712 Otsuka & Lundbeck “Due to replace aripiprazole” ( patent exp 2014/2015)D2 partial agonist & 5HT2a antagonistIndication acute schizophreniaThree 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 2015If successful marketing unlikely before 2016?? UK marketing plans
17Cariprazine Forest labs Indication schizophrenia Preferential D3, partial agonist at D2 & D3TheoryD3 selectivity may improve cognition and reduce likelihood of EPSE6 phase 3 trails N>3000 patients, including placebo controlled and aripiprazole comparisonMain side effect reported Akathisia, EPS, dyspepsia, vomiting, (weight gain& metabolic effects also reported)Outcome from FDA submission expected late 2014Unsure if EU/UK submission –Appears effective but unsure about tolerability(US stock investors caution about tolerability)
18Nicotinic alpha -7 agonist Envivo pharmaceuticals EVP 6124Targacept pharmaceuticals TC-5619Indication schizophrenia ( also investigated in Alzheimer's disease)Enhances synaptic transmission in brain & acts as co agonist with achTheoryNicotinic ACH - important for cognitionAlpha 7 agonists enhance cognition without the addictive effects of nicotineEVP 6124Adverse effects (Phase 2 studies)Less than 4% nasopharyngitis, nausea and headacheTwo Phase 3 (n=700) studies looking at combination with atypical antipsychotics just startedUnlikely to be submitted for approval before 2016TC-5619AZ – withdrawn option to licence ( Targacept exclusive rights)2014 phase 2 studies failed to show effect as add on in negative sysmptoms
19Iloperidone Dopamine D2 and 5HT2 antagonist Vanda pharmaceuticals Oral iloperidone launched in US 2010Novartis discontinued development of long acting version Oct 2012EMA 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
20Lisdexampfetamine Shire pharmaceuticals Already licensed by Shire pharmaceuticals for ADHD where inadequate response to methylphenidateProposed IndicationAugmentation in schizophrenia for negative symptomsPhase 3 ( US)Prodrug consists of lysine linked to dexamfetamine –Activation occurs by splitting lysine in red blood cells – therefore independent of route of administration –TheoryLeads to longer duration of action & reduced likelihood of misuseRealityLots of INTERNET tips how to split lysine prior to administrationE.g PROTEASEBUT Don’t try this at home
21New old drugs - Loxapine DibenzoxazepineD2/D3 antagonist – higher affinity for D3 than D2 also 5HT2 antagonistFirst reports of loxapine as antipsychotic France 1965Similar chemical structure to clozapine (dibenzodiazepine)Half life following oral administration 4-5hoursT1/2 major metabolite 8-OHloxapine around 8 hoursSimilar to other antipsychoticsMore EPSE than “atypicals”
22(Loxapine adasuve) - Alexza pharmaceuticals Vaporised LoxapineUS FDA approval Dec 2012Single dose only (no repeat within 24 hours)SeeEU approved Feb 2013licensed for acute agitation in schizophrenia and bipolar disorderSecond dose allowed after 2 hoursSeeMarketing plans Germany & Austria 2013UK ( withdrawn from NICE TA 2013)May 2013 Nice published “terminated appraisal”
24Undesirable effectsLess likely to be effective in patients taking antipsychoticsBased on two Phase 3 and one Phase 2 short-term (24-hour) placebo-controlled clinical trialsAgitation 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,UncommonCommon in subjects with active airways disease,Very common: (≥ 1/10);Dysgeusia,Common (≥ 1/100 to < 1/10Sedation/somnolence and dizziness (dizziness was more common after placebo treatment than loxapine treatment).throat irritationDry mouthFatigueUncommon: (≥ 1/1,000 to < 1/100);dystonia, dyskinesia, oculogyration, tremor, akathisia/restlessnesshypotension
26Lurasidone Takeda pharmaceuticals D2 and 5HT2/7 antagonist Indication SchizophreniaSee NICE reviewFDA approved 2011EU approval OCT 2012Marketing 2014Likely emphasis on cognitive effects of 5HT7 antagonismNon inferior to Quetiapine XLLow incidence of wt gain & metabolic effectsTwo published studiesAkathisia 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 goingeg n= 400 low dose ( 20mg ) for acute psychosis (completion 2014)
27Lurasidone ( Latuda) Regulators opinion SeeAndTake with food !
28Pomaglumetad methioneil (mglu2/3) ly2140023 Glutamate agonistLilly discontinued studies – drug as single agent as the drug did not show any benefits over placeboTrial as add on to atypical also failed to show benefit
29Zicronapine (LU 31-130) Lundbeck D1 D2 and 5HT2a antagonist Phase 3 study completed Aug (n=160) zicronapine 7.5mg vs risperidone 5mgPhase 2 study looked at weekly dosing vs daily dosing (n=42)If successful marketing unlikely before 2015
30Drug Treatments beyond 2020 See Miyamoto et alAlternative pharmacologic targets for the treatment of schizophrenia: results from phase I and II trials. Current Opinion in Psychiatry. 2013, 26(2):
31New 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."