D R U G F O C U S
`Paliperidone: quo vadis?
`
`L. Citrome
`
`doi: 10.1111/j.1742-1241.2007.01321.x
`
`Department of Psychiatry, New
`York University School of
`Medicine, and the Nathan S.
`Kline Institute for Psychiatric
`Research, Orangeburg, NY, USA
`
`Correspondence to:
`Dr Leslie Citrome, MD, MPH,
`Nathan Kline Institute for
`Psychiatric Research, 140 Old
`Orangeburg Road, Orangeburg,
`NY 10962, USA
`Tel.: 845 398 5595
`Fax: 845 398 5483
`Email: citrome@nki.rfmh.org
`
`Disclosures
`Leslie Citrome, MD, MPH, is a
`consultant for, has received
`honoraria from, or has
`conducted clinical research
`supported by the following:
`Abbott Laboratories,
`AstraZeneca Pharmaceuticals,
`Barr Laboratories, Bristol-Myers
`Squibb, Eli Lilly and Company,
`Forest Research Institute,
`GlaxoSmithKline, Janssen
`Pharmaceuticals, Jazz
`Pharmaceuticals and Pfizer Inc.
`
`S U M M A R Y
`Paliperidone, the 9-hydroxy metabolite of risperidone, was approved on 20 Decem-
`ber, 2006 by the US Food and Drug Administration for the treatment of schizo-
`phrenia.
`It is also being tested for the treatment of bipolar mania. An on-line
`query of http://www.pubmed.gov and http://www.clinicaltrials.gov for ‘paliperidone’
`and ‘9-hydroxy-risperidone’ was done, along with an examination of poster presen-
`tations at scientific meetings held in 2006. Three 6-week pivotal clinical trials of
`paliperidone extended-release at fixed doses ranging from 3 to 15 mg adminis-
`tered orally once daily in the treatment of acute schizophrenia demonstrated super-
`ior efficacy to placebo. A favourable tolerability profile was also evidenced, except
`for prolactin elevation and dose-related extra-pyramidal effects. A relapse preven-
`tion study provides evidence of superiority of paliperidone over placebo in the
`maintenance of response. Safety has also been assessed in patients with schizo-
`phrenia who are 65 years or older. At present there are no studies available that
`are powered to directly compare paliperidone to other second-generation anti-
`psychotics, including risperidone. With the impending availability of oral risperidone
`as a generic medication, cost of oral paliperidone will likely become a significant
`obstacle to its use.
`
`Review Criteria
`On-line query of http://www.pubmed.gov and
`http://www.clinicaltrials.gov for ‘paliperidone’ and
`‘9-hydroxy-risperidone’. Poster presentations at
`scientific meetings held in 2006.
`
`Message for the Clinic
`Paliperidone, the 9-hydroxy metabolite of
`risperidone, was recently approved by the US Food
`and Drug Administration for the treatment of
`schizophrenia. It is also being tested for the
`treatment of bipolar mania. An intramuscular depot
`formulation is being developed as well. Advantages
`over risperidone are unclear. Cost may become the
`driving issue regarding its utilisation.
`
`Introduction
`
`Paliperidone is a second-generation antipsychotic
`and was approved on 20 December, 2006 by the US
`Food and Drug Administration for the treatment of
`schizophrenia. Also known as 9-hydroxy-risperidone,
`it is the major plasma metabolite of risperidone, a
`second-generation antipsychotic that was launched
`commercially in 1994. Risperidone is extensively
`used, and has received regulatory approval for the
`treatments of
`schizophrenia, bipolar mania, and
`more recently, irritability associated with autistic dis-
`order in children and adolescents. Risperidone was
`demonstrated in a meta-analysis to be superior to
`first-generation antipsychotics for the treatment of
`schizophrenia (1). However, risperidone was inferior
`to clozapine in a large clinical trial that examined
`head-to-head multiple second-generation antipsych-
`otics (2). It is anticipated that paliperidone will have
`an efficacy profile similar to risperidone when tested
`under the same conditions.
`
`Data sources
`
`Clinical
`query
`
`trial
`of
`
`information was accessed by on-line
`http://www.pubmed.gov
`and
`http://
`
`www.clinicaltrials.gov for the search terms ‘paliperi-
`done’ and ‘9-hydroxy-risperidone’. No date or lan-
`guage constraints were utilised. Proceedings of the
`following scientific meetings were searched for paper
`and poster presentations: 159th Annual Meeting of
`the American Psychiatric Association, Toronto, ON,
`Canada, 20–25 May, 2006; 46th Annual Meeting of
`the NCDEU, Boca Raton, FL, 12–15 June, 2006; 25th
`Congress of the Collegium Internationale Neuro-psy-
`chopharmacologicum, Chicago, IL, 9–13 July, 2006;
`19th Congress of the European College of Neuropsy-
`chopharmacology, Paris, France, 16–20 September,
`2006. Where there are differences between the sub-
`mitted abstract and the copy of the poster provided,
`the data from the poster copy is used. To ensure that
`all publicly available information was collected, a
`request for information was made to Ortho-McNeil
`Janssen Scientific Affairs, LLC of Titusville, NJ, USA
`and was fulfilled on 2 October, 2006.
`
`Mechanism of action and metabolism
`
`Paliperidone is the 9-hydroxy metabolite of risperi-
`done. The pharmacological properties of paliperi-
`done are comparable with risperidone itself (3). It is
`a monoaminergic antagonist that exhibits binding at
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`ª 2007 The Author
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`653
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`654
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`Paliperidone
`
`dopamine type 2 and serotonin type 2A receptors
`(4), as generally expected for members of the class of
`second-generation antipsychotics. Other potentially
`important therapeutic receptor actions for risperi-
`done and paliperidone include affinities for serotonin
`type 2C, 1D and 1A receptors (4,5). The different
`secondary binding affinities (i.e. other than at dop-
`amine type 2 and serotonin type 2A receptors) for
`the different second-generation antipsychotics may
`explain individual patient differences in therapeutic
`response from drug to drug and from dose to dose
`(5). Binding affinities may also be helpful in predict-
`ing a medication’s potential for adverse effects. Pali-
`peridone is active as an antagonist at alpha 1 and
`alpha 2 adrenergic receptors and at histaminergic 1
`receptors, which may explain weight gain, orthostatic
`hypotension or sedative side effects (5,6). Paliperi-
`done has no muscarinic cholinergic antagonist prop-
`erties, which would predict a low propensity for
`causing anticholinergic side effects, including cogni-
`tive dysfunction and gastrointestinal disturbances
`(5).
`In the rat, the distribution of paliperidone to the
`different brain regions was more limited than that of
`risperidone, and the conclusion was that paliperidone
`contributes to the in vivo activity of risperidone, but
`to a smaller extent
`than would be predicted by
`plasma levels (3). Mean residence times in the frontal
`cortex and striatum were 4–6 h for risperidone and
`about 12 h for paliperidone (3). These mean resi-
`dence times were 3–5 times longer than what was
`observed in plasma and in the cerebellum (3).
`Paliperidone is primarily excreted renally (7), and
`hepatic metabolism is not the major clearance route.
`When the immediate release (IR) formulation of pal-
`iperidone (1 mg single oral dose) was administered
`to persons with moderate hepatic
`impairment,
`unbound plasma paliperidone concentrations were
`similar to that observed for healthy subjects (7).
`In essence, many patients taking risperidone are
`already being treated with paliperidone. When meas-
`uring plasma levels of risperidone, it is imperative to
`measure plasma levels of paliperidone, as a substan-
`tial percentage of patients may have non-detectable
`plasma levels of risperidone, yet have measurable
`amounts of paliperidone (8). Examining the relation-
`ship between paliperidone plasma levels and poten-
`tial effects has been the focus of several studies of
`risperidone. In one study, there was no correlation
`between plasma levels of risperidone or paliperidone
`on antipsychotic response measured by the Positive
`and Negative Syndrome Scale (PANSS), but active
`moiety concentrations
`in plasma were higher
`in
`patients who developed clinically significant Par-
`kinsonian symptoms (9). The effects of co-medica-
`
`tion of risperidone with carbamazepine or valproate
`were
`examined in a pharmacokinetic
`study in
`patients with schizophrenia, schizoaffective disorder
`or bipolar disorder (10). Valproate co-administration
`did not impact plasma concentrations of risperidone
`or paliperidone; however, carbamazepine co-adminis-
`tration resulted in statistically significant decreases of
`paliperidone concentrations. Active moiety concen-
`trations were reduced by approximately 70%, attrib-
`uted to the induction of CYP3A4 metabolism by
`carbamazepine (10).
`The effect of risperidone and paliperidone on pro-
`lactin has also been examined. In a study of 25
`patients with psychotic disorders, the plasma concen-
`tration of paliperidone, but not risperidone, correla-
`ted significantly with increases in plasma prolactin,
`leading the authors to conclude that paliperidone
`may play a predominant role in risperidone’s effect
`on prolactin release (11). The investigators attribute
`this to the different pharmacokinetics of risperidone
`and paliperidone, namely protein binding being less
`for paliperidone (77.4% vs. 90.0%) (12) and paliperi-
`done being less lipophilic. In addition, the half-life of
`paliperidone is substantially longer than that for ris-
`peridone (20 h vs. 2–4 h) (13).
`
`Formulations
`
`Several formulations of paliperidone have been tes-
`ted, including an oral immediate-release formulation,
`an oral extended-release (ER) formulation, and a
`depot intramuscular formulation.
`Currently available is the oral ER formulation of
`paliperidone. It uses a patented technology called
`osmotic-controlled release oral delivery system (14).
`The ER formulation of paliperidone consists of an
`osmotically active trilayer core, composed of
`two
`drug layers and a push layer (14). The intent is to
`ensure a gradual rise in the blood concentrations of
`paliperidone so that a therapeutically effective start-
`ing dose can be given. The medication can be
`administered once daily and it is expected that by
`reducing the amplitude of the peaks and troughs,
`which are seen with IR oral therapies in general, it is
`thought
`that
`the risk of adverse effects can be
`reduced.
`
`Clinical trials
`
`Table 1 lists the clinical trials of paliperidone that
`have been registered on http://www.clinicaltrials.gov,
`a repository operated by the US National Institutes
`of Health and the National Library of Medicine. Of
`the 22 studies registered, 18 are with patients with
`schizophrenia (including one study for patients age
`
`ª 2007 The Author
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 653–662
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1004 p. 002
`
`

`

`Paliperidone
`
`655
`
`65 years and over), one in schizoaffective disorder,
`and three in bipolar, manic or mixed episodes.
`Twenty Phase III studies are listed, one Phase II
`study and one Phase I study. Fifteen studies are
`using the oral ER formulation of paliperidone, and
`seven are for the depot intramuscular formulation.
`According to the registry, seven studies are actively
`recruiting patients, two have not yet begun, nine are
`no longer recruiting and four have been completed.
`There are several more studies that have been done
`but have not been registered because the requirement
`for doing so has only recently been mandated in
`2005, and then again, is necessary only if publication
`is desired in a journal that ascribes to standards pro-
`mulgated by the International Committee of Medical
`Journal Editors (15,16).
`At the time of this review there has been only one
`published efficacy trial of paliperidone (17). In that
`study, the efficacy and safety of paliperidone ER was
`assessed over a 6-week period by comparing fixed
`doses of 6, 9 and 12 mg administered once daily vs.
`placebo. Olanzapine 10 mg administered once daily
`was used as an active control. In total, 628 patients
`with an acute episode of schizophrenia were random-
`ised at 47 centres in Europe and six centres in India.
`The primary efficacy outcome measure was change in
`PANSS total score from baseline to end-point. Aver-
`age age of the study participants was 37 years; 86%
`were white, and 52% male. The average age at diag-
`nosis was 27 years and 42% had been hospitalised at
`least four times. Mean baseline PANSS score was 94.
`Only 45.6% of the patients randomised to placebo
`completed the 6-week double-blind period, compared
`with 65.0% of patients
`randomised to paliperi-
`done 6 mg, 70.5% of patients randomised to paliperi-
`done 9 mg, 77.7% of patients
`randomised to
`paliperidone 12 mg, and 70.3% of patients random-
`ised to olanzapine 10 mg. This translates to number
`needed to treat (NNT) for completion vs. placebo of
`6, 4, 4 and 4 for paliperidone 6, 9, 12 mg and olanza-
`pine 10 mg respectively [for a discussion of NNT and
`related concepts see Ref. (18)].
`The efficacy outcomes demonstrated that paliperi-
`done was efficacious (17). The mean decreases in
`PANSS total scores were 4.1 for placebo, 17.9, 17.2
`and 23.3 for paliperidone 6, 9 and 12 mg respect-
`ively, and 19.9 for olanzapine. Thus paliperidone
`demonstrated statistically significant
`improvements
`over placebo at all three doses tested. This was also
`the case for the factor scores examining positive
`symptoms, negative symptoms, depression/anxiety,
`uncontrolled hostility/excitement and disorganisa-
`tion. Superiority over placebo was evident at day 4
`for paliperidone 12 mg and at day 8 for the 6 and
`9 mg doses. Responder analyses examining percent-
`
`age improvement in PANSS as well as improvements
`in Clinical Global Impression-Severity scores were
`consistent with the above. Personal and social func-
`tioning were also tested using novel
`scales, and
`improvements were greater for paliperidone com-
`pared with placebo.
`Tolerability outcomes demonstrated that paliperi-
`done is reasonably well
`tolerated (17). Treatment
`emergent adverse events led to study discontinuation
`in 7% of those randomised to placebo, 7%, 3% and
`6% of those randomised to paliperidone 6, 9 and
`12 mg respectively and 7% of those randomised to
`olanzapine. The most common adverse event that led
`to discontinuation was tachycardia (2% in the pali-
`peridone 12 mg group vs. 1% in all other groups).
`Tachycardia itself occurred in 10% of those random-
`ised to placebo, 18%, 14% and 22% of those rand-
`omised to paliperidone 6, 9 and 12 mg respectively
`and 14% of those randomised to olanzapine. The
`occurrence of serious adverse events was 2% of the
`placebo group, 4%, 1% and 5% for the paliperidone
`6, 9 and 12 mg groups respectively, and 2% for the
`olanzapine group.
`increased among
`Mean plasma prolactin levels
`patients receiving paliperidone,
`from a baseline of
`17.4 to 45.3 ng/ml for the men, and from 38.0 to
`124.5 ng/ml for the women. The changes in plasma
`prolactin for each dose of paliperidone were not
`reported, nor were the percentages of patients who
`experienced categorical shifts from a normal plasma
`prolactin level to an abnormally high level. Mean
`prolactin levels decreased from baseline to end-point
`in both men and women in the placebo and olanza-
`pine groups. Potentially prolactin-related adverse
`events were reported by 1% of participants (three
`men, one in each of the paliperidone arms), and
`four women (one in each of the active treatment
`arms).
`frequency of movement disorder-related
`The
`adverse events was
`similar between paliperidone
`6 mg and placebo, but more patients in the 9 and
`12 mg groups reported these than those in the pla-
`cebo group. This
`is
`consistent with what was
`observed with the Simpson Angus Scale (SAS), Bar-
`nes Akathisia Scale (BAS), and the Abnormal Invol-
`untary Movement Scale (AIMS). At end-point the
`use of anticholinergic medication was 6% in the pla-
`cebo group, 11%, 17% and 22% in the paliperidone
`6, 9 and 12 mg groups respectively, and 8% in the
`olanzapine group. There were no glucose-related
`adverse events or substantial changes in glucose,
`insulin,
`low-density
`lipoprotein-cholesterol, high-
`density lipoprotein-cholesterol or
`triglycerides
`for
`any of the groups. Weight increase ‡ 7% was seen in
`2% of the placebo group, 5%, 7% and 3% of the
`
`ª 2007 The Author
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 653–662
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1004 p. 003
`
`

`

`656
`
`Paliperidone
`
`Table 1 Paliperidone clinical trials registered at http://www.clinicaltrials.gov*
`
`Phase
`
`Condition
`
`N
`
`Paliperidone doses and comparator
`
`Comments
`
`ClinicalTrials.
`gov identifier
`
`Duration
`(weeks)
`
`NCT00299715
`
`3
`
`NCT00309699
`
`Acute 3,
`total 12
`
`NCT00309686
`
`6
`
`NCT00105326
`
`?
`
`NCT00119756
`
`?
`
`NCT00397033
`
`6
`
`NCT00334126
`
`NCT00210548
`
`Acute 2,
`total 6
`13
`
`NCT00210769
`
`52
`
`NCT00210717
`
`52
`
`III
`
`III
`
`III
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`II
`
`Bipolar, manic or mixed
`
`464
`
`ER 3, 6 or 12 mg/day vs. placebo
`
`Bipolar, manic or mixed
`
`475
`
`ER 3–12 mg/day vs. quetiapine
`400–800 mg/day vs. placebo
`ER 3–12 mg/day vs. placebo, added to
`lithium or valproate
`
`296
`
`?
`
`ER 9 mg/day vs. placebo
`
`282
`
`PD dose not listed
`
`315
`
`ER 6 vs. 12 mg/day vs. placebo
`
`395
`
`376
`
`350
`
`700
`
`45
`
`Bipolar, manic or mixed,
`and taking lithium or
`valproate
`Schizophrenia and
`schizophrenia-related
`insomnia, otherwise
`stable
`Schizophrenia
`
`Schizoaffective disorder,
`psychotic disorder
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia
`
`Began 1/2006, USA and international
`sites. Recruiting
`Began 4/2006, USA and international
`sites. Recruiting
`Began 4/2006, USA and international
`sites. Recruiting
`
`Began 2/2005. Completed. Conducted
`in a total of nine sites in France,
`Poland and Romania. Studied sleep
`architecture using polysomnography
`Began 6/2005. Study sites not listed.
`No longer recruiting. Studies safety
`and tolerability comparing injection
`in shoulder vs. buttock muscles
`Not yet recruiting
`
`Began 5/2006, USA sites. Recruiting
`
`Began 4/2005, USA and international
`sites. Recruiting
`Began 1/2004. Study sites not listed.
`No longer recruiting
`
`ER 9–12 mg/day vs. quetiapine
`600–800 mg/day
`PD 50, 100 or 150 mg eq vs. placebo,
`4 injections on days 1, 8, 36 and 64
`Following a 6-week double-blind study
`comparing ER 6 or 12 mg/day vs.
`olanzapine 10 mg/day, subjects received
`open-label ER 3–12 mg/day open-label
`PD 25–100 mg eq every 4 weeks vs.
`risperidone depot 25–50 mg every 2 weeks
`Open-label ER 3, 9 or 15 mg/day for 6 weeks
`
`III
`
`III
`
`III
`
`I
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia
`
`Schizophrenia,
`age ‡ 65 years
`Schizophrenia
`
`?
`
`595
`
`595
`
`72
`
`105
`
`300
`
`ER dose not listed vs. placebo, with optional
`open-label extension
`ER 6, 9 or 12 mg/day vs. olanzapine 10 mg/day
`vs. placebo, with optional open-label extension
`ER 3, 9 and 15 mg/day vs. olanzapine 10 mg/day
`vs. placebo, with optional open-label extension
`PD open-label pharmacokinetic study of
`injections in the arm or buttock
`ER flexible-dose (details not listed) vs. placebo,
`with optional open-label extension
`ER 3–12 mg/day vs. olanzapine 5–15 mg/day
`
`Schizophrenia
`
`440
`
`ER doses not listed
`
`Schizophrenia
`
`Schizophrenia
`
`329
`
`640
`
`ER 6 mg/day vs. olanzapine 10 mg/day vs.
`placebo
`PD doses not listed
`
`Schizophrenia
`
`480
`
`PD 25, 50 or 100 mg eq vs. placebo
`
`Schizophrenia
`
`376
`
`PD 50, 100 and 150 mg eq vs. placebo
`
`Began 2/2005. Study sites not listed.
`No longer recruiting
`Began 2/2005. Done in Japan.
`No longer recruiting
`Began 10/2004, USA sites. Completed
`
`Began 3/2004, international sites.
`No longer recruiting
`Began 3/2004, USA and international
`sites. No longer recruiting
`Began 8/2003. Done in Texas, USA.
`Completed
`Began 7/2004, international sites.
`No longer recruiting
`To be done in China. Not yet
`recruiting
`Begun 2/2004, only one USA site
`listed. Completed
`Begun 6/2006, Japan. Recruiting
`
`Begun 3/2005, USA and international
`sites. Recruiting
`Begun 12/2004, USA and international
`sites. No longer recruiting
`Begun 6/2005, USA and international
`sites. No longer recruiting
`
`NCT00257023
`
`NCT00086320
`
`NCT00078039
`
`NCT00083668
`
`NCT00073320
`
`NCT00085748
`
`NCT00350467
`
`NCT00077714
`
`NCT00396565
`
`NCT00111189
`
`NCT00101634
`
`NCT00147173
`
`8
`
`?
`
`6
`
`6
`
`?
`
`6
`
`6
`
`?
`
`6
`
`?
`
`?
`
`?
`
`*Accessed 24 November, 2006. ER, extended release; PD, palmitate depot.
`
`ª 2007 The Author
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 653–662
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1004 p. 004
`
`

`

`Paliperidone
`
`657
`
`paliperidone 6, 9 and 12 mg groups respectively, and
`13% of
`the olanzapine group. There were no
`instances of patients
`randomised to paliperidone
`developing prolonged QT intervals as measured by
`electrocardiogram.
`There are two other short-term efficacy studies of
`paliperidone ER for acute schizophrenia that have
`been presented as posters, and hence not subject to
`peer review (19,20). They are similar in design to the
`study described above in that they are of 6-week dur-
`ation,
`placebo-controlled
`and
`used
`olanzapine
`10 mg/day as an active control (17). All active treat-
`ment arms demonstrated superiority over placebo in
`terms of reductions in PANSS total scores. The high-
`lights are presented in Table 2, and contrast all three
`of these pivotal trials.
`The safety and efficacy of flexible doses of paliperi-
`done ER in patients with schizophrenia age 65 years
`or older was tested in a 6-week placebo-controlled
`clinical trial and presented as a poster (21). This is
`of interest because it would be expected that older
`people would be more sensitive to adverse effects of
`medications. A total of 114 patients were randomised
`to receive paliperidone 6 mg or placebo once daily.
`After 7 days, patients could receive flexible dosing in
`the range of 3–12 mg daily, in 3 mg dose increments.
`Mean age was 70 years. Mean modal paliperidone
`daily dose was 8.3 mg. Completion rates were high:
`68% for placebo and 84% for paliperidone (NNT 7).
`Study discontinuation because of adverse events
`occurred in 7% of the paliperidone group and 8% of
`the placebo group. Serious adverse events occurred
`in 3% of the paliperidone group and 8% in the pla-
`cebo group. The most common adverse event was
`tachycardia, reported in 16% of
`the paliperidone
`group and in none of the patients receiving placebo.
`Median global scores on the SAS and median AIMS
`total scores showed no change from baseline in
`either treatment group. Akathisia, as measured by
`the BAS, was absent in 85.5% of the paliperidone
`patients and in 86.8% of the placebo patients at end-
`point. No substantial changes in mean glucose or
`mean bodyweight were noted. Efficacy measures were
`secondary in this study. Patients receiving paliperi-
`done had greater improvement in PANSS total scores
`from baseline to end-point compared with patients
`receiving placebo. Responder
`analysis
`(response
`defined as an improvement in the total PANSS score
`by at least 30% from baseline to end-point) revealed
`response rates of 38% for paliperidone and 29% for
`placebo (NNT 12).
`A small study (N ¼ 36) of paliperidone ER vs.
`placebo was conducted at nine sites
`in Europe
`among patients with schizophrenia to examine chan-
`ges in sleep architecture. The results were presented
`
`as a poster (22). Patients with schizophrenia and
`schizophrenia-related insomnia, but without signs of
`acute psychosis, were randomised to receive paliperi-
`done 9 mg or placebo for 2 weeks. Improvements in
`sleep continuity were noted for paliperidone vs. pla-
`cebo, including mean total sleep time and decreases
`in latency to sleep onset.
`Once a patient with acute schizophrenia is stabi-
`lised, the goal of treatment is to prevent relapse.
`Paliperidone’s potential utility for this was exam-
`ined in a double-blind placebo-controlled trial, and
`presented as a poster (23). A total of 530 patients
`with acute schizophrenia were enrolled and began
`an 8-week open-label
`run-in phase where they
`received a starting daily dose of paliperidone 9 mg.
`Increases of 3 mg could occur every 7 days (maxi-
`mum dose 15 mg daily). Decreases of 3 mg were
`permitted at any time if
`there were tolerability
`problems. The run-in phase was
`followed by a
`6-week stabilisation phase where the fixed dose
`established in the run-in phase was continued. The
`poster did not specify the specific response criteria
`for patients to be eligible to enter the stabilisation
`phase. A total of 312 patients entered the stabilisa-
`tion phase and 207 patients subsequently entered
`the double-blind phase where they were randomised
`to receive placebo or paliperidone at the dose they
`were receiving in the stabilisation phase. The poster
`did not specify the specific response criteria for
`patients to be eligible to enter the double-blind
`phase. Participation in the double-blind phase was
`to be of variable duration, and would continue
`until the patient experienced a recurrence (defined
`as hospitalisation, specified increase in PANSS, spe-
`cified dangerous behaviour or specified worsening
`on the Clinical Global Impression-Severity scale) or
`until the study was terminated. The poster does not
`indicate how the quickly patients were converted
`from active drug to placebo once they were rand-
`omised to placebo. A prespecified interim analysis
`was performed after 43 recurrence events, and the
`study was terminated on the basis of significant
`efficacy results. Recurrence occurred more swiftly
`for patients
`randomised to placebo – 25% of
`patients
`experienced a predefined recurrence
`at
`23 days with placebo vs. 68 days with paliperidone
`(Kaplan–Meier,
`p < 0.001). Overall,
`recurrence
`occurred in 52% of patients on placebo vs. 22% of
`patients receiving paliperidone (NNT 4).
`
`Post hoc analyses
`
`Several post hoc analyses combining the datasets from
`the three acute schizophrenia trials (17,19,20) have
`been presented as posters (24–28). They have focused
`
`ª 2007 The Author
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 653–662
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1004 p. 005
`
`

`

`658
`
`Paliperidone
`
`AIMS,AbnormalInvoluntaryMovementScale;BAS,BarnesAkathisiaScale;NNT,numberneededtotreat;PANSS,PositiveandNegativeSyndromeScale;SAS,SimpsonAngusScale.
`
`group
`3,9and15mggroupsrespectively,andnoneintheolanzapine
`Twopatientsintheplacebogroup,and2,1and1inthepaliperidone
`
`andin2patientsintheolanzapinegroup
`Twopatientsinthepaliperidone6mggroup
`
`theposter
`thepaliperidonegroupsbuttheactualvalueswerenotincludedin
`Meanplasmaprolactinlevelsincreasedfrombaselinetoend-pointin
`anticholinergicmedicationswasnotreported
`globalscoreforpaliperidone9mg.Thepercentagereceiving
`globalscore,AIMStotalorBASglobalscore,exceptfortheSAS
`paliperidonegroupsandplacebointermsofchangesintheSAS
`statisticallysignificantdifferenceswereobservedbetweenthe
`incidencewasreportedinthepaliperidone9and15mggroups.No
`similarforpaliperidone3mg,placeboandolanzapine,whileahigher
`Extra-pyramidaldisorder(nototherwisespecified)andhyperkinesias
`incidenceswerereportedinthepaliperidone9mggroup.
`paliperidone3and15mg,placeboandolanzapine,buthigher
`Frequencyofhypertonia,dystoniaandtremorweresimilarfor
`Olanzapine10mg,4%
`Paliperidone15mg,3%
`Paliperidone9mg,5%
`Paliperidone3mg,2%
`Placebo,4%
`Olanzapine10mg,52%,NNT3
`Paliperidone15mg,53%,NNT3
`Paliperidone9mg,46%,NNT4
`Paliperidone3mg,40%,NNT5
`Placebo,18%
`Paliperidone15mg:day4
`Paliperidone9mg:day4
`Paliperidone3mg:day4
`Olanzapine10mg,68.8%,NNT4
`Paliperidone15mg,71.3%,NNT3
`Paliperidone9mg,62.4%,NNT5
`Paliperidone3mg,55.1%,NNT6
`Placebo,38.2%
`74,International(14countries)
`618
`
`theplaceboorolanzapinegroups
`women),butdidnotappreciablychangein
`inmen,andfrom29.2to108.2ng/mlin
`paliperidonegroups(from14.5to38.1ng/ml
`Increasedfrombaselinetoend-pointinthe
`
`anticholinergicmedicationswasnotreported
`globalscore.Thepercentagereceiving
`theSASglobalscore,AIMStotalorBAS
`groupsandplacebointermsofchangesin
`differencesobservedbetweenthepaliperidone
`6mggroup.Nostatisticallysignificant
`thepaliperidone12mggroupthaninthe
`placeboandolanzapine.Morecommonin
`Frequencyinthe6mggroupsimilarto
`
`Olanzapine10mg,7%
`Paliperidone12mg,5%
`Paliperidone6mg,7%
`Placebo,5%
`
`Olanzapine10mg,46%,NNT9
`Paliperidone12mg,51%,NNT6
`Paliperidone6mg,50%,NNT7
`Placebo,34%
`
`Paliperidone12mg:day15
`Paliperidone6mg:day4
`
`Olanzapine10mg,45.4%,NNT9
`Paliperidone12mg,48.2%,NNT7
`Paliperidone6mg,45.5%,NNT9
`Placebo,33.6%
`45,USA
`444
`
`None
`placeboandolanzapinegroups
`end-pointinbothmenandwomeninthe
`women).Decreasedfrombaselineto
`men,andfrom38.0to124.5ng/mlforthe
`(fromabaselineof17.4to45.3ng/mlforthe
`Increasedamongpatientsreceivingpaliperidone
`respectively,and8%intheolanzapinegroup
`paliperidone6,9and12mggroups
`placebogroup,11%,17%and22%inthe
`anticholinergicmedicationwas6%inthe
`12mggroups.Atend-pointtheuseof
`placebogroups,buthigherinthe9and
`scoressimilarinthepaliperidone6mgand
`intheplacebogroup.ChangeinSASglobal
`12mggroupsreportedthesethanpatients
`andplacebo,butmorepatientsinthe9and
`Frequencysimilarbetweenpaliperidone6mg
`Olanzapine10mg,7%
`Paliperidone12mg,6%
`Paliperidone9mg,3%
`Paliperidone6mg,7%
`Placebo,7%
`Olanzapine10mg,52%,NNT5
`Paliperidone12mg,61%,NNT4
`Paliperidone9mg,51%,NNT5
`Paliperidone6mg,56%,NNT4
`Placebo,30%
`Paliperidone12mg:day4
`Paliperidone9mg:day8
`Paliperidone6mg:day8
`Olanzapine10mg,70.3%,NNT4
`Paliperidone12mg,77.7%,NNT4
`Paliperidone9mg,70.5%,NNT4
`Paliperidone6mg,65.0%,NNT6
`Placebo,45.6%
`53,EuropeandIndia
`628
`
`Glucose-relatedadverseevents
`
`Meanplasmaprolactin
`
`Extra-pyramidaladverseevents
`
`leadingtodiscontinuation
`Treatment-relatedadverseevents
`
`placebo
`baselinetoend-point,NNTvs.
`inthePANSStotalscorefrom
`Responsebyatleast30%improvement
`
`Timingofimprovementoverplacebo
`
`completionvs.placebo
`Arms,completionrate,NNTfor
`Numberofsites,location
`N(randomised)
`
`Davidsonetal.(20)
`
`Marderetal.(19)
`
`Kaneetal.(17)
`
`Table2Thethreepivotal6-weekefficacytrialsofpaliperidoneextended-releaseforthetreatmentofacuteschizophrenia(17,19,20)
`
`ª 2007 The Author
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 653–662
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1004 p. 006
`
`

`

`Paliperidone
`
`659
`
`recently diagnosed
`(24),
`on metabolic outcomes
`patients (25), young adults (26), negative symptoms
`(27) and speed of onset of action (28).
`In the poster examining metabolic outcomes,
`mean increases in bodyweight at end-point increased
`in a dose-related manner (24). Weight gain ‡ 7% of
`baseline was observed in 5% of patients receiving
`placebo and in 7%, 6%, 9%, 9% and 18% of the
`patients receiving paliperidone 3, 6, 9, 12 and 15 mg
`respectively. No clinically relevant changes were
`observed in terms of glucose, insulin, cholesterol or
`triglycerides. This is consistent with risperidone’s
`metabolic profile.
`In patients diagnosed with schizophrenia within
`the prior 5 years, outcomes were similar to patients
`diagnosed >5 years prior, except for a small but sta-
`tistically significant worsening of the SAS score for
`patients receiving paliperidone 3–12 mg daily (25).
`Patients receiving paliperidone 15 mg daily were not
`included in the primary analysis. The results of this
`analysis suggest that patients early on in their disease
`course may be more sensitive to extra-pyramidal side
`effects.
`paliperidone
`18–25 years,
`aged
`patients
`In
`3–15 mg resulted in statistically significant decreases
`in PANSS total
`scores
`(26). Responder analysis
`(response defined as an improvement in the total
`PANSS score by at least 30% from baseline to end-
`point), revealed rates of 22%, 42%, 52%, 54%, 49%
`and 59% for placebo, paliperidone 3, 6, 9, 12 or
`15 mg respectively (corresponding NNTs vs. placebo
`are 5, 4, 4, 4 and 3 for paliperidone 3, 6, 9, 12 and
`15 mg respectively). Extra-pyramidal-related adverse
`events occurring most frequently with paliperidone
`were akathisia and tremor (8% each event). In con-
`trast to the analysis of recently diagnosed patients,
`no changes were seen in the movement-related rating
`scales. A dose-dependent increase in bodyweight was
`observed.
`The hypothesis that paliperidone has effects on
`negative symptoms of schizophrenia was tested in
`another report (27). A path analysis revealed that
`33% of the negative symptom improvement was a
`direct effect of paliperidone. The indirect effects on
`negative symptoms were modulated through changes
`in positive symptoms (51%) and depressive symp-
`toms (18%). Changes in movement disorders accoun-
`ted for a 2.1% inverse effect on negative symptoms.
`Inconsistent results were observed in the pivotal
`trials (17,19,20) with regard to time of onset when
`paliperidone statistically separates from placebo in
`terms of the reduction in the PANSS total score. In
`one, superiority over placebo was evident at day 4
`for paliperidone 12 mg, and at day 8 for the 6 mg
`and 9 mg doses (17). In another, improvement vs.
`
`placebo occurred as early as day 4 for paliperidone
`6 mg, and at day 15 for paliperidone 12 mg (19). In
`the third study, improvement vs. placebo occurred as
`early as day 4 for all three paliperidone arms: 3, 9
`and 15 mg (20). In a po