The Newest of the New Antipsychotic Medications; Just More of the Same?

Transcription

1 The Newest of the New Antipsychotic Medications; Just More of the Same? Del Miller, PharmD, MD October 07, 2016 Research Funding Del Miller Disclosures Otsuka Pharmaceutical and Vanguard Research Group (J. Kane, PI) Stocks none Speaking Honorarium or Consulting Fees none Bottom Line Our field can be encouraged by the developments in the psychopharmacology of schizophrenia While new antipsychotics are most often similar to other antipsychotics, they all have unique pharmacological properties Our patients can benefit from having a large selection of antipsychotic medicines to chose from Our ever expanding task is to find the most effective and tolerable medicine for given patients Page 1 1

2 Antipsychotic Therapy: Historical Perspective in the U.S.A. Reserpine FGAs Chlorpromazine Perphenazine Fluphenazine Thioridazine Haloperidol Clozapine Olanzapine Quetiapine Risperidone SGAs Pimavanersin Cariprazine Brexpiprazole Iloperidone Asenapine Ziprasidone Lurasidone Paliperidone Antipsychotic Therapy: Historical Perspective in the U.S.A. Clozapine Risperidone Olanzapine Quetiapine Risperidone LAI Ziprasidone Paliperidone Iloperidone Asenapine LAI Lurasidone Paliperidone LAI Lauroxil Brexpiprazole Cariprazine ITI-007 MIN-101 Pimavanersin ? Comparative Efficacy of Antipsychotics in Schizophrenia Multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of RTCs to compare 15 antipsychotics (12 available in US; 10 SGAs and 2 FGAs) and placebo in the acute treatment of schizophrenia They identified 212 RCTs with 43,049 participants Leucht S, et al. Lancet 2013; 382: Leucht S, et al. Focus XII 2014; 2: Page 2 2

3 Comparative Efficacy of Antipsychotics in Schizophrenia: Efficacy Clozapine > Olanzapine, Risperidone, Paliperidone, Haloperidol, Quetiapine,, Ziprasidone, Chlorpromazine, Asenapine, Lurasidone & Iloperidone Olanzapine = Risperidone = Paliperidone Olanzapine & Risperidone > Haloperidol, Quetiapine,, Ziprasidone, Chlorpromazine, Asenapine, Lurasidone & Iloperidone Paliperidone > Lurasidone & Iloperidone Haloperidol > Iloperidone Leucht S, et al. Lancet 2013; 382: Leucht S, et al. Focus XII 2014; 2: Comparative Adverse Effects of Antipsychotics in Schizophrenia Sedation (least most) Paliperidone, Iloperidone,, Lurasidone, Risperidone, Haloperidol, Asenapine, Olanzapine, Quetiapine, Ziprasidone, Chlorpromazine, Clozapine EPS (least most) Clozapine, Olanzapine, Quetiapine,, Iloperidone, Ziprasidone, Asenapine, Paliperidone, Risperidone, Lurasidone, Chlorpromazine, Haloperidol Leucht S, et al. Lancet 2013; 382: Leucht S, et al. Focus XII 2014; 2: Comparative Adverse Effects of Antipsychotics in Schizophrenia Weight Gain (least most) Haloperidol, Ziprasidone, Lurasidone,, Asenapine, Paliperidone, Risperidone, Quetiapine, Chlorpromazine, Iloperidone, Clozapine, Olanzapine QTc Prolongation (least most) Lurasidone,, Paliperidone, Haloperidol, Quetiapine, Olanzapine, Risperidone, Asenapine, Iloperidone, Ziprasidone Leucht S, et al. Lancet 2013; 382: Leucht S, et al. Focus XII 2014; 2: Page 3 3

4 FDA Indications LAI (Abilify Maintena) Lauroxil (Aristada) Brexpiprazole (Rexulti) Cariprazine (Vraylar) Acute SCZ SCZ Maintenance Pimavanserin (Nuplazid) Schizoaffective Disorder BP - Mania + BP - Maintenance BP - Depression BP- Child/Adolescence SCZ- Child/Adolescence BP - Child/Adolescence MDD (adjunctive) + Psychosis in PD + Dopamine (D) D 2 antagonist FGAs SGAs D 1 blockade SGAs D 2 partial agonist Brexpiprazole Cariprazine D 3 partial agonist Cariprazine (D3>D2) Brexpiprazole Antipsychotics Mechanism of Action Serotonin (HT) 5-HT 2A antagonist All SGAs 5-HT 2B antagonist Cariprazine 5-HT 1A agonist Brexpiprazole 5-HT 1A partial agonist Iloperidone Asenapine Cariprazine 5-HT 2A inverse agonist Pamavanserin LAI (Abilify Maintena) LAI is available in 300 mg & 400 mg strengths LAI s efficacy was documented in a 12-week DB trial (n = 340) and in 2 maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403) LAI was more effective than placebo, and non-inferior to oral, in delaying relapse and reducing relapse rates in schizophrenia It had a tolerability profile consistent with that of oral aripiprazole Treatment with oral antipsychotic is recommended for 14 days after the 1 st injection Potkin SG, Preda A, Expert Opin Pharmacother 2016; 17(3): Shirley M, Perry CM, Drugs 2014; 74(10): Page 4 4

5 LAI vs. Paliperidone Palmitate LAI 28-week, randomized, non-inferiority, open-label, rater-blinded study of LAI (AOM) and Paliperidone Palmitate (PP) in adults with schizophrenia There was a statistically significant difference in change from baseline to week 28 on QLS total score (p=0.036) confirming noninferiority and established superiority of AOM vs. PP There were also significant improvements in the CGI-S scale and the Investigator's Assessment Questionnaire for AOM vs. PP Common treatment-emergent adverse events were more frequent with PP vs. AOM, and adverse events were the most frequent reason for discontinuation, (19.7%) for PP and (11.1%) for AOM Naber D, et al., Schizophr Res 2015; 168(1-2): Lauroxil (Aristada) Lauroxil is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths Lauroxil 441 mg and 882 mg administered monthly demonstrated efficacy in an acute, DB, placebo-controlled, RCT Its pharmacokinetic profile of Lauroxil led to approval of dosing intervals of every 6 weeks for the 882 mg dose The tolerability profile is consistent with oral aripiprazole Treatment with oral aripiprazole is recommended for 21 days after the 1 st injection There is no available data comparing Lauroxil to other antipsychotics or LAI formulations Citrome L, Expert Rev Clin Pharmacol.2016; 9(2): Brexpiprazole (Rexulti) Two - 6-week, randomized controlled trials in acute schizophrenia demonstrated superiority of Brexpiprazole over placebo Pooled responder rates were 46% for Brexpiprazole 2-4 mg/d vs. 31% for placebo (NNT=7) The most commonly encountered adverse events ( 4% & 2X rate of placebo) was increased weight Short-term weight gain appears modest (~10% with Brexpiprazole 1-4 mg/d gained 7% vs. 4% for placebo (NNH=17) Effects on glucose and lipids were small. Rates of akathisia as an adverse event were 5.5% for Brexpiprazole 1-4 mg/day vs. 4.6% for placebo (NNH=112) Minimal effects on prolactin were observed McEvoy J & Citrome L, Clin Schizophr Relat Psychosis 2016; 9(4): Page 5 5

6 Brexpiprazole vs. 6-week, randomized, open-label, flexible-dose study of Brexpiprazole (3.58 mg/d) and (18.20 mg/d) in subjects with acutely exacerbated schizophrenia Subjects treated with brexpiprazole (n=64) or aripiprazole (n=33) showed significant reductions in PANSS total score ( 22.9 and 19.4, respectively) Changes in Impulsivity and Cogstate scores were not significantly different between Brexpiprazole & The incidence of akathisia was lower in patients treated with brexpiprazole (9.4%) than aripiprazole (21.2%) Citrome L, et a;., Int Clin Psychopharm 2016; 9(4): Cariprazine (Vraylar) Three - 6-week, Phase 2/3, randomized controlled trials in acute schizophrenia demonstrated superiority of Cariprazine over placebo Pooled responder rates were 31% for Cariprazine mg/d vs. 21% for placebo (NNT=10) The most commonly encountered adverse events ( 5% & 2X rate of placebo) are EPS (NNH=15 for Cariprazine mg/d and NNH=10 for mg/d vs. placebo) and akathisia (NNH=20 for mg/d and NNH=12 for mg/d vs. placebo) Short-term weight gain ( 7%) were small (~8% with cariprazine mg/d, compared with 5% for placebo, NNH=34) Cariprazine is associated with no clinically meaningful alterations in metabolic variables, prolactin, or the ECG QT interval Citrome L, Clin Schizophr Relat Psychosis 2016; 10(2): Cariprazine (Vraylar) A randomized, double-blind, placebo-controlled study evaluated the efficacy, safety, and tolerability of Cariprazine for relapse prevention in adults with schizophrenia Stable patients who completed open-label treatment with oral Cariprazine were randomized to continue Cariprazine (3, 6, or 9mg/d) or placebo for double-blind treatment (up to 72weeks) Time to relapse was significantly longer in Cariprazine vs. placebotreated patients (P=0.0010) Relapse occurred in 24.8% of Cariprazine and 47.5% of placebotreated patients (HR [95% CI]=0.45 [0.28, 0.73]) Long-term Cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia Durgam S, et al., Schizophr Res 2016; 176(2-3): Page 6 6

7 Pimavansersin (Nuplazid) Pimavanserin is the first FDA-approved medicine for the treatment of hallucinations and delusions associated with PD 6-week, DB, placebo-controlled study with adults (>40 years) with PD psychosis Pamavanserin associated with a change in SAPS-PD compared to with placebo (p=0.001; ES=0.5) onset after day 15 Pimavanserin was well tolerated with no worsening of motor function Most common adverse effects: UTIs (13% vs 12%), falls (11% vs 9%), edema (7% vs 3%), hallucinations (7% vs 4%), confusion (6% vs 3%) Pimavanserin had a mean increase of 7.3 ms in QTc interval (contraindicated in patients with known QT prolongation or in combination with other drugs known to prolong QT interval) Cumming J, et al., Lancet 2014; 383: Pimavansersin (Nuplazid) in Schizophrenia 6-week study, 423 patients were randomized to either haloperidol (2mg) + pimavanserin (17 mg), haloperidol (2 mg) + placebo, risperidone (2 mg) + pimavanserin (17 mg), risperidone (2 mg) + placebo, or risperidone (6 mg) + placebo Reductions in PANSS total with risperidone 2 mg + pimavanserin was significantly > risperidone 2 mg + placebo (p = 0.007), and not significantly different than with risperidone 6 mg + placebo 62.3% of the patients in the risperidone 2 mg + pimavanserin group had a 20% improvement at day 15, a significantly greater proportion than risperidone 6 mg + placebo (p = 0.01) and risperidone 2 mg + placebo groups (p = 0.002) Meltzer H, et al., Schizophr Res. 2012;141: ITI-007 ITI-007 has a unique pharmacological profile, combining potent 5- HT2a receptor antagonism, dopamine-d 2 post-synaptic antagonist and pre-synaptic partial agonist, increases phosphorylation of mesolimbic glutamatergic NMDA-NR2B receptors and inhibits the 5- HT transporter Two phase 3 trials with ITI-007 demonstrated antipsychotic efficacy superior to placebo in individuals with exacerbated schizophrenia ITI-007 was associated with minimal safety risk compared to placebo for EPS, prolactin changes, weight gain and metabolic abnormalities Lieberman JA, et al., Biol Psych. 2016; (79)12: : Page 7 7

8 Take Home Points With several exceptions 1 st line antipsychotics differ mainly in their side effect profiles and cost The newest antipsychotics have unique pharmacological properties and are effective in treating psychosis. It Is currently difficult to determine whether they have significant advantages (better efficacy or less adverse effects) over other antipsychotics Pimavanserin is effective in treating the psychosis in PD without worsening Parkinson s disease symptoms Clinicians and patients benefit from having a large selection of medicines to chose from Our ever expanding task is to find the most effective and tolerable medicine for given patients Page 8 8