LongActing Injectables 50 years of thinking ahead for

Long-Acting Injectables 50 years of thinking ahead for the treatment of psychosis Jeroen Wyckmans, MD 07 February 2019 | Janssen Benelux Melinda, Tree of Life Melinda’s artwork reflects her journey living with HIV.

Introduction § Name: Jeroen Wyckmans, MD § Medical Science Liaison – Neuroscience 2

Content table § § Introduction to schizophrenia Difficulties in treating LAIs: history and usage LAIs vs oral medication 3

Schizophrenia Me, myself and I: the voices in my head

Schizophrenia § Prevalence ~ 1% – EU: 2. 5 – 5 million patients – BE: 50. 000 – 100. 000 patients § Incidence ~ 1. 5 per 10. 000 people § Age of onset ~ adolescence © Janssen-Cilag NV - 2019 – Men: 18 – 25 y – Women: 25 – 35 y – Mostly after many years of prodromal symptoms in adolescence 5

Schizophrenia: the Dopamine theory 2 3 1 D 2 -activity Figure adapted from Stahl S. Essential Psychopharmacology, 2011. © Janssen-Cilag NV - 2019 4 1) Mesolimbic 2) Nigrostrial 3) Mesocortical 4) Tubero-infundibular 6

Schizophrenia: signs and symptoms Symptoms: • Abnormal thinking 1 Symptoms • Perceptual disturbances 1 • Reduced interest in day-to-day activities 2 Recurrence of symptoms/ relapse Homelessness • Poor quality of life 3 Burdens of schizophrenia Discrimination and stigmatisation • Drug/alcohol/nicotine abuse Reduced life expectancy Unemployment • Prejudice/discrimination 3 • Homelessness 3 • Difficulty with personal relationships 3 • Hepatitis and HIV Psychiatric comorbidities include: 3 • Unemployment 3 • • Respiratory problems • Depression © Janssen-Cilag NV - 2019 Quality of care • Social isolation/difficulty integrating into society 3 Stigma 3 • Cardiovascular disease • Metabolic disease • Fear 3 Patient’s experience: Physical comorbidities include: 5 • Suicide Comorbidities Substance abuse • Financial challenges 4 HIV, human immunodeficiency virus. 1. Fleischhacker WW et al. Schizophr Bull 2014; 40: 1385– 1403. 2. National Institute for Health and Clinical Excellence Psychosis and schizophrenia in adults: prevention and management (CG 178). NICE 2014. 3. Millier A et al. J Psych Res 2014; 54: 85– 93. 4. Tajima-Pozo K et al. F 1000 Res 2015; 182: 4– 11. 5. Bitter I et al. Eur Psychiatry 2017; 45: 97– 103. 7

Schizophrenia: more than psychosis alone § Impairments in social and occupational functioning 1 – Most disabling and economically catastrophic medical disorders © Janssen-Cilag NV - 2019 § Top 10 illnesses contributing to the global burden of disease 1 Murray, C. J. , & Lopez, A. D. (1996). Evidence-based health policy--lessons from the Global Burden of Disease Study. Science, 274(5288), 740 -743. 9

Schizophrenia: more than psychosis alone § Risk for suicide 1, 2: SUICIDE ATTEMPT 10 to 13% 20 to 50% of patients § Decrease in life expectancy 3: 9. 6 year General (n=22 studies) Natural causes (n=8 studies) © Janssen-Cilag NV - 2019 10. 1 year 21. 6 year Unnatural causes (n=4 studies) 1 Stahl, S. M. (2013). Stahl's essential psychopharmacology : neuroscientific basis and practical application (4 th ed. ). Cambridge ; New York: Cambridge University Press. 2 Besnier, N. , Gavaudan, G. , Navez, A. , Adida, M. , Jollant, F. , Courtet, P. , & Lancon, C. (2009). [Clinical features of suicide occurring in schizophrenia (I). Risk-factors identification]. Encephale, 35(2), 176 -181. doi: 10. 1016/j. encep. 2008. 02. 009 3 Walker, E. R. , Mc. Gee, R. E. , & Druss, B. G. (2015). Mortality in mental disorders and global disease burden implications: a systematic review and meta-analysis. JAMA Psychiatry, 72(4), 334 -341. doi: 10. 1001/jamapsychiatry. 2014. 2502 10

Schizophrenia: a progressive disease that worsens as repeated relapses occur 1– 5 Schizophrenia disease progression 6 Prodromal phase Psychotic phase Stable phase Healthy Level of functioning Initial response Worsening severity of signs and symptoms Without schizophrenia Decreasing response Chronic relapsing/residual symptoms First episode With schizophrenia First relapse Second relapse Treatment resistance Third relapse © Janssen-Cilag NV - 2019 Premorbid phase Timeline The natural course of schizophrenia can be modified by introducing effective treatments early in the course of the disease, and thereby help to avoid the progressive decline associated with relapses 7 Figure adapted from Nasrallah & Smeltzer 2011. 1. Tandon R et al. Schizophr Res 2009; 110(1– 3): 1– 23; 2. Cahn W et al. Eur Neuropsychopharmacol 2009; 19: 147– 151; 3. Sullivan EV et al. Biol Psychiatry 1996; 39: 234– 240; 4. Crespo-Facorro B et al. Int Rev Psychiatry 2007; 19: 325– 336; 5. Emsley R et al. Schizophr Res 2013; 148(1– 3): 117– 121; 6. Nasrallah HA & Smeltzer DJ. Contemporary diagnosis and management of the patient with schizophrenia, 2 nd edn. Newtown, PA: Handbooks in Health Care Co, 2011; 7. Stahl SM. CNS Spectr 2014; 19: 3– 5. 11

I’m not crazy… © Janssen-Cilag NV - 2019 I don’t need medication!

Lack of patient insight: 1– 7 A core symptom of schizophrenia • Highly prevalent: 50– 98% Predicts treatment nonadherence Impacts outcomes • Increases refusal/negative attitude vs medication • Linked with poor functioning, higher chance of relapses and hospitalisation DUP, duration of untreated psychosis. 1. DSM-V, Diagnostic and Statistical Manual of Mental Disorders. Fifth edition. American Psychiatric Association 2013. 2. Ouzir M, et al. Psychiatry Clin Neurosci 2012; 66: 167– 179. 3. Hamann J, Heres S. Psychiatr Serv 2014; 65: 1483– 1486. 4. Amador X. I am not sick, I don’t need help. Tenth edition. Vida Press. 2011. 5. Lysaker PH et al. World Psychiatry 2018; 17: 12– 23. 6. Lehrer DS et al. Innov Clin Neurosci 2014; 11(5– 6): 10– 17. 7. Misdrahi D et al. Nord J Psychiatry 2012; 66(1): 49– 54. © Janssen-Cilag NV - 2019 “A majority of individuals with schizophrenia have poor insight regarding the fact that they have a psychotic illness. Evidence suggests that poor insight is a manifestation of the illness itself rather than a coping strategy… comparable to the lack of awareness of neurological deficits seen in stroke, termed anosognosia. ” 4 13

Schizophrenia: difficult to treat? Partial adherence 1– 4 Frequent stops 1 Strongest indicator of relapse and hospitalisation 7– 10 days after discharge from the hospital: 25% of patients are only partially adherent 3 >50% of patients discontinue treatment within the first 2 months after a first hospitalisation (n=2, 588) Patients who are treated irregularly are more likely to relapse than patients who receive continuous treatment © Janssen-Cilag NV - 2019 24– 90% (58%) of patients do not follow their antipsychotic treatment plans 2 Interruption of treatment 10 days/year: hospitalisation risk per year doubles 4 1. De Nayer A et al. Supplement à Neurone 2013; 18(10): 1– 23; 2. Cramer JA et al. Psychiatr Serv 1998; 49: 196– 201; 3. Keith SJ et al. J Clin Psychiatry 2003; 64: 1308– 1315; 4. Weiden PJ et al. Psychiatr Serv 2004; 55: 886– 891. 14

Partial adherence increases over time. Partial adherence rate after discharge from an inpatient facility 1 80 75% 70 60 50% 40 30 Up to 25% 20 10 0 7– 10 days 1 year © Janssen-Cilag NV - 2019 Proportion of patients partially adherent (%) 50 2 years Patients who are partially adherent or who are treated irregularly are more likely to relapse than patients who receive continuous treatment 2 Figure adapted from Keith et al. 2003. 1. Keith SJ et al. J Clin Psychiatry 2003; 64: 1308– 1315; 2. De Nayer A et al. Supplement à Neurone 2013; 18(10): 1– 23. 69 16

Why continue treatment? Consequences of non-adherence 1 -10 Benefits of adherence 4, 10, 11 § Increased psychotic symptoms § Improved quality of life 4 § Relapse/rehospitalisation § Improved functional outcomes 4 § Long-term functional disabilities § Improved survival 10 § Loss of autonomy, education, or employment possibilities § Improved plasma concentrations 11 § Homelessness § Decreased costs for care 3 § Decreased risk of relapse 2 § Likelihood of dropping out of care completely § Suicide © Janssen-Cilag NV - 2019 § Increased mortality risk Long-acting antipsychotics (LAT) could help to overcome some of the challenges of non-adherence with daily oral antipsychotic medication 1. Llorca PM. Psychiatry Res 2008; 161 (2): 235 -247; 2. Robinson D, et al Arch Gen Psychiatry 1999; 56(3): 241 -247; 3. Haddad PM, et al. Patient Relat Outcome Meas 2014; 5: 43 -62; 4. Ascher-Svarum H. et al. J Clin Psychiatry 2006; 67(3): 453 -460; 5. Keith SJ & Kane JM. J Clin Psychiatry 2003; 64(11): 1308 -1315; 6. Valenstein M. et al. Med Care 2002; 40(8): 630 -639; 7. Olfson M, et al. Psychatr Serv 2000; 51(2): 216 -222; 8. Herings R & Erkins J. Pharmacoepidemiol Drug Saf 2003; 12(5): 423 -424; 9. Llorca PM, et al. Schizophr Res 2009; 113: 218 -225; 10. Nasrallah HA. Schizophr Res 2018 [Epub ahead of print]. 17

A history of the future © Janssen-Cilag NV - 2019 Long-actings by Janssen

More than 60 years experience in Neuroscience ANTIPSYCHOTICS Haldol® (haloperidol) - Tablets - Drops - Injection IM/IV Haldol® Decanoas (haloperidol decanoate) - Injection with extended release IM Risperdal® (Risperidon) - Flm covered tablets (deelbaar) - Orodspensable tablets – instasolv - Solution ADHD Concerta® (methylfenidate, HCl) - tablets (extended release) ALZHEIMER Reminyl® (galantamine, HBr) - Capsules extended release - Solution © Janssen-Cilag NV - 2019 Risperdal® Consta® (Risperidon) - Injection suspension extended release IM Invega® (Paliperidon) - Tablets (extended release) Xeplion® (Paliperidonpalmitate) - Injection suspension extended release IM Trevicta® (Paliperidonpalmitate) - Injection suspension extended release IM 20 20

How it all began… § Observation : amphetamines hallucinations, stereotypy, delirium. § Theory : anti amphetamine = antihallucinatory © Janssen-Cilag NV - 2019 § Chemistry : pethidine butyrophenone R 1187 R 1625 - haloperidol 11 February 1958. Awouters FHL & Lewi P. Arzneimittel-Forschung (Drug Research) 2007 ; 57(10) : 625– 632// Awouters FHL. The History of Psychopharmacology and the CINP Vol. 4, Animula Publishing, Budapest 2004 ; p 35 -37 // Healy D. The psychopharmacologists II. Chapman & Hall, London 1998, p. 39 -70 // Janssen PAJ. A History of the CINP, J. M. Productions, Brentwood USA 1996, P. 440 -448, 21

© Janssen-Cilag NV - 2019 A history of making history in psychiatry 2016 Paliperidone

A history of making history in psychiatry 23

A history of making history in psychiatry 2016 Paliperidone palmitaat TREVICTA® (3 maanden) 24

© Janssen-Cilag NV - 2019 From 1 -monthly to 3 -monthly injections INVEGA TRINZA™

Pharmacokinetics of PP 1 M to PP 3 M § § • Gopal et al. . 2015 Cur Med Res & Opin 31 (11): 2043 -2054 Release of the drug starts as early as Day 1 and lasts for as long as 18 months Maximum plasma concentrations at a median Tmax of 30 to 33 days following a single intramuscular dose Deltoid injections have an 11% to 12% higher Cmax compared with gluteal injections The total exposure and Cmax following administration was dose-proportional over the available dose range The mean steady-state peak to trough ratio for a dose was 1. 6 (gluteal) and 1. 7 (deltoid administration) © Janssen-Cilag NV - 2019 § The median half-life following administration over the full dose range (175 – 525 mg ): o 84 to 95 days following deltoid injections o 118 to 139 days following gluteal injections 26

Real World Evidence Reality represented

LAT can improve survival vs oral antipsychotics Adjusted hazard ratios and 95% confidence intervals for FG and SG oral and long-acting antipsychotic treatments compared with no antipsychotic treatment SG-LAT 0. 52 (0. 45, 0. 6) FG-LAT 0. 58 (0. 52, 0. 65) SG-Oral 33% 0. 75 (0. 66, 0. 85) FG-Oral 0. 0 0. 5 1. 0 Hazard ratio 1. 5 Use of LAT results in a 33% risk reduction of mortality compared with the equivalent oral antipsychotic © Janssen-Cilag NV - 2019 Treatment This study prospectively gathered nationwide Swedish register-based data for patients* with schizophrenia (F 20 and F 25) in order to investigate the impact of antipsychotic use and formulation on mortality 0. 38 (0. 3, 0. 47) During the maximum follow-up of 7. 5 years, the lowest cumulative mortality rate of 7. 5% was observed for second-generation LATs Figure adapted from Taipale H. 2017. *n=29, 823 patients in the prevalent cohort; n=4, 603 patients in the incident cohort FG, first generation; LAT, long-acting therapy; SG, second generation. Taipale H et al. Schiz Res 2017; S 0920– 9964(17): 30762– 4. 29

LAT can reduce risk of rehospitalisation vs oral antipsychotics N=29, 823 32% 30% 25% 20% Prevalent cohort (n=29, 823): Risk of rehospitalisation was 22% lower during use of LAT compared with use of corresponding oral formulations (HR = 0. 78; 95% CI: 0. 72– 0. 84; p<0. 001 22% 15% Incident cohort (n=4, 603): For newly diagnosed patients, risk of psychiatric rehospitalisation was 32% with LAT compared with an equivalent oral formulation (HR = 0. 68 [95% CI: 0. 53– 0. 86]) 10% 5% © Janssen-Cilag NV - 2019 Reduction in risk (%) 35% 0% Prevalent cohort* Incident cohort* Figure adapted from Tiihonen J. 2017. *The prevalent cohort included all individuals residing in Sweden aged 16– 64 years in 2006, who received a diagnosis of schizophrenia during the period from July 1, 2006, to December 31, 2013 (n=29, 823). The incident cohort comprised persons who received a diagnosis of schizophrenia for the first time (n=4, 603 patients) CI, confidence interval; HR, hazard ratio; LAT, long-acting therapy. Tiihonen J et al. JAMA Psychiat 2017; 74(7): 686‒ 693. 30

Relapse rates in FEP patients on orals vs LAIs At the 1 -year follow-up: there was a ~650% difference in relapse rate of the oral therapy group relapsed RLAT, Risperidone long-acting therapy. Subotnik KL et al. JAMA Psychiatry 2015; 72: 822– 829. 5% of the LAT group relapsed © Janssen-Cilag NV - 2019 33% 31

Use of LAT results in significant improvements in carer burden A pooled analysis of two double-blind, randomized, phase-3 studies evaluated predictors of improvement or worsening of schizophrenia-related carer burden following PP 1 M and PP 3 M treatment. Carers completed an involvement evaluation questionnaire A total of 1, 498 carers were included: 49% were parents and >50% carers spent >32 hours/week in caring 28. 0 25 p<0. 001 19. 3 20 15 10 5 © Janssen-Cilag NV - 2019 19. 3 Carer mean IEQ total score at open-label baseline and double-blind endpoint for patients on an oral antipsychotic prior to study entry Mean IEQ total score 30 0 Baseline Endpoint For patients receiving oral antipsychotics at baseline, treatment with LAT resulted in significant improvement in overall carer burden (mean IEQ total score: 28. 0 at baseline vs 19. 3 at endpoint) with reduced impact on workdays missed (p=0. 0023), leisure days and hours spent caring (p < 0. 001). Figure adapted from Gopal S. 2017. IEQ, Involvement Evaluation Questionnaire; LAT, long-acting therapy; PP 1 M, paliperidone palmitate 1 -monthly; PP 3 M, paliperidone palmitate 3 -monthly Gopal S et al. NPJ Schizophr 2017; 3: 23. 32

LAIs have a number of benefits regarding efficcity, safety and tolerability and can be seen as an important strategy in suicide prevention by reducing indirect a number of risk factors in schizophrenia. Pompili M. et al. . Suicide Prevention in Schizophrenia: Do Long-Acting Injectable Antipsychotics (LAIs) have a Role ? CNS & Neurological Desorders – Drug Targets, . 2017; © Janssen-Cilag NV - 2019 Suicide prevention – Role of LAIs ?

Take home messages A history of the future

Benefits of LAIs on the road to recovery Symptomatic remission √ Relapse prevention √ Adequate functioning / ADL √ © Janssen-Cilag NV - 2019 Satisfaction with treatment (options), life, … √ Distance from treatment? Hope ↑? Next step towards recovery? 35

Take Home Messages § Schizophrenia Top 10 illnesses contributing to the global burden of disease § Long-term treatment hampered by – lack of insight in disease – Partial adherence § Benefits: © Janssen-Cilag NV - 2019 – 33% risk reduction for mortality – 22 -32% risk reduction for rehospitalization – Reduction of carer burden 36

Thank you jwyckman@its. jnj. com 07 February 2019 Melinda, Tree of Life Melinda’s artwork reflects her journey living with HIV.