Schizophrenia is a chronic, highly debilitating mental disorder afflicting more than 3 million people in the United States and more than 60 million people worldwide.1 Of the US total, approximately 2.9 million individuals are diagnosed, and 92% receive antipsychotic drug therapy.1 However, the unmet medical need remains high, with a necessity for improvement in residual negative symptoms, cognitive deficits, or improvements in overall schizophrenia symptoms.2,3 The safety and tolerability profile of current therapies is also an area of major concern, especially regarding weight gain, metabolic syndrome, and onset of diabetes, in addition to the established risk of movement disorders.2–4 A mechanistically novel approach in the treatment of schizophrenia is phosphodiesterase 10A (PDE10A) inhibition.5,6 PDE10A is a dual substrate enzyme that is expressed at very high levels in the brain, where it regulates intracellular concentrations of the ubiquitous second messengers cAMP and cGMP. The localization of PDE10A within the brain is similar to that of D1 and D2 dopamine receptors, being most highly expressed in projection neurons of the striatum, the primary input nucleus of the basal ganglia and a subcortical system thought to be involved in the pathophysiology of schizophrenia.7–9
The development of selective inhibitors enabled experiments showing that PDE10A inhibitors are active in a number of rodent models that are also responsive to D2 dopamine antagonists. These models are therefore used to assess the potential for clinical antipsychotic activity.6,10–14 The effects of the PDE10A inhibitors were absent in PDE10A knockout mice, confirming that PDE10A modulation is the mechanism underlying the D2 receptor antagonist-like activity of these compounds.10 Based on negative modulation of behavioral responses to sensory cues, additional studies demonstrated that the effects of PDE10A inhibition are the result of activation of D2 receptor–expressing striatopallidal projection neurons (the so-called no-go pathway).15–17 Given that enhanced striatopallidal activity is also believed to contribute to the clinical antipsychotic efficacy of D2 receptor antagonists, these results supported the prediction that PDE10A inhibition would produce similar clinical effects.
We have tested this hypothesis with PF-02545920 (also known as MP-106), a subnanomolar, competitive inhibitor of PDE10A that demonstrates greater than 1000-fold selectivity over representative examples from each of the other 10 PDE gene families, and is selective for PDE10A when compared against a panel of 79 additional targets.18,19 In addition, whole cell and membrane studies using photoaffinity probes based on the structure of PF-2545920 demonstrated highly specific binding to PDE10A with virtually no off-target binding.19 This high level of selectivity is consistent with the interaction of PF-02545920 with a binding pocket that is unique to PDE10A, as determined by x-ray crystallography.20 The pharmacokinetic profile of PF-02545920 is considered favorable for clinical development, with a rapid absorption (0.5–1 hours), dose-proportional exposure, and mean half-life of 8 to 16 hours allowing for twice-daily dosing.21 PF-02545920 is metabolized primarily by CYP3A4, producing an active metabolite (PF-01001252), which had a limited ability to cross the blood-brain barrier in preclinical experiments.21,22
This phase 2 study evaluated the efficacy of PF-02545920 in the treatment of the acute exacerbation of schizophrenia and the safety and tolerability of 2 fixed-dose regimens of PF-02545920.
MATERIALS AND METHODS
This was a phase 2, multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group study conducted in patients with an acute exacerbation of schizophrenia (NCT01175135). The protocol was approved by the relevant institutional review board and/or independent ethics committee for each investigational site (additional details on each study site and institutional review board are provided in Table S3 in Supplementary Materials, Supplemental Digital Content, http://links.lww.com/JCP/A623). The study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent.
Patients aged 18 to 65 years with a diagnosis of schizophrenia according to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition–Text Revision), confirmed with the Mini International Neuropsychiatric Interview, were eligible for the study if they were currently experiencing an acute exacerbation of schizophrenia that altered their ability to function (<4 weeks' duration; <2 weeks' current hospitalization).
Key inclusion criteria included a total Positive and Negative Syndrome Scale (PANSS-derived) Brief Psychiatric Rating Scale (BPRS)23 score of ≥45 at screening and ≥4 (moderate) on at least 2 of the 4 core psychosis items (items 4 [conceptual disorganization], 11 [hallucinatory behavior], 12 [suspiciousness], and 15 [unusual thought content]) at screening and baseline, a total score of ≥12 on the 4 BPRS core psychosis items at screening and baseline, and a Clinical Global Impression of Severity (CGI-S) score of ≥4 (moderately ill) at screening and baseline.24 Key exclusion criteria were a >25% decrease in the combined score for BPRS core psychosis items between screening and baseline, and evidence that the exacerbation of schizophrenia or change in behavior was due to substance abuse. Other key exclusion criteria included a recent history of dystonia, dystonic reactions to ≥3 prior antipsychotics, a current Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition–Text Revision) axis I diagnosis of schizoaffective disorder, major depression, bipolar disorder, or obsessive-compulsive disorder, or an attempted suicide within 3 months before screening. Additional exclusion criteria are detailed in the Supplementary Material, Supplemental Digital Content, http://links.lww.com/JCP/A623. This study also incorporated a novel audio recording–based assessment that helped with quality assurance and external confirmation of the eligibility process.25 This assessment focused on independent scoring of a subset of prioritized screening assessments and confirmation of key study entry criteria to optimize the quality of study rating assessments and the homogeneity of the study population across both sites and countries.
This trial was conducted with participants becoming inpatients until the end of treatment. After screening, eligible patients discontinued prior antipsychotic and prohibited medications (tapering if needed). Prohibited medications included those with central nervous system activity that may have caused a safety risk during the trial and those that significantly inhibit CYP3A4. Randomization was achieved using an interactive voice response system to access a random allocation sequence. Patients received a single-blind placebo for 2 days before beginning their randomized double-blind treatment (2:2:1:2 ratio): PF-02545920 5 mg every 12 hours (Q12H), PF-02545920 15 mg Q12H (titrated as 5 mg Q12H for 2 days, 10 mg Q12H for 2 days), risperidone 3 mg Q12H (titrated as 1 mg Q12H for 2 days, 2 mg Q12H for 2 days), or matching placebo. The doses of PF-02545920 used in this study were selected based on preclinical and clinical data, which projected a mean plasma steady-state concentration of 26 ng/mL (0.5 to 1.6 times in vivo half-maximal inhibitory concentration [IC50]) and 78 ng/mL (1.6–4.9 times in vivo IC50) in the 5 mg Q12H and 15 mg Q12H groups, respectively. The findings of earlier clinical studies demonstrated that multiple doses of PF-02545920 were well tolerated up to doses of 20 mg Q12H.21
Doses were taken ≥1 hour before or 2 hours after meals, for 28 days. Rescue medications were permitted for the management of agitation/anxiety, insomnia, and extrapyramidal symptoms; however, benzodiazepines and other drugs used to treat agitation/anxiety/insomnia, anticholinergics, and drugs with sedative effects were not permitted within 6 hours before efficacy assessments. At the end of the study, patients could enter an optional inpatient restabilization period of ≤7 days for the reintroduction of marketed antipsychotic therapy.
The primary objectives of the study were as follows: (1) to evaluate the efficacy of PF-02545920 compared with placebo in the treatment of acute exacerbation of schizophrenia during a 4-week double-blind treatment period using the change in PANSS measure from baseline, (2) to evaluate the safety and tolerability of 2 fixed-dose regimens of PF-02545920 in the treatment of acute exacerbation of schizophrenia, and (3) to evaluate the incidence rate of dystonia associated with 2 fixed-dose regimens of PF-02545920 compared with placebo in the treatment of acute schizophrenia.
The primary end point of the study was the change from baseline in the total PANSS score after 28 days' treatment with PF-02545920 (5 and 15 mg Q12H) as compared with placebo. Assessments of PANSS were made using information from a semistructured patient interview and from caregivers, family, and clinical material, at screening and time points throughout the 28 days' treatment.
Safety and tolerability evaluations included physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory tests. Patients were monitored for suicide risk using the Columbia-Suicide Severity Rating Scale. Dystonia burden was quantified with the Movement Disorder Burden Composite Score for Dystonia.
Secondary objectives were to assess the efficacy of PF-02545920, risperidone, and placebo in the treatment of acute exacerbation of schizophrenia using the Clinical Global Impression of Improvement (CGI-I),24 CGI-S, PANSS subscales (Positive, Negative, General),26,27 PANSS-derived Marder factor scores (positive, negative, disorganized thought, hostility/excitement, and anxiety/depression),28 PANSS-derived BPRS core psychosis items, and Global Assessment of Function (GAF). The PANSS, PANSS-derived BPRS, and CGI-S were derived at screening, at day 1 (baseline), and at time points throughout the 28-day treatment. An independent BPRS was conducted at screening and day 1 only. The CGI-I and GAF were assessed at day 7 and day 1, respectively, and at time points throughout treatment.
To quantify PF-02545920 concentrations, blood (4 mL) was collected in tubes (containing no preservative, anticoagulant, or serum separator) before the morning dose of PF-02545920 (0 hours) on days 7, 14, 21, and 28. Postdose samples were also collected on days 7, 14, 21, and 29 at the following times (window): 20 minutes (15–60 minutes), 1.5 hours (1–2 hours), 4.5 hours (3–6 hours), and 24 hours, respectively. Whole blood was kept at room temperature until clotting occurred. Samples were centrifuged at approximately 1700 g for approximately 10 minutes at 4°C to separate the serum for analysis. Serum was stored in screw-capped polypropylene tubes at approximately −20°C within 1 hour of collection.
Serum samples were analyzed for PF-02545920 by a validated high-performance liquid chromatography (HPLC) tandem mass spectrometric assay at Covance Bioanalytical Services, LLC (Indianapolis, Indiana). The internal standard used was PF-03638737, which is a structurally similar analog of PF-02545920. Serum samples of 0.1 mL were used, and PF-02545920 and PF-03638737 were extracted by liquid-liquid extraction. The liquid-liquid extraction solution used was a 50:50 mixture of methyl-t-butyl ether and ethyl acetate. After centrifugation, the supernatant was injected into the HPLC tandem mass spectrometric system for analysis. The HPLC analytical column was a Betasil silica 50 × 3.0-mm column with 5-μm particle size (Keystone Scientific). The liquid chromatography method involved using a gradient of 2 mobile phases. Mobile phase A was 10 mM ammonium acetate in 0.2% formic acid, and mobile phase B was 0.2% formic acid in acetonitrile. Mass-to-charge (m/z) ratios were monitored in multiple-reaction monitoring mode. The m/z transitions that were monitored for PF-02545920 were 393.3 → 143.2, whereas 382.3 → 143.2 was used for PF-03638737. The assay was linear over the range 0.500 to 100 ng/mL, and the lower limit of quantitation was 0.500 ng/mL for both PF-02545920 and PF-03638737. Samples with concentrations above the upper limit of quantitation were diluted so that they were within the calibration range. For the low-quality (1.50 ng/mL), medium-quality (9.00 ng/mL), and high-quality (80.00 ng/mL) control samples that were analyzed with the study samples, between-day accuracy (expressed as percent relative error) ranged from −3.3% to −0.9% for PF-02545920, and interassay precision (expressed as percent coefficients of variation) was ≤7.5%.
Descriptive statistics, that is, n, mean, SD, median, minimum, and maximum, were calculated for the baseline and change from baseline, by treatment group and visit data.
The primary analysis used least squares (LS) means of the PANSS total score, based on a linear mixed-effects repeated-measures model with effects for treatment, time (visit), baseline value, and investigator site. A random effect for subject was used to analyze the change from baseline in the PANSS total score. The model also included effects for treatment by time interaction and baseline value of PANSS total score by time interaction. Confidence intervals (CIs) were estimated using the covariance structure among repeated measures. Because there was only one primary end point, no adjustments for multiple comparisons or dose comparisons were made.
Using estimates from 3 previous Pfizer-sponsored schizophrenia studies (a 34.8% discontinuation rate across treatment groups, a PANSS SD at day 28 of 19.75, and a 7% reduction in sample size due to using repeated measures), 74 patients/group were calculated to provide 88% power for a difference in the true mean change from baseline in the PANSS total score equal to −10 in the PF-02545920 15 mg Q12H group. This was for a test conducted at a 1-sided level of significance of 10%, which is frequently used for phase 2 studies. Using a 2:2:1:2 randomization ratio, as described previously, the total planned sample size of the study was 260 subjects.
The study was conducted at 7 sites in the Ukraine and 22 sites in the United States from October 18, 2010, to August 4, 2011.
Overall, 368 patients were screened, 259 randomized, and 195 completed the study (Fig. S1, Supplemental Digital Content, http://links.lww.com/JCP/A623). Demographics and baseline characteristics are presented in Table 1. Treatment groups were reasonably comparable with respect to age, race, weight, and sex. Across treatment groups at baseline, the mean PANSS total score ranged from 97.2 to 98.1, and the mean BPRS total score ranged from 58.1 to 59.8 (Table 1).
The durations of exposure (median [range]) to study drug were 28 (4–28) days for PF-02545920 5 mg Q12H, 28 (2–29) days for PF-02545920 15 mg Q12H, 28 (1–28) days for risperidone, and 28 (6–29) days for placebo.
Efficacy analyses were conducted on the 254 patients who received study drug, had a baseline evaluation, and had ≥1 post–baseline evaluation. At day 28, there were no statistically significant differences in mean change in the total PANSS score from baseline between either the PF-02545920 groups (5 or 15 mg Q12H) and the placebo group (Table 2). For this reason, the study failed its primary end point. The study demonstrated a statistically significant reduction in mean change from baseline in the total PANSS score for risperidone as compared with placebo (Fig. 1).
Findings from the secondary efficacy analyses were consistent with the primary analysis. Although the 5 mg Q12H group was associated with a greater mean change from baseline in the PANSS Negative subscale score at day 28 as compared with placebo (P = 0.094 [significant at the set level of significance 0.1]; Table 2), change from baseline in the PANSS Positive subscale score, PANSS General subscale score, PANSS-derived Marder factor scores, PANSS-derived BPRS score, CGI-I score, CGI-S score, and GAF were not statistically significant between either the PF-02545920 dose groups and placebo (Table 2; Tables S1, S2, Supplemental Digital Content, http://links.lww.com/JCP/A623).
Patients in the risperidone group showed larger magnitude changes from baseline than did the PF-02545920 groups and had statistically significant differences from the placebo group in the change for the PANSS Total, Positive, and General subscale scores (P ≤ 0.017 compared with placebo); PANSS-derived Marder factor scores (except Marder negative factor score; P ≤ 0.035 compared with placebo); and PANSS-derived BPRS scores (P = 0.003 compared with placebo). Least squares mean change from baseline at day 28 were −0.8 (80% CI, −1.1 to −0.4) for the CGI-I score (P = 0.002 compared with placebo) and −0.4 (−0.6 to −0.1) for the CGI-S score (P = 0.040 compared with placebo).
Serum PF-02545920 concentrations before dosing and at specific collection time points postdose are provided in Table 3. Serum PF-02545920 concentrations increased proportionately with daily dosage. Steady state seemed to be achieved by day 7, and trough concentrations at steady state indicated that PF-02545920 levels were stable over multiple weeks of dosing.
Safety and Tolerability
A total of 258 patients were treated and included in the safety analysis. In general, there were few differences in the incidence of individual and overall adverse events (AEs) between the treatment groups, and most AEs were mild or moderate in severity (Table 4). The most frequent AEs were headache, constipation, dyspepsia, and nausea. Neutropenia occurred in 6.8% of patients in the PF-02545920 5 mg Q12H group, 2.7% in the PF-02545920 15 mg Q12H group, 2.8% in the risperidone group, and 5.4% in the placebo group. Akathisia occurred more frequently with the PF-02545920 groups (8.1% and 6.8% with 5 and 15 mg Q12H, respectively) than with either risperidone (2.8%) or placebo (1.4%). Somnolence and sedation occurred in 12.2% of the PF-02545920 15 mg Q12H group compared with 6.8% in the 5 mg Q12H group, 5.6% with risperidone, and 6.8% with placebo.
Dystonia was noted in 1 and 6 patients in the 5 mg Q12H and 15 mg Q12H PF-2545920 groups, respectively; no patients in the risperidone group; and 3 patients in the placebo group. Among the 6 patients in the 15 mg Q12H PF-2545920 group, 5 dystonia events occurred before day 7, of which only 1 was reported as severe (oculogyric crisis). Statistical analysis did not show significant differences in the incidence of dystonias between any of the PF-2545920 or risperidone group and placebo (differences in proportion [80% CI, adjusted due interim] were −0.03 [−0.07 to 0.01] and 0.04 [−0.02, 0.10] for PF-02545920 5 mg Q12H and 15 mg Q12H, respectively). Dystonia AEs were managed successfully with anticholinergic medication administered as needed and, in one case, administered prophylactically for 4 days. The changes in the Abbreviated Extrapyramidal Symptom Rating Scale at day 28 showed no clinically meaningful differences between groups.
The numbers of patients who discontinued because of AEs in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups were 2 (2.7%), 5 (6.8%), 2 (5.6%), and 4 (5.4%), respectively. The corresponding numbers of patients who had dose reductions or who were temporarily discontinued from the study because of AEs were 1 (1.4%), 2 (2.7%), 1 (2.8%), and 2 (2.7%). Across the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, serious AEs occurred in 3 (4.1%), 6 (8.1%), 2 (5.6%), and 1 (1.4%) patient, respectively. Serious AEs were predominantly due to exacerbation of psychosis or schizophrenia symptoms. The serious AEs included 2 deaths that occurred in the PF-02545920 5 mg Q12H group, both at approximately 2.5 weeks after the last dose of study drug; both were considered unrelated to study drug and were attributed to cardiac disease and other cardiac risk factors by the study investigator. No treatment-related serious AEs occurred.
No laboratory test values or physical examination findings were considered clinically significant by the investigator. Vital signs and mean electrocardiogram results were normal. Change in weight and waist circumference was greatest in the risperidone group. The mean (SD) changes in body weight at day 28 (or early termination) in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups were 0.2 (2.2), −1.2 (3.2), 2.7 (3.0), and 1.0 (2.6) kg, respectively. The corresponding mean (SD) changes in waist circumference were 0.7 (5.1), 0.7 (5.7), 3.3 (4.5), and 0.7 (4.3) cm, respectively.
This study used the selective and potent inhibitor PF-02545920 to evaluate the efficacy, safety, and tolerability of PDE10A inhibition as a monotherapy for the treatment of acute exacerbation of schizophrenia, as compared with placebo and the active comparator risperidone. Results showed no significant overall benefit for PF-02545920 monotherapy in the treatment of acute schizophrenia; PANSS total score at day 28 was not different between either PF-02545920 fixed-dose regimens or placebo, and therefore, the trial failed its primary end point. The 5 mg Q12H PF-02545920 group did show a significantly better improvement than did the placebo group at day 28 for the change from baseline in PANNS Negative subscale; however, other secondary efficacy end points were in line with the primary, that is, no benefit versus placebo. The widely used dopamine D2 receptor antagonist, risperidone, showed significant separation from placebo for most efficacy measures, demonstrating that the trial was adequately powered and conducted to detect efficacy.
Despite negative efficacy findings, both doses of PF-02545920 had an overall tolerability profile comparable with that of risperidone. However, the risperidone group had greater mean weight gain than did the PF-02545920 groups. The most common AEs that were also more frequent with PF-02545920 were akathisia in both dose groups, and dystonia and sedation/somnolence in the 15 mg Q12H group. Regarding dystonia, there was insufficient statistical evidence to suggest that the incidence with either PF-02545920 dose was different from that with placebo, although a greater number of cases of dystonia occurred with the 15 mg Q12H dose. This observation is in accordance with earlier studies of PF-02545920, which demonstrated that the incidence of dystonia was dose related.21 Furthermore, recent studies have linked mutations in PDE10A with movement disorders such as childhood-onset chorea and magnetic resonance imaging evidence of striatal pathologic legions.29,30
These results indicate that inhibition of PDE10A does not mimic the clinical effects of currently marketed D2 receptor antagonists despite the observed similarities in the location of these targets, as well as striatal activity in laboratory studies. Acute psychotic episodes in schizophrenia are currently treated with dopamine D2 receptor antagonists, which primarily reduce positive symptoms.2,3 However, not all patients benefit from treatment with D2 antagonists, and many experience troublesome motor adverse effects.2–4 Newer (atypical) treatments with mixed mechanisms of action, for example, 5-HT 2A receptor blockade with D2 receptor antagonism, are associated with fewer motor adverse effects but offer few improvements in efficacy. Thus, there remains an unmet need for new medications that can improve treatment across the entire spectrum of symptoms associated with schizophrenia. Preclinical studies from multiple laboratories have demonstrated that PDE10A inhibition mimics the activation of striatal D2-expressing projection neurons produced by the pharmacological blockade of D2 receptors. This activation of the striatopallidal/no-go pathway by both PDE10A inhibitors and D2 receptor antagonists is presumably related to their ability to preferentially increase cAMP- and cGMP-mediated signaling in these neurons.5,10,14,31–35 Because “disinhibition” of the D2 expressing output neurons of the striatum is a leading hypothesis for explaining the efficacy of currently marketed antipsychotic medications, the circuitry effects of PDE10A inhibitors (such as PF-2545920) in preclinical studies warranted consideration of the potential for this mechanism to provide similar clinical efficacy. The results of the present study clearly show no evidence of efficacy in the targeted patient population, suggesting that indirect pathway activation is insufficient for antipsychotic activity or that the compound did not produce the desired circuitry effect owing to some failure of the study design or a confounding effect of PDE10A inhibition in the target population.
We believe that the current study tested adequate concentrations of PF-2545920 to test the hypothesis. The rodent conditioned avoidance model is sensitive to D2 receptor antagonists and predictive of their clinically active exposures. It is similarly disrupted by PDE10A inhibitors at free plasma concentrations below the IC50 for PDE10A inhibition and the half-maximal effective concentration for striatal cGMP/cAMP increases.6 PF-02545920 concentrations observed in the current study were approximately 12 and 45 ng/mL at predose steady state for the 5 mg Q12H and 15 mg Q12H doses, respectively. This places steady-state trough concentrations at the 15 mg Q12H dose well within the target range identified in rodent studies (IC50 at 21 to 42 ng/mL, half-maximal effective concentration between 16 and 50 ng/mL). Considering the expected Tmax, peak plasma levels were approximately 50 and 150 ng/mL in the 2 groups, respectively; it is expected that the PF-02545920 exposures in this study were adequate for at least 50% enzyme inhibition at 5 mg Q12H, particularly in the hours after dosing. In previous rodent studies, extracellular striatal cGMP and cAMP increased approximately 3-fold within 1 hour of a single dose and remained elevated through to the end of monitoring at 4 hours after dosing, suggesting that the effect of enzyme inhibition lasts for several hours after peak exposure.6 However, it should also be noted that a higher 30-mg single oral dose of PF-02545920 was found to be incompatible with clinical use in previous trials, due to emerging tolerability issues.21 A recent radioligand study in healthy participants showed that single oral doses of 10 and 20 mg of PF-2545920 achieved 14% to 27% and 45% to 63% striatal PDE10A engagement, respectively, at 1 to 2.5 hours after dosing, an interval suggested to include Tmax. The serum concentration associated with 50% enzyme occupancy was estimated to be 93.2 ng/mL.21 Together, these findings may suggest that, although the IC50 was not achieved throughout the 28 days' treatment, sufficient enzyme inhibition should have occurred to allow meaningful clinical efficacy to be observed.
The decision to advance PF-2545920 into the clinic was strongly influenced by the similar effects of PDE10A inhibition and D2 receptor blockade on the circuitry of the basal ganglia. The failure of PF-2545920 in the clinic is therefore relevant to our understanding of the mechanism by which D2 antagonists produce an antipsychotic effect. An obvious question arising from our data is whether striatopallidal pathway activation is sufficient for clinical efficacy or is an additional consequence of D2 receptor blockade also needed. Alternatively, PDE10A inhibition may have other circuitry effects that interfere with clinical efficacy. In this regard, the activation of the D1-expressing striatonigral pathway by PDE10A inhibitors has been discussed.36 In the search for predictive models of antipsychotic activity, it would be of interest to evaluate PDE10A inhibitors in models based on adaptive effects of D2 receptor blockade such as depolarization-induced blockade,37 both with and without prior long-term D2 antagonist exposure.38
Since this study was completed, additional studies have evaluated the potential adjunctive effect of the same doses of PF-02545920 on the clinical response to currently used antipsychotic therapy. The clinical development of PF-2545920 has since been halted because of the lack of observable efficacy compared with placebo in phase 2 studies (NCT01829048; NCT01939548; DeMartinis et al22). Studies evaluating other PDE10A inhibitors such as TAK-063 have also been completed and published, with promising results from preclinical work.32,39 However, the results of a phase 2 study conducted in patients with an acute exacerbation of schizophrenia failed to meet its primary end point of change from baseline on the PANNS total score at week 6.40
In conclusion, this study showed that monotherapy with PF-02545920 was not an effective treatment of acute exacerbation of schizophrenia. Findings for the primary efficacy and most secondary efficacy end points did not show statistically significant differences from placebo. The active control, risperidone, demonstrated statistically significant efficacy compared with placebo. Pharmacokinetic analyses suggested that PDE10A engagement in the striatum would be sufficient and at a similar level to that observed in the preclinical models predicting efficacy. These results indicate that inhibition of PDE10A (with PF-02545920) in the clinic does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.
Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the United States and/or European Union or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
Medical writing support was provided by Tuli Ahmed, of JetStream Clinical, LLC, and Jennifer Bodkin, PhD, CMPP, and Jon Edwards, PhD, CMPP, of Engage Scientific, Horsham, UK, funded by Pfizer.
AUTHOR DISCLOSURE INFORMATION
The study was sponsored by Pfizer, which was involved in the study design and data analysis. N.D., V.D., A.B., S.B., and C.J.S. are current or former employees of Pfizer. D.P.W. has received grant/research support from Novartis, J&J PRD, Sunovion, Janssen, Pfizer, Shire, Eli Lilly, Abbott, AbbVie, Forest, Allergan, Eisai, Takeda, Otsuka, Zogenix, Omeros, CoMentis, and IntraCellular, and has served as a consultant to Otsuka, Eli Lilly, Janssen, and Acadia.
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