New Approaches in schizophrenia treatment: recent studies’ results & their implications in real clinical practice

Prof. Alessandro Serretti Department of Biomedical and NeuroMotor Sciences University of Bologna Oral

1st Generation (FGAs) 2nd Generation (SGAs) Thorazine® () Clozaril® () Haldol® () Risperdal® () Prolixin® () Geodon® () Stelazine® (trifluperazine) Seroquel® () Trilafon® () Zyprexa® () Navane® (thiothixene) Abilify® (aripipirazole) Loxitane® () Invega® () Mellaril® () Fanapt® () Saphris® () Latuda® () Long Acting Injectable Antipsychotics

1st Generation 2nd Generation Risperdal Consta® Fluphenazine decanoate Invega Sustenna® Zyprexa Relprevv® Abilify Maintena® Which is the best ???

Heres et al. Am J Psych 2006 4/43 New Antipsychotics Receptors Affinity

Zacher et al. 2012

New Oral Antipsychotics Iloperidone • FDA approved in 2009 • Indicated for the treatment of schizophrenia in adults • Mechanism of action – primarily

(D2) antagonism with some (5HT2) antagonism

Fanapt®. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014. Iloperidone - Efficacy

• 6-week trial with placebo and risperidone showed superiority over placebo and comparable efficacy of risperidone at 6 weeks • 4-week trial with placebo and ziprasidone found superiority over placebo and similar efficacy to ziprasidone at 4 weeks

Fanapt®. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014. Iloperidone – Possible Side Effects

• Metabolic changes – weight gain, ↑cholesterol – Not as significant as other 2nd gen drugs • Extrapyramidal symptoms (EPS) • QTc prolongation • Orthostasis, low blood pressure, and dizziness • Rarer side effects – priapism, seizure, agranulocytosis

Iloperidone - Dosing

• Starting dose 1 mg twice daily • Target dosage range 6-12 mg twice daily • Increase by no more than 2 mg twice daily every day until target range – Slow titration due to increased risk of low blood pressure, dizziness, and falls • Maximum dose of 12 mg twice daily

Fanapt®. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised April, 2014. Iloperidone – Role in therapy

• New second generation antipsychotic choice • Lower risk for EPS and weight gain than other options • Higher risk of orthostasis, dizziness, and falls especially during the initial titration phase • Slow titration phase and twice daily dosing may be difficult for some patients to work with Asenapine • FDA approved in 2009 • Indications – Treatment of schizophrenia in adults – Acute treatment, either as monotherapy or adjunctive, or manic or mixed episodes of bipolar I disorder in adults • Mechanism of action thought to be a combination of

dopamine D2 and serotonin 5HT2 receptor blockade

Saphris®. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013. Asenapine – Efficacy in Schizophrenia

• Short term studies 1. A 6-week trial comparing asenapine to placebo showed superior efficacy asenapine at 6 weeks 2. A 6-week trial comparing asenapine to placebo and haloperidol showed asenapine to be superior to placebo, but not haloperidol. It also showed no difference between 5 mg twice daily and 10 mg twice daily dosing 3. A 6-weeks trial comparing asenapine to placebo olanzapine showed that asenapine and placebo failed to separate and that olanzapine was superior to both

Saphris®. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013. Asenapine – Efficacy in Bipolar I Disorder • Monotherapy – Two 3-week trials of asenapine and placebo showed that asenapine was superior to placebo for controlling acute mania • Adjunctive – A 12-week trial of asenapine or placebo added to lithium or valproic acid showed asenapine was superior to placebo at reducing manic symptoms at 3 weeks

Saphris®. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013. Asenapine – Possible Side Effects

• Metabolic changes and weight gain – Not as significant as other 2nd gen drugs • EPS – higher rates of akathisia • QTc prolongation • Sedation or somnolence • Headache • Rarer side effects – agranulocytosis, seizures, and orthostasis Saphris®. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013.

Asenapine - Dosing • Asenapine is supplied as sublingual tablets – Do not swallow tablets – Dissolve under the tongue – No food or drink for 10 minutes after dose

Indication Starting Dose Dosage Range Maximum Schizophrenia 5 mg twice daily 5-10 mg twice daily 10 mg twice daily Acute Bipolar I 10 mg twice daily 5-10 mg twice daily 10 mg twice daily

Saphris®. Whitehouse Station, NJ; Merck & Co., Inc.; Revised March, 2013. Asenapine – Role in Therapy

• Can be utilized in both schizophrenia and bipolar disorder • Unique sublingual administration • Relatively small metabolic side effects • Higher rates of sedation and akathisia than other agents Lurasidone • FDA approved in 2010 • Indications – Treatment of schizophrenia in adults – Treatment of depressive episodes in bipolar disorder in adults as both monotherapy and adjunctive therapy • Mechanism of action thought to be a combination

of dopamine D2 and serotonin 5HT2 receptor blockade

Latuda®. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013. Lurasidone – Efficacy in Schizophrenia

• Five total trials, all 6 weeks long – Two trials of fixed dose lurasidone vs. placebo showed superior efficacy of lurasidone – One trial of 40 mg, 80 mg, and 120 mg lurasidone vs. placebo showed that only the 80 mg dose was superior to placebo – One trial of lurasidone, olanzapine and placebo showed that both lurasidone and olanzapine were superior to placebo – One trial of lurasidone, quetiapine ER, and placebo showed both lurasidone and quetiapine ER were superior to placebo

Latuda®. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013. Lurasidone – Efficacy in Bipolar Depression • As monotherapy – A 6-week trial vs placebo for symptom reduction in bipolar depression showed that both doses of lurasidone studied were superior to placebo at 6 weeks • As an adjunct – A 6-week trial of patients who were still symptomatic on lithium or valproic acid were given placebo or lurasidone. At 6 weeks, there was a superior symptom reduction in the lurasidone group vs. the placebo group

Latuda®. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013. Lurasidone – Possible Side Effects

• Metabolic changes and weight gain – Possibly the most weight and metabolic neutral • EPS – akathisia more common than others • QTc prolongation • Sedation or somnolence • Nausea and vomiting • Rarer side effects – agranulocytosis, seizures, and orthostasis Latuda®. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013.

Lurasidone - Dosing

• For schizophrenia, starting dose is 40 mg/day with a range of 40-160 mg/day • For bipolar depression, starting dose is 20 mg/day with a range of 20-120 mg/day • All doses should be taken with a meal of at least 350 calories to improve absorption • Dosing is recommended in the evening due to the possibility of sedation and somnolence

Latuda®. Marlborough, MA; Sunovion Pharmaceuticals, Inc.; Revised July, 2013. Lurasidone – Role in Therapy

• Can be utilized in schizophrenia and bipolar depression • Has a very favorable long-term metabolic profile • Once daily dosing is most patient friendly • Appears to be the most rigorously studied of the newer agents Long Acting Injection Antipsychotics (LAIS) Rationale

• LAIs are options to improve compliance – Less frequent administration than oral agents – Doses converted from stable oral regimens – Guaranteed drug level in the body post-injection – Improved clinician contact Available Options

1st Generation 2nd Generation Haloperidol decanoate Risperdal Consta® Fluphenazine decanoate Xeplion® Trevicta® Zyprexa Relprevv® Abilify Maintena® Paliperidone – Xeplion® · Manufacturer: Janssen, LP

· Is the active metabolite of risperidone (9-hydroxy risperidone) and is excreted mainly in the kidneys with little hepatic metabolism

· Long-acting IM formulation approved in 2006 by FDA

· Invega Trinza® : a long-acting IM formulation to be administrated every 3 months, still under approval

Abilify Maintena®

• FDA approved in 2013 • Long acting intramuscular injection of intended for gluteal injection only • Indicated for the treatment of schizophrenia • Designed to be initiated after a stable regimen of aripiprazole is established

Abilify Maintena®. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013. Abilify Maintena® Dosing

• Recommended starting dose in 400 mg monthly • Continuation of oral aripiprazole 10-20 mg/day is necessary for 14 days after initial injection • Maintenance dose is also 400 mg monthly – Dose reduction to 300 mg can be used if 400 mg dose is intolerable

Abilify Maintena®. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013. Adverse Events

• Very similar to oral aripiprazole – Slight metabolic changes – Some EPS – mostly akathisia – Anxiety – Headache – Orthostasis

Abilify Maintena®. Tokyo, Japan; Otsuka Pharmaceutical Co. Ltd; Revised February, 2013.

Antipsychotics

The Forthcoming Arrives Medicines in Development

• Currently developing 119 medicines for mental health • Limits to drug research – Limited understanding of how current treatments work – Lack of biomarkers for diagnosis – Current diagnostic entities are not completely reliable – Complexity of mental disorders etiology – Lack of reliable animal models The Forthcoming Drugs for Schizophrenia Phase III

Name Sponsor Indication Development Phase for SCZ

Aripiprazole lauroxil Alkermes SCZ Phase III (ALKS 9072) www.alkermes.com Bitopertin Roche SCZ incomplete Phase III - Discontinued (GlyT1 inhibitor) response, OCD www.roche.com SCZ, Agitation in AD, Phase III (DA partial agonist) Otsuka Pharma ADHD, www.lundbeck.com Depression www.otsuka.com Forest Laboratories SCZ, BP, depression Phase III (D3>D2 partial agonist) www.allergan.com Encenicline Forum Pharma CIAS Phase III (alpha7 agonist) www.forumpharma.com RBP-7000 Reckitt Benckiser SCZ Phase III (Long acting risperidone) Pharma www.rb.com Zicronapine Lundbeck SCZ Phase III www.lundbeck.com

CIAS: Cognition impairment associated with schizophrenia The Forthcoming Drugs for Schizophrenia Phase II

Name Sponsor Indication Development Phase for SCZ MIN-101 Minerva SCZ Phase II (5-HT2A/sigma2 receptor Neurosciences www.minervaneurosciences.com antagonist) OMS824 Omeros SCZ Phase II (PDE10 inhibitor) www.omeros.com PF-02545920 Pfizer SCZ (adjunctive Phase II (PDE10 inhibitor) treatment) www.pfizer.com ACADIA Pharma. SCZ, psychosis in AD & Phase II PD www.acadia-pharm.com RP5063 Reviva Pharma. SCZ, SCZ-affective Phase II (DA and 5HT partial agonist) www.revivapharma.com Syntocinon nasal spray Retrophin SCZ, autism Phase II www.retrophin.com Conclusion

• New antipsychotics are available • In the future further new ones • A careful choice is necessary to improve patient wellbeing Any Questions?

Thank You For Your Attention