Paliperidone: presente e futuro

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1 Paliperidone: presente e futuro
Dipartimento di Scienze mediche e Sanità Pubblica Università di Cagliari S.C. Clinica Psichiatrica AOU Cagliari Paliperidone: presente e futuro Bernardo Carpiniello

2 The problem of stable remission and non-adherence

3 Advantages of LAIs i. Non-adherence can be accurately measured by receiving injections at clinic visits ii. Eliminates the need for daily medication use iii. Drug concentrations can be maintained in a stable state; less fluctuations in troughs and peaks iv. Decrease risk of accidental or deliberate overdose v. Reduce hospitalizations and rate of relapse Heres, S. Lambert, M. Vauth, R. Treatment of early episode in patients with schizophrenia: the role of long acting antipsychotics. European Psychiatry. 2014; 29(S2): Jeong HG, Lee MS. Long-acting injectable antipsychotics in first-episode schizophrenia. Clinical Psychopharmacological and Neuroscience. 2013;11(1):1-6.

4 How does the Longer Administration Interval translate Clinically?
Slow release Longer half life Longer administration interval Due to their slow release from the administration site, LATs provide a longer duration of therapeutic drug plasma levels than oral antipsychotics Potentially reduce the risk of relapse of schizophrenia symptoms and potentially increase adherence LAT, long-acting antipsychotic therapy Kim et al. Poster presented at the 15th ICOSR; March 28 – April 1, 2015; Colorado Springs, CO, USA

5 Concentrazione plasmatica
Modifica del profilo PK/PD degli antipsicotici attraverso l’uso di tecnologie di somministrazione diverse Antipsicotici atipici orali a rilascio immediato Antipsicotici atipici orali a rilascio prolungato Antipsicotici atipici iniettabili a lunga durata Concentrazione plasmatica Tempo Adattata da Keith et al. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:996–1008 PK, farmacocinetica; PD, farmacodinamica

6 Limitations of LAIs i. Delayed disappearance of medication-related side effects ii. Limited number of medications available in LAI form iii. Not easy to adjust small doses iv. Stigmatism towards injectable medications and patients feeling of being controlled v. Negative attitudes of clinicians based on presumptions that patients would not accept treatment with LAIs vi. May cause pain and discomfort at the injection site Stevens GL, Dawson G, Zummo J. Clinical benefits and impact of early use of long-acting injectable antipsychotics for schizophrenia. Early Intervention in Psychiatry. 2015;1-13.

7 The challenge of offering long-acting antipsychotic therapies: a preliminary discourse analysis of psychiatrist recommendations for injectable therapy to patients with schizophrenia. Weiden PJ1, Roma RS, Velligan DI, Alphs L, DiChiara M, Davidson B. J Clin Psychiatry Jun;76(6): METHOD: This was an observational study conducted at 10 community mental health centers in 3 waves from July 2010 to May The final dataset for discourse analysis was 33 recorded conversations in which a psychiatrist offered an injectable antipsychotic to a patient with schizophrenia. These visits were transcribed and analyzed by a team of linguists and social scientists. RESULTS: Our primary finding is that, based on analyses of their language during the interview, psychiatrists presented LAI therapy in a negative light. Supporting this, 11 of 33 recommendations (33%) were accepted during the discussion, whereas in the postvisit interview, 27 of 28 patients (96%) who seemed to decline the initial recommendation said they actually would be willing to try LAI treatment. These data support a preliminary hypothesis that the relatively low use of injectable antipsychotic therapies in the United States relative to other parts of the world is not fully attributable to patient rejection of the injectable modality. Rather, psychiatrists' ambivalence regarding the value of LAIs may play a significant role in the perceived difficulty with patient acceptance of this recommendation

8 Do LAIs are an example of coercive nature of psychiatry?
…..with regard to the hypothesized coercive nature of LAI, it should be underlined how, as a general ethical principle, all treatment should be given on a voluntary basis, with the sole exception of involuntary treatments provided and regulated by law throughout the majority of countries; the creation of a valid therapeutic alliance, the acquisition of informed consent, and of adequate adherence to treatment is one of the fundamental duties of psychiatrists, and forms the basis of an effective treatment. In our opinion, it is not the drug that is coercive per se, but rather the means adopted in fulfilling a duty of care. Carpiniello B,Pinna F ,Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia, Drug Des Devel Ther May 24;10:

9 Do LAIs diminish intensity of clinical care?
….Regarding the second point, to what extent the use of LAI actually results in a diminishing of clinical care of the patient is a matter of debate, particularly in view of a lack of reliable data. It would however seem to be an inherent problem in the professional and educational setting, work ethics, and staff resources of community teams rather than an intrinsic problem linked to LAI therapy….. Carpiniello B,Pinna F ,Critical appraisal of 3-monthly paliperidone depot injections in the treatment of schizophrenia, Drug Des Devel Ther May 24;10:

10 Source Reccomendations APA1 NICE2 an acute episode WFSBP3
Patients with recurrent relapses related to non-adherence are candidates for LAIs For patients who prefer this mode of administration NICE2 Consider offering to patients who would prefer such treatment after an acute episode • Offer to patients, where avoiding covert non-adherence to antipsychotics is a clinical priority within the treatment plan WFSBP3 Part 1: Acute treatment of schizophrenia: Depot antipsychotics can be considered if there has been poor adherence, but clozapine may also be preferable because the improving psychopathology and the required monitoring often enhances adherence. Part 2: Long term treatment of schizophrenia: Depot Preparation should be the application method of choice when a patient expresses preference for such treatment because of its convenience or as a part of treatment plan in which the avoidance of covert non-adherence is a clinical priority LAI, long-acting injectable; APA, American Psychiatric Association; NICE, National Institute for Health and Clinical Excellence; WFSBP, World Federation of Societies of Biological Psychiatry 1. APA Practice Guidelines, 2004, 2nd edition; 2. NICE Schizophrenia full guidelines CG82 (update), September 2010, 3. Hasan eta al WFSBP The World Journal of Biological Psychiatry, 2012; 13: 318–378; The World Journal of Biological Psychiatry, 2013; 14: 2–44

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12 Br J Psychiatry, 2009

13 Evoluzione delle terapie antipsicotiche Long-acting (LAI)
1960 1960s 1970s 1980s 2003 2010 2014 Flufenazina Enantato Risperidone a Rilascio Prolulgato Flufenazina Decanoato Olanzapina Pamoato Paliperidone Palmitato Aloperidolo Decanoato Zuclopentixolo Decanoato e Acetato Flupentixolo decanoato Perfenazina Enantato e decanoato Aripiprazolo ER sospensione iniettabile

14 Paliperidone palmitato
Principio attivo Nome commerciale Indicazioni approvate Risperidone RISPERDAL RP® RISPERDAL iniettabile è indicato per la terapia di mantenimento della schizofrenia in pazienti attualmente stabilizzati con antipsicotici orali. Olanzapina pamoato ZYPADHERA® Trattamento di mantenimento dei pazienti adulti con schizofrenia sufficientemente stabilizzati durante un trattamento acuto con olanzapina orale Paliperidone palmitato XEPLION® XEPLION è indicato per la terapia di mantenimento della schizofrenia in pazienti adulti stabilizzati con paliperidone o risperidone. In pazienti adulti selezionati con schizofrenia e che abbiano precedentemente risposto a paliperidone o risperidone orale, è possibile usare XEPLION senza una precedente stabilizzazione con trattamento orale se i sintomi psicotici sono da lievi a moderati e se è necessario un trattamento iniettabile ad azione prolungata Aripripazolo Abilify Maintena® Abilify Maintena è indicato per il trattamento di mantenimento della schizofrenia in pazienti adulti stabilizzati con aripiprazolo orale

15 Paliperidone: la molecola
Prevalentemente escreto per via renale Circa l’80% recuperato nelle urine1 Non metabolizzato in modo significativo nel fegato 59% escreto immodificato nelle urine1,2 Non si presume abbia interazioni clinicamente significative con altri farmaci metabolizzati dal sistema CYP450 Simile profilo farmacocinetico in metabolizzatori lenti o veloci CYP2D6 1 Nessun aggiustamento di dosaggio è necessario per pazienti con compromissione epatica lieve-moderata e nei fumatori1 Original notes CYP, citocromo P450 1. Invega® (paliperidone ER) prolonged-release tablets SmPC; 2. Vermeir et al. Drug Metab Dispos 2008;36:769–779

16 Paliperidone palmitato: la tecnologia1
Paliperidone palmitato è l’estere palmitico del paliperidone L’estere palmitico del paliperidone è praticamente insolubile Paliperidone palmitato utilizza la tecnologia Nanocrystal® brevettata da Elan Pharma International Limited2 per creare una sospensione acquosa per la somministrazione IM 2,3 Dopo somministrazione IM, il paliperidone palmitato si scioglie lentamente al sito di iniezione e viene idrolizzato enzimaticamente a paliperidone3 Paliperidone palmitato: un estere praticamente insolubile4 O N F CH3 1. Xeplion® EU SmPC, March 2011; technology; accessed 18 June 2010; 3. Citrome. Int J Clin Pract 2010;64:216–239; 4. Gopal et al. Curr Med Res Opin 2010;26:377–387 IM, intramuscolare 16

17 Paliperidone palmitato
Risperidone a rilascio prolungato Olanzapine Pamoato Aripiprazolo a rilascio prolungato Formulazione Sospensione a base acquosa Sospensione di microsfere a base acquosa Sospensione a base acquosa Inizio del trattamento Iniezioni iniziali al giorno 1 e giorno 8. Non è necessaria supplementazione orale E’ richiesto un periodo di 3 settimane di sovrapposizione con antipsicotico orale Diverse strategie per la dose di carico E’ richiesto un periodo di 14 giorni consecutivi di sovrapposizione con aripiprazolo orale Terapia di mantenimento Iniezioni mensili Ogni 2 settimane Ogni 2 o 4 settimane Somministrazione Iniezioni intramuscolari (IM) nel muscolo deltoide e gluteo IM deltoide e gluteo IM gluteo Intervallo di dosi 50, 75, 100 e 150 mg eq. 25, 37.5 e 50 mg 210, 300 e 405 mg 400 mg (300 mg in caso di reazioni avverse) Come viene fornito Siringhe pre-riempite Non è necessaria la ricostituzione (volume da 0.5 a 1.5 ml) E’ necessaria la ricostituzione; tutti i dosaggi sono in un volume di 2 ml E’ necessaria la ricostituzione (volumi variabili da ml)) E’ necessaria la ricostituzione: (volume da 1.5 a 2 ml) Conservazione Non è necessaria la refrigerazione E’ necessaria la refrigerazione Ago in dotazione o raccomandato Ago 23G da 1 pollice (25mm) o ago 22G da 1 pollice e ½ (38mm) (a seconda del peso del paziente e del sito di iniezione) Ago 21G UTW da1 pollice (25mm) oppure ago 20G TW da 2 pollici (50mm) (a seconda del sito di iniezione) 1½ pollice (38 or 50 mm) 19G Ago 21G da 1.5 pollice (38 mm) Ago 21G da 2 pollici (50 mm) Monitoraggio post-iniezione • No • Si (3 ore)

18 XEPLION® presenta alcuni aspetti differenzianti rispetto agli altri antipsicotici atipici long-acting: Rapidità dell’effetto terapeutico; la formulazione di XEPLION® consente il rilascio di paliperidone sin dal 1° giorno e il raggiungimento di concentrazioni terapeutiche entro la prima settimana. Non richiede supplementazione con antipsicotico orale (richiesta per RRP nelle prime 3 settimane di latenza dopo la 1a iniezione e ad ogni successivo cambio di dose). Ha un limitato potenziale di interazione farmacologica: grazie allo scarso metabolismo epatico, le sue concentrazioni non sono modificate da induttori o inibitori del citocromo P450 né risentono di variazioni legate ai metabolizzatori estensivi e scarsi di substrati del CYP2D6. COSA CARATTERIZZA PALIPERIDONE PALMITATO RISPETTO AD ALTRI LAI

19 Non richiede un periodo di osservazione a scopo precauzionale dopo l’iniezione.
E’ somministrato una volta al mese, sia nel muscolo deltoide sia nel gluteo (RRP necessita di somministrazioni bisettimanali). Si presenta in siringhe pre-riempite, pronte all’uso, in un’ampia gamma di dosi (RRP necessita di ricostituzione). Non richiede refrigerazione (RRP deve essere conservato in frigorifero tra 2-8°C). Il volume di iniezione è esiguo e si somministra con un ago di piccolo diametro (RRP ha la necessità di misure di aghi maggiori).

20 Paliperidone Palmitate 1 M Overview
Bernardo M, Bioque M, Exp Rev Clin Pharmacol, 2016

21 Antipsicotici Long Acting di seconda generazione Perché nuove formulazioni?
Semplificazione dello schema di somministrazione Possibilità d’uso in pazienti non complianti Migliorare l’aderenza al trattamento Rapido raggiungimento di concentrazioni efficaci (in acuto) Concentrazioni plasmatiche di equilibrio meno soggette a fluttuazioni (in cronico) Migliorare il profilo farmacocinetico

22 3-Monthly Paliperidone Palmitate Formulation (PP3M)
Approved in the US (FDA, 2015; Invega Trinza®) and in the EU (EMA, 2016; Trevicta®) Similar aqueous based particle technology used in the 1-monthly formulation Administered once every 3 months PP3M is a palmitate ester of paliperidone which can be administered intramuscularly once every three months. It is the same active substance as paliperidone palmitate once monthly (PP1M), using the same technology, but in a different concentration and with a different particle size thereby allowing administration once every three months. PP3M is intended to be used in patients who have already demonstrated clinical stability and an ability to tolerate PP1M preferably over a treatment period of at least 4 months at the time of initiation of PP3M. Accordingly, the Phase III clinical program was designed so that patients were first treated with PP1M prior to conversion to PP3M Rate of absorption dependent on:1 Volume Suspension strength Particle size 1. Hirano et al. Chem Pharm Bull 1981;29:817–827

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24 PP3M Pharmacokinetics vs PP1M
Simulated paliperidone plasma concentrations for PP1M and PP3M 100 PP3M, administered at doses 3.5-fold higher than PP1M, results in similar paliperidone exposure over 3 months as 3 consecutive administrations of PP1M 10 Concentration (ng/mL) 1 90% PI: PP1M 150/100 mg eq day 1/8, PP1M 75 mg eq wk 5-65 90% PI: PP1M 150/100 mg eq day 1/8, PP1M 75 mg eq wk 5-17, PP3M 263 mg eq wk 17-65 Median: PP1M 150/100 mg eq day 1/8, PP1M 75 mg eq wk 5-65 Median: PP1M 150/100 mg eq day 1/8, PP1M 75 mg eq wk 5-17, PP3M 263 mg eq wk 17-65 0.1 5 9 13 17 29 41 53 65 PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate three-monthly Time (weeks) Gopal et al. Curr Med Res Opin 2015;31:2043–2054

25 PP3M: Studies Included in the Regulatory Extension Application
Clinical development of PP3M began in The EU Extension application includes two Phase 3 studies in adults with schizophrenia (PSY-3012 and PSY-3011): PSY-3012: a multinational, randomised, double blind, placebo-controlled, relapse prevention study to establish the efficacy and safety of PP3M over a variable length period in subjects with schizophrenia after initiation of treatment with PP1M/PP3M over a period of 29 weeks (Berwaerts et al, 2015; NCT ) PSY-3011: a multinational, randomised, double-blind, active controlled non-inferiority study to compare PP3M with the PP1M over a period of 48 weeks in subjects with schizophrenia after initiation of treatment with PP1M over a period of 4 months (Savitz et al, 2016; NCT )

26 PSY-3012: Study Objectives
Primary: - To evaluate the efficacy and safety of PP3M vs. placebo in Schizophrenic patients delaying time to relapse of schizophrenia Secondary Assessments: Improvement in the symptoms of schizophrenia (PANSS) Change in the severity of illness (CGI-S) Change in functional status (PSP) Safety and tolerability of PP3M PK of PP3M, including its relationship with demographic and dose-related variables PANSS= Positive and Negative Sindrome Scale CGI-S= Clinical Global Impression – Severity PSP= Personal and Social Performance Scale JAMA Psychiatry. doi: /jamapsychiatry Published online March 29, 2015.

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28 PSY-3012: Study Design A Randomized, Multicenter, Double-Blind, Relapse Prevention Study of PP3M for the Treatment of Subjects with Schizophrenia PP3M mg eq. Fixed dose PP1M Flex dose mg Eq. PP3M Fixed dose mg Eq. Screening Period Placebo 17 weeks Transition Phase 12 weeks Maintenance Phase 3 weeks Variable Lenght DB Maintenance Phase JAMA Psychiatry. doi: /jamapsychiatry Published online March 29, 2015.

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30 Interim Analysis Results
The interim analysis revealed a significant difference between the 2 treatment groups for time to relapse of schizophrenia symptoms, in favor of 3-month paliperidone palmitate: Hazard Ratio = 3.45; 95% CI, ;P < .001 Median Time to Relapse = 274 days for the placebo group (not estimable for the group receiving PP3M) Based on the interim analysis, 31 patients (23%) in the placebo group and 11 patients (7%) in the group receiving PP3M experienced a relapse event during the DB phase Consequently, the independent data monitoring committee recommended early study termination for efficacy Berwaerts et al. JAMA Psychiatry 2015;72:830–839

31 PSY-3012: Time to Relapse during DB phase (Interim Analysis)
Kaplan-Meier Plot A significant difference for time to relapse of schizophrenia symptoms in favor of PP3M was observed (HR = 3.45; 95%CI, ; p< .001) The median time to relapse was 274 days for placebo and was not estimable for PP3M Final analysis confirmed PP3M’s superiority over placebo for delaying time-to-relapse of schizophrenia symptoms (P < ; hazard ratio (Placebo vs. PP3M, 3.81; 95% CI, 2.08 to 6.99). Median time-to-relapse: 395 days, placebo group; not estimable, PP3M group. Number of Patients left Time PP3M Placebo JAMA Psychiatry. doi: /jamapsychiatry Published online March 29, 2015.

32 PSY-3012: Time-to-Relapse during Double-Blind Phase (final analysis)
Final analysis confirmed PP3M’s superiority over placebo for delaying time-to-relapse of schizophrenia symptoms (P < ; hazard ratio (Placebo vs. PP3M, 3.81; 95% CI, 2.08 to 6.99). Median time-to-relapse: 395 days, placebo group; not estimable, PP3M group. A total of 42 patients (29%) in the placebo group and 14 patients (9%) in the group receiving PP3M experienced a relapse event Final analysis results were consistent with that of interim analysis, confirming superiority of PP3M over placebo for delaying time to relapse; the median time to relapse was 395 days for placebo group but was not estimable for PP3M PP3M, paliperidone palmitate three-monthly Berwaerts et al. JAMA Psychiatry 2015;72:830–839

33 Abbreviations: EPS, extrapyramidal symptom; TEAEs, treatment-emergent
adverse events. a The TEAEs reported herein occurred during the double-blind phase; if a patient developed a TEAE during the open-label phase (either transition or maintenance) and the TEAE did not worsen during the double-blind phase, it would not be captured. b Sample size was 42 women. Berwaerts et al. JAMA Psychiatry 2015;72:830–839

34 Abbreviations: EPS, extrapyramidal symptom; TEAEs, treatment-emergent
adverse events. a The TEAEs reported herein occurred during the double-blind phase; if a patient developed a TEAE during the open-label phase (either transition or maintenance) and the TEAE did not worsen during the double-blind phase, it would not be captured. b Sample size was 42 women. Berwaerts et al. JAMA Psychiatry 2015;72:830–839

35 PSY-3011: Study Objectives
Primary efficacy: Percentage of patients who remained relapse-free (based on the Kaplan-Meier cumulative estimate of survival) at the end of the 48-week DB phase1 Secondary Assessments2: Changes in PANSS total score , PANSS subscale and Marder factor scores Clinical Global Impression-Severity (CGI-S) score Personal and Social Performance (PSP) scores Clinical response3 Symptomatic remission4 1 Non-inferiority was concluded if the lower limit of the 2-sided 95% confidence interval of the difference in relapse-free rates exceeded -15%) 2 From DB baseline to DB endpoint / 3 ≥ 20% reduction in PANSS total scores 4 Defined as meeting the Andreasen remission criteria during the 6 months before the end of DB phase, with one excursion allowed Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

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37 PSY-3011: Study Design A Randomised, Multicenter, Double-Blind, Active Controlled Non-Inferiority Study to Compare PP3M with the PP1M in Subjects with Schizophrenia Double-blind Phase: PP3M fixed dose mg Eq. Open-label phase PP1M flex doses: mg Eq. Screening Phase Follow-up Phase Double-blind Phase: PP1M fixed dose mg Eq. 17 weeks Open-label Phase 48 weeks Double-blind Phase 4 or 12 weeks Follow-up Phase 3 weeks Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

38 PSY-3011: Time-to-Relapse during Double-Blind Phase
A similar percentage of patients in both groups (PP3M: n=37 [8%]; PP1M: n=45 [9%]) experienced a relapse event; the lower limit of the 95% CI was larger than the pre-specified non-inferiority margin so not-inferiority was established CI, confidence interval; PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate three-monthly Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

39 Results A similar percentage of patients in both groups (PP3M: n = 37 [8%]; PP1M: n = 45 [9%]) experienced a relapse event during the DB phase (PP analysis set) The lower bound of the 95% CI (-2.7%, 5.1%) between the treatment groups (PP3M-PP1M) in the percentages of patients who remained relapse free was larger than the prespecified non inferiority margin of -15% PP3M can be declared noninferior to PP1M More than 50% of patients in both groups showed symptomatic remission for the last 6 months of the DB phase (PP3M: 58%; PP1M: 59%). Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

40 PSY-3011: Summary of 10 Most Frequent TEAEs (≥2%)
ITT (OL) Safety OL PP1M PP3M PP1M (N=1429) (N=504) (N=512) n (%) Most common TEAEs Weight increased 64 (4) 105 (21) 109 (21) Nasopharyngitis 66 (5) 36 (7) 33 (6) Anxiety 83 (6) 27 (5) 24 (5) Headache 46 (3) 18 (4) 26 (5) Insomnia 96 (7) 16 (3) Akathisia 82 (6) 20 (4) 14 (3) Schizophrenia 41 (3) Weight decreased 10 (1) Injection site pain 127 (9) 12 (2) Somnolence 29 (2) 5 (1) During the OL phase, 59% of patients experienced TEAEs, 7% of patients experienced ≥1 serious TEAEs, and 4% of patients had TEAEs leading to study drug discontinuation. During the DB phase, a similar percentage of patients in the PP3M and PP1M groups experienced TEAEs (68% vs 66%). Overall, 5% patients in the PP3M group and 7% of patients in the PP1M group experienced serious TEAEs. 3% of patients in each group reported TEAEs leading to discontinuation of study drug in the DB phase (most commonly related to worsening of the psychiatric symptoms) ITT, intent-to-treat; OL, open label; PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate three-monthly; TEAE, treatment-emergent adverse event Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

41 Summary of Treatment Emergent Adverse Events during the Study1: TEAE related to EPS
1 ITT [OL] Analysis Set and Safety Analysis Set) Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

42 Summary of Treatment Emergent Adverse Events during DB Phase1: Body Weight
Overall, 136 (27%) patients in the PP3M group and 150 (30%) in the PP1M group had ≥7% increase in their body weight from OL baseline to DB endpoint 1 ITT [OL] Analysis Set and Safety Analysis Set) Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

43 Safety during the study: Prolactin
Prolactin-related TEAEs, incidence: low in both the groups Serum Prolactin Levels, mean change (SD) from OL baseline to OL endpoint: Men, 7.65 (16.717) μg/L Women, (55.208) μg/L from DB baseline to DB endpoint in the PP3M group : - Men, (10.351) μg/L Women, (33.307) μg/L from DB baseline to DB endpoint in the PP1M group: - Men, 0.45 (8.943) μg/L for men Women, 0.69 (27.983) μg/L Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

44 Median Prolactin Level over Time1
1 intent to treat [ITT] open label [OL] analysis set and safety analysis set). Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

45 Median Prolactin Level over Time1
1 intent to treat [ITT] open label [OL] analysis set and safety analysis set). Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

46 Treatment-emergent Potentially Prolactin-related Adverse Events1
1 During OL and DB phases (ITT [OL] Analysis Set and Safety Analysis Set) Abbreviations: DB, double-blind; OL, open-label; PP1M, paliperidone palmitate1-month formulation; PP3M, paliperidone palmitate 3-month formulation. Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

47 QT Values during the DB phase
One patient in the PP1M group (and none in the PP3M group) had a shift from a normal average predose value to maximum corrected QT interval value of ≥500 milliseconds (based on QTcB, QTcF, QTLc, and QTcLD during the DB phase) Based on QTcLD, 10% of patients in the PP3M group and 6% of patients in the PP1M group had a maximum increase of >30 to 60 milliseconds from the average predose value, and 1 patient each in the PP3M and PP1M groups had a maximum increase of >60 milliseconds from the average predose value Adam J. Savitz et al. - International Journal of Neuropsychopharmacology, 2016, 1–14

48 Summary PP3M is effective at preventing relapse and maintains improvements in symptoms and patient functioning1,2 PP3M was more than three times more effective at preventing relapse vs placebo (23% vs 7%) in a long-term maintenance trial1 PP3M is at least as effective at preventing relapse as PP1M2 The safety and tolerability profile of PP3M is consistent with that of other paliperidone formulations1,2 PP3M was not associated with any new or unexpected adverse events1–3 PP3M significantly delayed median time to relapse in patients who discontinue medication compared with those who discontinue other formulations of paliperidone PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate three-monthly 1. Berwaerts et al. JAMA Psychiatry 2015;72:830–839; 2. Savitz et al. Int J Neuropsychopharmacol Epub ahead of print; 3. Ravenstijn et al. J Clin Pharmacol 2016:56:330–339

49 The 3-monthly injection is expected to be more convenient to patients and improve their adherence to treatment, and no new safety concerns were raised with this formulation compared with the known safety profile of paliperidone European Public Assessment Report Utile, comodo… EMA/278749/2016 EPAR summary for the public

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52 Open-label transition phase
Time-to-Relapse in Studies of 3 Different Administration Forms of Paliperidone Three similarly designed, randomized, double-blind, placebo-controlled, relapse-prevention studies1–3 of oral paliperidone ER, PP1M, and PP3M were conducted over 10 years Active drug Open-label transition phase Placebo Double-blind phase In each trial, subjects were stabilized during an open-label (OL) phase and randomly assigned to either continue active drug or switch to placebo during a double-blind (DB) relapse-prevention phase Each study’s primary efficacy end point was time to relapse of schizophrenia symptoms during the double-blind phase ER, extended-release; PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate 3-monthly Kramer et al. J Clin Psychopharmacol 2007;27:6–14; 2. Hough et al. Schizophr Res 2010;116:107–117; 3. Berwaerts et al. JAMA Psychiatry 2015;72:830–839

53 Median Time-to-Relapse: oral Paliperidone ER vs Placebo
Placebo (N=101) Pali ER (N=104) Log-rank test, P value <0.0001 100 + + 90 80 70 60 Percentage of subjects without relapse 50 40 30 20 10 58 days 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Days since randomization ER, extended-release Kramer et al. J Clin Psychopharmacol 2007;27:6–14; Kim et al. Poster presented at the 15th ICOSR; March 28 – April 1, 2015; Colorado Springs, CO, USA

54 Median Time-to-Relapse: PP3M vs Placebo
Placebo (N=145) PP3M (N=160) Log-rank test, P value <0.0001 100 + + 90 80 70 60 Percentage of subjects without relapse 50 40 30 20 10 395 days 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 PP3M, paliperidone palmitate three-monthly Days since randomization Berwaerts et al. JAMA Psychiatry 2015;72:830–839; Kim et al. Poster presented at the 15th ICOSR; March 28 – April 1, 2015; Colorado Springs, CO, USA

55 Median Time-to-Relapse: PP1M vs Placebo
Placebo (N=203) PP1M (N=205) Log-rank test, P value <0.0001 100 + + 90 80 70 60 Percentage of subjects without relapse 50 40 30 20 10 172 days 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Days since randomization PP1M, paliperidone palmitate once-monthly Hough et al. Schizophr Res 2010;116:107–117; Kim et al. Poster presented at the 15th ICOSR; March 28 – April 1, 2015; Colorado Springs, CO, USA

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57 PP3M doses for Patients adequately Treated with PP1M
If the last PP1M dose was: Initiate pp3m at the following dose: VOLUME OF PP3M ADMINISTRATION 50 mg eq 175 mg eq 0.875 mL 75 mg eq 263 mg eq 1.315 mL 100 mg eq 350 mg eq 1.750 mL 150 mg eq 525 mg eq 2.625 mL TREVICTA EU SmPC -4.2 Posology and method of administration The dose of PP3M should be based on the previous PP1M dose using a 3.5-fold higher dose *25mg eq. dose of PP1M is not commercially available in all countries; there is no PP3M dose equivalent to the PP1M 25mg eq. dose. PP1M, paliperidone palmitate once-monthly; PP3M, paliperidone palmitate three-monthly Srihari Gopal et al Current Medical Research & Opinion

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65 Sospensione degli antipsicotici orali quando si inizia il paliperidone palmitato

66 Linee Guida NICE: From evidence to recommendations
“…considerare l’uso di formulazioni iniettabili a rilascio prolungato nel caso di preferenza del paziente o quando evitare la non aderenza al trattamento diventa priorità clinica...” “L’efficienza di un antipsicotico nel prevenire le ricadute è un fattore determinante nell’ambito del rapporto costo-efficacia, in quanto (…) la prevenzione delle recidive, oltre al miglioramento clinico, porta a una riduzione sostanziale delle percentuali di ospedalizzazione e dei rispettivi costi...”. (linee guida NICE, 2010 Website NICE:

67 Un impiego iniziale dei LAI di seconda generazione può ridurre significativamente il rischio di ricadute e migliorare così non solo il potenziale sociale e lavorativo dei pazienti, ma anche la loro Qualità di Vita

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