A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia

A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of... Neurol Ther (2018) 7:129–139 https://doi.org/10.1007/s40120-017-0085-5 ORIGINAL RESEARCH A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia . . . David Brown Kristen Daniels Solen Pichereau Michael Sand Received: August 24, 2017 / Published online: November 24, 2017 The Author(s) 2017. This article is an open access publication and 217 to 2020 nmol•h/L, respectively. Elimi- ABSTRACT nation was rapid (gMean t range 1.10–1.85 h). 1/2 After multiple doses, C was reached within max,ss Introduction: This randomized, double-blind, 1 h; elimination was similar to that observed parallel-group study investigated the safety, after a single dose. Total exposure at steady state tolerability, pharmacokinetics (PK), and cogni- and after a single dose were similar (accumula- tive outcomes of BI 409306—a selective phos- tion ratio range: AUC, 0.758–1.13 and C , max phodiesterase 9A (PDE9A) inhibitor—in 0.768–1.40). No deaths, adverse events (AEs) patients with schizophrenia. leading to discontinuation, or serious AEs were Methods: Patients with mild-to-moderate observed. Treatment-emergent AEs were mild, schizophrenia were randomized (1:1:1:1) to with no apparent dose-related trends. There was receive BI 409306 at 25, 50, or 100 mg or placebo no worsening of schizophrenia symptoms once daily over 14 days. The primary endpoints (Positive and Negative Syndrome Scale) and no were safety and tolerability; the secondary end- trends in suicidality (Columbia Suicide Severity points were PK and cognitive outcomes. Rating Scale). The Hopkins Verbal Learning Results: Of the 40 randomized patients, 38 Test–Revised (HVLT-R) and Brief Visuospatial (95%) completed the study. Patients were pre- Memory Test–Revised (BVMT-R) showed no dominantly male (87.5%; mean age, 40.2 years). effect on cognitive function. After a single dose, C was reached within max Conclusion: Administration of BI 409306 in 30–45 min. The geometric mean (gMean) C max patients with mild-to-moderate schizophrenia and AUC ranged from 138 to 998 nmol/L 0-? resulted in satisfactory safety and tolerability. BI Enhanced content To view enhanced content for this 409306, PK was characterized by rapid absorp- article go to http://www.medengine.com/Redeem/62DC tion, monophasic to biphasic elimination, and F0600F4FDF01. minor accumulation with multiple dosing. Trial Registration: ClinicalTrials.gov identifier D. Brown NCT01892384. Community Clinical Research, Inc., Austin, TX, USA Funding: Boehringer Ingelheim Pharma GmbH K. Daniels  M. Sand (&) & Co. KG. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA e-mail: michael.sand@boehringer-ingelheim.com Keywords: BI 409306; Cognitive outcome; Phosphodiesterase inhibitor; PDE9A; S. Pichereau Pharmacokinetics; Phase I; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Safety; Schizophrenia; Tolerability 130 Neurol Ther (2018) 7:129–139 blurred vision. These AEs occurred shortly after INTRODUCTION administration and were resolved within 1–2 h. In a proof-of-mechanism study conducted in Impaired N-methyl-D-aspartic acid (NMDA) healthy male volunteers, BI 409306 adminis- receptor signaling and reduced levels of cyclic tered orally as a single dose crossed the guanosine monophosphate (cGMP) have been blood–brain barrier and triggered a dose- and demonstrated in animal models of schizophre- concentration-dependent increase in cGMP in nia [1, 2], and increasing evidence suggests that the CSF [14]. glutamatergic dysfunction may play a key role The objective of this study was to investigate in mediating risk for conversion to psychosis the safety and tolerability of BI 409306, a novel [3–5]. Phosphodiesterase 9A (PDE9A), which has PDE9 inhibitor, in patients with mild-to-mod- the highest affinity of all PDEs, hydrolyzes erate schizophrenia. The associated pharma- cGMP to regulate its intracellular concentration cokinetics (PK) and cognitive outcomes were within glutamatergic neurons [6]. Conse- also explored. BI 409306 was administered quently, PDE9A inhibition may augment orally at a dosage of 25, 50, or 100 mg for synaptic plasticity and memory function 14 days. through increased cGMP availability and, thus, improved NMDA receptor signaling [6, 7]. PDE9A is highly expressed in the neocortex and METHODS hippocampus; therefore, it is likely to be a sig- nificant determinant of intracellular basal Study Design cGMP levels in these brain regions [6, 8]. BI 409306 is a potent and selective PDE9A This was a randomized, double-blind, inhibitor. Application of BI 409306 to rat hip- placebo-controlled, parallel-group, phase I pocampal slices resulted in significant study in patients with mild-to-moderate enhancement of long-term potentiation (LTP) schizophrenia. The study was conducted from 8 [9]. Furthermore, BI 409306 induced a dose-de- July 2013 to 5 December 2013 at the Commu- pendent increase in cGMP in rat cerebrospinal nity Clinical Research, Inc., Austin, TX. The fluid (CSF) and prefrontal cortex and improved duration of the study from screening through memory performance [10]. In healthy male completion of the end-of-treatment visit was up volunteers, BI 409306 was rapidly absorbed and to 8 weeks. The end-of-treatment visit was eliminated and showed a good safety and tol- planned 7–14 days after the administration of erability profile [11–13]. In these studies, the the last dose of the study drug (Fig. 1). Patients most frequent adverse events (AEs) were visual were randomized (1:1:1:1) on day 1 to receive BI symptoms such as photopsia (flashing light), 409306 at 25, 50, or 100 mg or placebo, photophobia (increased sensitivity to light), administered orally once daily (qd) for 14 days. chromatopsia (change in color perception), and Fig. 1 Study design Neurol Ther (2018) 7:129–139 131 Sequentially numbered blinded medication kits hematological, or hormonal disorders; a history were assigned to the patients at the study site. or new diagnosis of human immunodeficiency All the patients provided written informed virus infection or malignancy; or a history of consent. All procedures followed in the study neurologic or psychiatric condition that might (ClinicalTrials.gov: NCT01892384) were in interfere with the interpretation of data. Preg- accordance with the protocol, ethical standards nant or breastfeeding women were also laid down in the Helsinki Declaration of 1964 excluded. (as revised in 2013), the International Confer- ence on Harmonisation of Technical Require- Study Assessments ments for Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guidelines for Safety Endpoints Good Clinical Practice, and relevant Boehringer The primary endpoints for safety and tolerabil- Ingelheim standard operating procedures. ity were evaluated based on AEs, vital signs, 12-lead electrocardiogram (ECG), clinical labo- Patients ratory tests, physical examination, Clinical Global Impression–Improvement (CGI-I) scale, Patients included in the study were 18–55 years disease severity on the Positive and Negative of age, with an established diagnosis of Syndrome Scale (PANSS), suicidality assessment schizophrenia as defined by the Diagnostic and by the C-SSRS, and visual acuity and color Statistical Manual of Mental Disorders (DSM)-IV vision assessed by Snellen chart and Ishihara criteria, with the following clinical features: plates, respectively. clinically stable and in the residual (non-acute) phase of illness or maintained on current Pharmacokinetic Endpoints antipsychotic medications and dose for The following PK parameters were assessed as C 8 weeks; and having no more than a ‘‘mod- secondary endpoints: area under the plasma erate’’ severity rating on hallucinations and concentration–time curve of BI 409306 from delusions, positive formal thought disorder and zero extrapolated to infinity after a single dose negative symptoms, and minimal extrapyrami- (AUC ); area under the plasma concentra- 0-? dal and depressive symptoms. All patients were tion–time curve of BI 409306 in plasma at genotyped for cytochrome P450 2C19 steady state over a uniform dosing interval tau (CYP2C19). (AUC ); maximum measured concentration tau,ss Patients were excluded if they were treated of BI 409306 in plasma following a single dose with [ 1 antipsychotic agent, not stabilized on (C ) and at steady state (C ); time from max max,ss antipsychotic treatment, or had electroconvul- dosing to maximum measured concentration of sive therapy within the last 30 days, or if the BI 409306 in plasma following a single dose severity of their cognitive impairment would (t ) and at steady state (t ); and terminal max max,ss affect the study outcome in the clinical judg- elimination half-life of BI 409306 (t ). 1/2 ment of the investigator. In addition, patients with any of the following were excluded from Cognitive Outcomes the study: suicidal behavior within the past Additional secondary endpoints included mea- 2 years or type 4 or 5 suicidal ideation on the surement of the total score on the Hopkins Columbia Suicide Severity Rating Scale (C-SSRS) Verbal Learning Test–Revised (HVLT-R) and within the past 3 months; findings from medi- total score on the Brief Visuospatial Memory cal examination or laboratory values deviating Test–Revised (BVMT-R). from normal limits and of clinical relevance; planned elective surgery; a history or diagnosis Statistical Analyses of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, car- Dose proportionality was explored after a single diovascular, metabolic, immunological, dose (day 1, C and AUC ) and after max 0-? 132 Neurol Ther (2018) 7:129–139 multiple dosing (day 14, C and AUC ) completed the study and two withdrew consent max,ss tau,ss using a linear regression model with log-trans- (Fig. 2). There were four important protocol formed dose as an independent variable applied deviations: one patient in the 25-mg group to log-transformed data. Two-sided 95% confi- received a prohibited medication (lorazepam) on dence intervals (CIs) for the slope were com- day 7; one patient in the 50-mg group tested puted from this model. For PK endpoints positive for cocaine on day -1, but had initiated AUC and AUC , a linear model with treatment before the drug screen results were 0-? tau,ss patient and order as fixed effects was applied to available; another patient had a prior suicide log-transformed data to assess linearity for each attempt; and one patient in the placebo group dose separately. Attainment of steady state was declined to provide informed consent for the assessed using a linear model with patient as a optional pharmacogenetic sample collection for fixed effect, time as a repeated effect, and DNA banking. However, none of these patients log-transformed pre-dose concentration from were excluded from the study analysis. Patients days 1 to 14 as the dependent variable for each were predominantly male (87.5%) and African dose separately. American (52.5%) or white (47.5%), with a mean Changes in HVLT-R and BVMT-R total scores (standard deviation [SD]) age of 40.2 (9.0) years. were compared between doses of BI 409306 and Demographics and baseline characteristics were placebo using an analysis of covariance model well balanced across all treatment groups, with with treatment as a fixed effect and baseline as a the exception of cognition (HVLT-R and covariate. Safety analyses were performed for all BVMT-R; Table 1). As BI 409306 oxidative meta- patients who received C 1 dose of the study bolism is dependent on CYP2C19, CYP2C19 drug; the results are summarized descriptively. phenotype was predicted for each patient based on genotype. Of the 40 randomized patients, 16 (40.0%) were predicted to be ultra-rapid metab- RESULTS olizers (UM) for CYP2C19; 11 (27.5%), extensive metabolizers (EM); and 8 (20.0%), intermediate Patient Characteristics metabolizers (IM). No patients were predicted to be poor metabolizers (PM) for CYP2C19. For five Of the 50 patients enrolled, 40 were randomized patients, the predicted CYP2C19 phenotype to receive either BI 409306 or placebo; 38 patients could not be determined based on genotype. Fig. 2 Patient disposition Neurol Ther (2018) 7:129–139 133 Table 1 Patient demographics and baseline characteristics BI 409306 Placebo (n 5 10) Total (N 5 40) 25 mg (n 5 10) 50 mg (n 5 10) 100 mg (n 5 10) Mean age (SD), years 37.9 (9.5) 42.5 (9.0) 42.5 (8.4) 37.8 (9.5) 40.2 (9.0) Gender, n (%) Male 10 (100.0) 7 (70.0) 10 (100.0) 8 (80.0) 35 (87.5) Female – 3 (30.0) – 2 (20.0) 5 (12.5) Race, n (%) African American 5 (50.0) 4 (40.0) 7 (70.0) 5 (50.0) 21 (52.5) White 5 (50.0) 6 (60.0) 3 (30.0) 5 (50.0) 19 (47.5) BMI, kg/m 26.0 (5.6) 31.5 (4.3) 29.1 (6.1) 28.7 (5.2) 28.8 (5.5) HVLT-R score 17.9 (5.5) 18.4 (3.7) 16.9 (6.4) 19.5 (5.2) 18.2 (5.2) BVMT-R score 9.2 (10.3) 17.5 (3.8) 12.9 (7.9) 16.2 (10.3) 14.0 (8.8) Smoking status, n (%) Never smoked – 1 (10.0) 1 (10.0) 3 (30.0) 5 (12.5) Ex-smoker – 1 (10.0) 3 (30.0) – 4 (10.0) Current smoker 10 (100.0) 8 (80.0) 6 (60.0) 7 (70.0) 31 (77.5) Alcohol status, n (%) Non-drinker 10 (100) 9 (90.0) 9 (90.0) 10 (100.0) 38 (95.0) Drinks–no interference – 1 (10.0) 1 (10.0) – 2 (5.0) Treated set includes all patients who received at least 1 dose of study medication Data are presented as mean (SD), unless indicated otherwise BMI body mass index, BVMT-R Brief Visuospatial Memory Test–Revised, HVLT-R Hopkins Verbal Learning Test–Re- vised, SD standard deviation Safety spontaneously without medical treatment. All but three events (blurred vision in one patient each in the 25-mg and 50-mg groups, and visual Table 2 summarizes the AEs. BI 409306 was well field defect in one patient in the 100-mg group) tolerated; treatment-emergent AEs were repor- were assessed as related to treatment. There ted in 23 (57.5%) patients. All AEs were mild in were no deaths, serious AEs or discontinuation intensity, and no apparent dose-related trends due to AEs. The incidence of treatment-emer- were observed for any AE. Eleven (27.5%) gent AEs was similar between BI 409306 and patients reported a total of 13 eye-related AEs, placebo. No clinically relevant or dose-related including blurred vision (n = 8), photopsia changes were observed in laboratory parame- (flashing lights; n = 2), visual impairment ters, vital signs, or ECGs in patients receiving BI (n = 2), and visual field defect (n = 1). The 409306 or placebo. number of patients reporting eye-related AEs CGI-I indicated no change or minimal was similar across all BI 409306 dose groups and improvement in the patients’ overall disease the placebo group. All eye-related AEs were status. The mean change from baseline in total non-serious and mild in intensity, and resolved 134 Neurol Ther (2018) 7:129–139 Table 2 Summary of adverse events System organ class/preferred term BI 409306 Placebo Total (n 5 10) (N 5 40) 25 mg 50 mg 100 mg n (%) n (%) (n 5 10) (n 5 10) (n 5 10) n (%) n (%) n (%) Total with adverse events 4 (40.0) 9 (90.0) 6 (60.0) 4 (40.0) 23 (57.5) Infections and infestations – 1 (10.0) 1 (10.0) – 2 (5.0) Furuncle – 1 (10.0) – – 1 (2.5) Tooth infection – – 1 (10.0) – 1 (2.5) Psychiatric disorders 1 (10.0) – 2 (20.0) 1 (10.0) 4 (10.0) Agitation – – 1 (10.0) 1 (10.0) 2 (5.0) Anxiety 1 (10.0) – 1 (10.0) – 2 (5.0) Nervous system disorders 1 (10.0) 1 (10.0) 2 (20.0) – 4 (10.0) Dizziness 1 (10.0) – – – 1 (2.5) Headache – 1 (10.0) 1 (10.0) – 2 (5.0) Tremor – – 1 (10.0) – 1 (2.5) Visual field defect – – 1 (10.0) – 1 (2.5) Eye disorders 2 (20.0) 4 (40.0) 2 (20.0) 2 (20.0) 10 (25.0) Vision blurred 2 (20.0) 3 (30.0) 1 (10.0) 2 (20.0) 8 (20.0) Photopsia – 1 (10.0) 1 (10.0) – 2 (5.0) Visual impairment 1 (10.0) 1 (10.0) – – 2 (5.0) Gastrointestinal disorders 2 (20.0) – 1 (10.0) – 3 (7.5) Gastroesophageal reflux disease 1 (10.0) – – – 1 (2.5) Nausea 1 (10.0) – – – 1 (2.5) Toothache – – 1 (10.0) – 1 (2.5) Vomiting 1 (10.0) – – – 1 (2.5) Musculoskeletal and connective tissue – 3 (30.0) – – 3 (7.5) disorders Musculoskeletal pain – 2 (20.0) – – 2 (5.0) Back pain – 1 (10.0) – – 1 (2.5) General disorders and administration site – – 1 (10.0) 1 (10.0) 2 (5.0) conditions Pain – – 1 (10.0) – 1 (2.5) Pre-existing condition improved – – – 1 (10.0) 1 (2.5) Injury, poisoning, and procedural – 1 (10.0) 1 (10.0) – 2 (5.0) complications Excoriation – 1 (10.0) 1 (10.0) – 2 (5.0) Percentages are calculated using total number of patients per treatment as the denominator PANSS scores for the 25-, 50-, and 100-mg BI visual acuity were reported intermittently for a 409306 and placebo groups were -0.1, -0.2, few patients across all treatment groups. Color -1.4, and -0.9, respectively, at day 7, and 2.3, discrimination was reported as normal at max- 0.0, -3.6, and 0.0, respectively, at day 13, sug- imum time points in all the patients. Visual gesting no deterioration in disease symptoms or examination of box-plots of C of BI 409306 max,ss clinical status. Mild suicidal ideation after or its major metabolites did not suggest any treatment initiation (C-SSRS score = 1) was association between higher exposure and wors- reported in one patient each in the 50-mg ening of visual acuity or color vision. BI 409306 and placebo groups. Changes in Neurol Ther (2018) 7:129–139 135 Administration of BI 409306 had a negligible Cognitive Outcomes effect on the mean pupil diameter relative to placebo. No significant treatment differences were observed with 25-, 50-, or 100-mg BI 409306 in Pharmacokinetics HVLT-R total scores (p = 0.0867, p = 0.2011, and p = 0.4103, respectively) or BVMT-R total scores (p = 0.5791, p = 0.605, and p = 0.7171, PK profiles of BI 409306 following single- and respectively) compared with placebo. multiple-dose administration were character- ized by a rapid increase in plasma concentration and rapid elimination. Table 3 shows the PK DISCUSSION endpoints after single- and multiple-dose administration of BI 409306. After single-dose In this study, BI 409306 at a dosage of 25, 50, or administration, BI 409306 was rapidly absorbed, 100 mg per day for 14 days was well tolerated in reaching C within 30–45 min (Fig. 3). Fol- max patients with mild-to-moderate schizophrenia. lowing absorption, BI 409306 was rapidly The PK of BI 409306 following single- and eliminated, with geometric mean (gMean) t 1/2 multiple-dose administration was characterized ranging from 1.10 to 1.85 h. After multiple-dose by very rapid absorption followed by rapid administration, BI 409306 was rapidly absorbed, monophasic to biphasic elimination. No evi- with C attained within the first hour after max,ss dence of deterioration in schizophrenia symp- dosing. Total exposure at steady state was sim- toms, suicidality, or overall clinical status was ilar to that following a single dose, with an observed in this study. accumulation ratio close to 1 (ranges: AUC The safety results for BI 409306 in this study 0.758–1.13; C 0.768–1.40), indicating minor max are comparable to those from studies conducted to no accumulation with multiple dosing. in healthy male volunteers. In previous studies, Dose-normalized gMean C , C , max max,ss AEs were mild to moderate in intensity and of AUC and AUC values were similar for 0-? tau,ss short duration [11, 14]. The most frequently the 50- and 100-mg dose groups following sin- reported AEs were visual AEs. Consistent with gle- and multiple-dose administration, suggest- the present study, there was no apparent ing dose proportionality. However, dose-dependent increase in AEs [14]. In young dose-normalized parameters for the 25-mg dose and elderly healthy subjects administered 25, group were lower than expected, with approxi- 50, or 100 mg BI 409306 or placebo, a majority mately threefold lower C and AUC- max,ss,norm of the AEs were mild in intensity, with a compared with the higher dose tau,ss, norm dose-dependent increase in subjects reporting groups. Linearity with respect to multiple dose eye disorders such as photophobia (increased administration could not be established due to sensitivity to light), chromatopsia (change in high inter-individual variability in the linearity color perception), visual impairment, blurred index within each dose group. vision, abnormal sensation in the eye, asthe- Inter-individual variability in BI 409306 PK nopia, and eye pain [12]. Similarly, in healthy parameters was moderate to high. The geometric male Chinese and Japanese subjects, most AEs coefficient of variation (gCV) after a single dose were mild; the most frequently reported AEs in ranged from 98.4% to 108% for AUC and from 0-? subjects receiving BI 409306 were eye disorders 73.3% to 106% for C ; gCV at steady state ran- max (29.8%), which were resolved within 1–2 h [13]. ged from 86.8% to 112% for AUC and from tau,ss Visual side effects have been proposed to be 74.4% to 90.9% for C . Exposure was highest max,ss associated with PDE9A, which regulates the in patients with the CYP2C19 IM predicted phe- level of cGMP by hydrolyzing it and modulates notype, followed by EM and UM patients. How- inhibitory processes in the cone pathway of the ever, inter-individual variability was lower in the retina [15]. Given the results in healthy sub- IM patients than in the EM and UM patients, with jects, eye-related AEs were of interest in this gCV% of 48.4%, 152%, and 154%, respectively. study, and indeed, these were the most 136 Neurol Ther (2018) 7:129–139 Table 3 Pharmacokinetic endpoints after single- and multiple-dose administration of BI 409306 BI 409306 25 mg (n 5 10) 50 mg (n 5 10) 100 mg (n 5 10) AUC , nmol•h/L 217 (107) 770 (98.4) 2020 (108) 0-? AUC , nmol•h/L 147 (112) 969 (104) 2280 (86.8) tau,ss C , nmol/L 138 (91.9) 431 (73.3) 998 (106) max C , nmol/L 99.2 (86.8) 631 (90.9) 1290 (74.4) max,ss t ,h 0.63 (0.33–1.50) 0.63 (0.33–2.0) 0.75 (0.33–2.0) max t ,h 0.75 (0.33–1.0) 0.33 (0.33–1.5) 0.63 (0.33–1.5) max,ss t , h 1.10 (43.1) 1.57 (27.0) 1.85 (31.0) 1/2 RA, C 0.768 (42.5) 1.40 (23.9) 1.29 (61.4) max RA, AUC 0.758 (26.9) 1.13 (17.8) 1.13 (42.5) Pharmacokinetic (PK) set included all patients in the treated set who had no important protocol violation(s) relevant to the evaluation of PK parameters and who provided at least 1 evaluable observation for a PK endpoint Data are presented as geometric mean (% gCV) unless otherwise noted Median (min–max) AUC , area under the plasma concentration–time curve of the analyte from zero extrapolated to infinity after single 0-? dose; AUC , area under the plasma concentration–time curve of the analyte in plasma at steady state over a uniform tau,ss dosing interval tau; C , maximum measured concentration in plasma following a single dose (and at steady state); gCV, max,ss geometric coefficient of variation; RA, AUC, accumulation ratio of the analyte in plasma at steady state corresponding to the ratio of AUC to AUC ; RA, C , accumulation ratio of the analyte in plasma at steady state corresponding to tau,ss 0-? max the ratio of C to C ; t , time from dosing to maximum measured concentration in plasma following a single dose max,ss max max,ss (and at steady state); t , terminal elimination half-life 1/2 Fig. 3 Geometric mean plasma concentration–time profiles after single and multiple doses of BI 409306 (25, 50, and 100 mg) frequently reported AEs. Unlike previous stud- reported intermittently and with similar sever- ies, however, eye-related AEs in this study were ity and frequency by patients across treatment reported with similar frequency in all treatment groups, and were typically mild and transient. groups. Overall, changes in visual acuity were While some changes in visual acuity in BI Neurol Ther (2018) 7:129–139 137 409306-treated patients occurred around the with chronic schizophrenia, many of whom are anticipated time of peak plasma concentrations on multiple medications or on medications that of BI 409306, a consistent relationship between were excluded. Nevertheless, the study results changes in visual acuity and BI 409306 C was provide guidance for design of future trials with max not observed. Interestingly, the frequency of BI 409306. total AEs in this study is comparable to that of a study in which the selective PDE9A inhibitor CONCLUSION PF-04447943 was used in patients with mild-to-moderate probable Alzheimer’s disease Overall, BI 409306 showed satisfactory safety [16]. and tolerability at 25-, 50-, or 100-mg qd doses The PK of BI 409306 in this study is in line for 14 days in patients with mild-to-moderate with that observed in previous studies in heal- schizophrenia. The PK profile of BI 409306 was thy subjects, which is characterized by very characterized by rapid absorption, rapid rapid absorption and elimination, with minor monophasic to biphasic elimination, and minor accumulation. In the current study, exposure accumulation with multiple dosing. There were was dose-proportional from 50 to 100 mg and no apparent effects on cognitive function over was comparable to that observed in a previous 14 days of treatment with BI 409306. study [12]. However, exposure in the 25-mg dose group was lower than expected, resulting in a lack of dose proportionality over the 25- to 100-mg dose range. Linearity with respect to ACKNOWLEDGEMENTS multiple-dose administration could not be established due to the high inter-subject vari- The study and the article processing charges were ability in the linearity index within each dose funded by Boehringer Ingelheim Pharma GmbH group. This variability could be partly due to & Co. KG (Ingelheim am Rhein, Germany). All differences in CYP2C19 predicted phenotype, as authors had full access to all the data in this study exposure in IM was highest, followed by expo- and take complete responsibility for the integrity sure in EM and UM. of the data and accuracy of the data analysis. The A previous study reported that BI 409306 authors would like to thank Diana Brewer of crossed the blood–brain barrier, with the maxi- Community Clinical Research, Inc., Austin, TX, mum concentration in CSF reaching 28.31% of USA, for her significant assistance in the opera- the maximum plasma concentration [14]. BI tional conduct of this study, and Dr. Lauren Liss 409306 had no effect on the chosen cognitive for her help in drafting the Introduction sec- tests over the 14-day treatment period in tion. All named authors meet the International patients with schizophrenia; however, that Committee of Medical Journal Editors (ICMJE) study was not of sufficient power or duration to criteria for authorship for this manuscript, take adequately assess the overall effect on cognition responsibility for the integrity of the work as a [17]. In a phase II placebo-controlled study, whole and have given final approval of the ver- PF-04447943 reached maximal concentrations sion to be published. Writing, editorial support of approximately five times the IC50 [16]. and formatting assistance was provided by Moreover, the estimated median exposure Suchita Nath-Sain, PhD, of Cactus Communica- remained above the IC50 for the entire dosing tions, which was contracted and funded by duration. Treatment with PF-04447943 over a Boehringer Ingelheim for these services. Boeh- 12-week period was not more effective than ringer Ingelheim was given the opportunity to placebo in terms of cognition, behavior, or review the manuscript for medical and scientific clinician-rated global change. accuracy as well as intellectual property consid- A limitation of this study is that the popu- erations. The results presented in this paper were lation was drawn from a single center. Further- published in part at the 15th International more, the patients who participated in this Congress on Schizophrenia Research, 28 March study may not represent the larger population to 1 April 2015, Colorado Springs, CO, USA, and 138 Neurol Ther (2018) 7:129–139 the 70th Annual Scientific Meeting of the Society 2. Nabeshima T, Mouri A, Murai R, Noda Y. Animal model of schizophrenia: dysfunction of NMDA of Biological Psychiatry, 14–16 May 2015, Tor- receptor-signaling in mice following withdrawal onto, Ontario, Canada. from repeated administration of phencyclidine. Ann N Y Acad Sci. 2006;1086:160–8. Disclosures. David Brown received a fee 3. Salisbury DF, Shenton ME, Griggs CB, Bonner-Jack- from Boehringer Ingelheim for consulting ser- son A, McCarley RW. Mismatch negativity in chronic vices on the clinical trial protocol. Kristen schizophrenia and first-episode schizophrenia. Arch Daniels is employed by Boehringer Ingelheim. Gen Psychiatry. 2002;59:686–94. Michael Sand is employed by Boehringer 4. Schobel SA, Chaudhury NH, Khan UA, et al. Imag- Ingelheim. Solen Pichereau was an employee of ing patients with psychosis and a mouse model Boehringer Ingelheim at the time that the study establishes a spreading pattern of hippocampal was conducted but is now employed by Roche dysfunction and implicates glutamate as a driver. Neuron. 2013;78:81–93. (Basel, Switzerland). Solen Pichereau has no conflicts to declare. The authors received no 5. Medoff DR, Holcomb HH, Lahti AC, Tamminga CA. direct compensation related to the develop- Probing the human hippocampus using rCBF: ment of the manuscript. The journal’s article contrasts in schizophrenia. Hippocampus. 2001;11:543–50. processing charges will be funded by the sponsor. 6. Dorner-Ciossek C, Baum-Kroker KS, Rosenbrock H. CNS functions and diseases-Chapter 15: role of Compliance with Ethics Guidelines. All PDE9 in cognition. In: Zhang H, Xu Y, O’Donnell JM, editors. Advances in neurobiology, vol. 17. procedures followed in this study (ClinicalTri- Basel: Springer International Publishing; 2017. als.gov: NCT01892384) were in accordance with the protocol, ethical standards laid down in the 7. Reneerkens OA, Rutten K, Steinbusch HW, et al. Helsinki Declaration of 1964 (as revised in Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharma- 2013), the International Conference on Har- cology. 2009;202:419–43. monisation Harmonised Tripartite Guidelines for Good Clinical Practice and relevant Boeh- 8. Schmidt CJ. Phosphodiesterase inhibitors as ringer Ingelheim standard operating proce- potential cognition enhancing agents. Curr Top Med Chem. 2010;10:222–30. dures. Informed consent was obtained from all patients for inclusion in the study. 9. Dorner-Ciossek C, Giovannini R, Rosenbrock H. BI 409306, a novel phosphodiesterase 9A inhibitor, Open Access. This article is distributed part I: potency, selectivity and in vitro functional under the terms of the Creative Commons characterization on synaptic plasticity. Interna- tional Congress on Schizophrenia Research. Attribution-NonCommercial 4.0 International Schizophrenia Bull. 2015; p. S31. License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any noncommer- 10. Rosenbrock H, Marti A, Koros E, et al. BI 409306, a cial use, distribution, and reproduction in any novel phosphodiesterase 9A inhibitor, part II: in vivo characterization regarding target engage- medium, provided you give appropriate credit ment and cognition tasks in rodents. International to the original author(s) and the source, provide Congress on Schizophrenia Research. Schizophre- a link to the Creative Commons license, and nia Bull. 2015; p. S36. indicate if changes were made. 11. Moschetti V, Boland K, Feifel U, Hoch A, Zim- dahl-Gelling H, Sand M. First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A REFERENCES inhibitor, in healthy males. Br J Clin Pharmacol. 2016;82:1315–24. https://doi.org/10.1111/bcp. 1. Neill JC, Barnes S, Cook S, et al. Animal models of cognitive dysfunction and negative symptoms of 12. Moschetti V, Boland K, Hoch A, et al. Safety, tol- schizophrenia: focus on NMDA receptor antago- erability, pharmacokinetics, and pharmacodynam- nism. Pharmacol Ther. 2010;128:419–32. ics of multiple rising doses of BI 409306 film-coated Neurol Ther (2018) 7:129–139 139 tablets given orally once or twice daily for 14 days 15. Dhingra A, Tummala SR, Lyubarsky A, et al. PDE9A in young and elderly healthy volunteers. Poster is expressed in the inner retina and contributes to presented at: Alzheimer’s Association International the normal shape of the photopic ERG waveform. Conference, 18–23 Jul 2015, Washington, DC, USA. Front Mol Neurosci. 2014;7:60. https://doi.org/10. 3389/fnmol.2014.00060. 13. Wunderlich G, Kim JM, Yum S.-Y.A., et al. Safety, tolerability, and pharmacokinetics of BI 409306: a 16. Schwam EM, Nicholas T, Chew R, et al. A multi- randomized, placebo-controlled, double-blinded center, double-blind, placebo-controlled trial of the phase I study in Chinese and Japanese healthy male PDE9A inhibitor, PF-04447943, in Alzheimer’s dis- volunteers. Poster presented at: Alzheimer’s Asso- ease. Curr Alzheimer Res. 2014;11:413–21. ciation International Conference, 18–23 Jul 2015, Washington, DC, USA. 17. Brown A, Daniels K, Zhang S, et al. Safety, tolera- bility, pharmacokinetics and pharmacodynamics of 14. Boland K, Moschetti V, Dansirikul C, et al. A phase BI 409306 film-coated tablets given orally qd for I, randomized, proof-of-clinical-mechanism study 14 days in patients with schizophrenia. Interna- assessing the pharmacokinetics and pharmacody- tional Congress on Schizophrenia Research. Schizophrenia Bull. 2015; p. S04. namics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers. Hum Psychopharmacol. 2017;. https://doi.org/10.1002/hup.2569. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurology and Therapy Springer Journals

A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia

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Abstract

Neurol Ther (2018) 7:129–139 https://doi.org/10.1007/s40120-017-0085-5 ORIGINAL RESEARCH A Phase IC Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Cognitive Outcomes of BI 409306 in Patients with Mild-to-Moderate Schizophrenia . . . David Brown Kristen Daniels Solen Pichereau Michael Sand Received: August 24, 2017 / Published online: November 24, 2017 The Author(s) 2017. This article is an open access publication and 217 to 2020 nmol•h/L, respectively. Elimi- ABSTRACT nation was rapid (gMean t range 1.10–1.85 h). 1/2 After multiple doses, C was reached within max,ss Introduction: This randomized, double-blind, 1 h; elimination was similar to that observed parallel-group study investigated the safety, after a single dose. Total exposure at steady state tolerability, pharmacokinetics (PK), and cogni- and after a single dose were similar (accumula- tive outcomes of BI 409306—a selective phos- tion ratio range: AUC, 0.758–1.13 and C , max phodiesterase 9A (PDE9A) inhibitor—in 0.768–1.40). No deaths, adverse events (AEs) patients with schizophrenia. leading to discontinuation, or serious AEs were Methods: Patients with mild-to-moderate observed. Treatment-emergent AEs were mild, schizophrenia were randomized (1:1:1:1) to with no apparent dose-related trends. There was receive BI 409306 at 25, 50, or 100 mg or placebo no worsening of schizophrenia symptoms once daily over 14 days. The primary endpoints (Positive and Negative Syndrome Scale) and no were safety and tolerability; the secondary end- trends in suicidality (Columbia Suicide Severity points were PK and cognitive outcomes. Rating Scale). The Hopkins Verbal Learning Results: Of the 40 randomized patients, 38 Test–Revised (HVLT-R) and Brief Visuospatial (95%) completed the study. Patients were pre- Memory Test–Revised (BVMT-R) showed no dominantly male (87.5%; mean age, 40.2 years). effect on cognitive function. After a single dose, C was reached within max Conclusion: Administration of BI 409306 in 30–45 min. The geometric mean (gMean) C max patients with mild-to-moderate schizophrenia and AUC ranged from 138 to 998 nmol/L 0-? resulted in satisfactory safety and tolerability. BI Enhanced content To view enhanced content for this 409306, PK was characterized by rapid absorp- article go to http://www.medengine.com/Redeem/62DC tion, monophasic to biphasic elimination, and F0600F4FDF01. minor accumulation with multiple dosing. Trial Registration: ClinicalTrials.gov identifier D. Brown NCT01892384. Community Clinical Research, Inc., Austin, TX, USA Funding: Boehringer Ingelheim Pharma GmbH K. Daniels  M. Sand (&) & Co. KG. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA e-mail: michael.sand@boehringer-ingelheim.com Keywords: BI 409306; Cognitive outcome; Phosphodiesterase inhibitor; PDE9A; S. Pichereau Pharmacokinetics; Phase I; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany Safety; Schizophrenia; Tolerability 130 Neurol Ther (2018) 7:129–139 blurred vision. These AEs occurred shortly after INTRODUCTION administration and were resolved within 1–2 h. In a proof-of-mechanism study conducted in Impaired N-methyl-D-aspartic acid (NMDA) healthy male volunteers, BI 409306 adminis- receptor signaling and reduced levels of cyclic tered orally as a single dose crossed the guanosine monophosphate (cGMP) have been blood–brain barrier and triggered a dose- and demonstrated in animal models of schizophre- concentration-dependent increase in cGMP in nia [1, 2], and increasing evidence suggests that the CSF [14]. glutamatergic dysfunction may play a key role The objective of this study was to investigate in mediating risk for conversion to psychosis the safety and tolerability of BI 409306, a novel [3–5]. Phosphodiesterase 9A (PDE9A), which has PDE9 inhibitor, in patients with mild-to-mod- the highest affinity of all PDEs, hydrolyzes erate schizophrenia. The associated pharma- cGMP to regulate its intracellular concentration cokinetics (PK) and cognitive outcomes were within glutamatergic neurons [6]. Conse- also explored. BI 409306 was administered quently, PDE9A inhibition may augment orally at a dosage of 25, 50, or 100 mg for synaptic plasticity and memory function 14 days. through increased cGMP availability and, thus, improved NMDA receptor signaling [6, 7]. PDE9A is highly expressed in the neocortex and METHODS hippocampus; therefore, it is likely to be a sig- nificant determinant of intracellular basal Study Design cGMP levels in these brain regions [6, 8]. BI 409306 is a potent and selective PDE9A This was a randomized, double-blind, inhibitor. Application of BI 409306 to rat hip- placebo-controlled, parallel-group, phase I pocampal slices resulted in significant study in patients with mild-to-moderate enhancement of long-term potentiation (LTP) schizophrenia. The study was conducted from 8 [9]. Furthermore, BI 409306 induced a dose-de- July 2013 to 5 December 2013 at the Commu- pendent increase in cGMP in rat cerebrospinal nity Clinical Research, Inc., Austin, TX. The fluid (CSF) and prefrontal cortex and improved duration of the study from screening through memory performance [10]. In healthy male completion of the end-of-treatment visit was up volunteers, BI 409306 was rapidly absorbed and to 8 weeks. The end-of-treatment visit was eliminated and showed a good safety and tol- planned 7–14 days after the administration of erability profile [11–13]. In these studies, the the last dose of the study drug (Fig. 1). Patients most frequent adverse events (AEs) were visual were randomized (1:1:1:1) on day 1 to receive BI symptoms such as photopsia (flashing light), 409306 at 25, 50, or 100 mg or placebo, photophobia (increased sensitivity to light), administered orally once daily (qd) for 14 days. chromatopsia (change in color perception), and Fig. 1 Study design Neurol Ther (2018) 7:129–139 131 Sequentially numbered blinded medication kits hematological, or hormonal disorders; a history were assigned to the patients at the study site. or new diagnosis of human immunodeficiency All the patients provided written informed virus infection or malignancy; or a history of consent. All procedures followed in the study neurologic or psychiatric condition that might (ClinicalTrials.gov: NCT01892384) were in interfere with the interpretation of data. Preg- accordance with the protocol, ethical standards nant or breastfeeding women were also laid down in the Helsinki Declaration of 1964 excluded. (as revised in 2013), the International Confer- ence on Harmonisation of Technical Require- Study Assessments ments for Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guidelines for Safety Endpoints Good Clinical Practice, and relevant Boehringer The primary endpoints for safety and tolerabil- Ingelheim standard operating procedures. ity were evaluated based on AEs, vital signs, 12-lead electrocardiogram (ECG), clinical labo- Patients ratory tests, physical examination, Clinical Global Impression–Improvement (CGI-I) scale, Patients included in the study were 18–55 years disease severity on the Positive and Negative of age, with an established diagnosis of Syndrome Scale (PANSS), suicidality assessment schizophrenia as defined by the Diagnostic and by the C-SSRS, and visual acuity and color Statistical Manual of Mental Disorders (DSM)-IV vision assessed by Snellen chart and Ishihara criteria, with the following clinical features: plates, respectively. clinically stable and in the residual (non-acute) phase of illness or maintained on current Pharmacokinetic Endpoints antipsychotic medications and dose for The following PK parameters were assessed as C 8 weeks; and having no more than a ‘‘mod- secondary endpoints: area under the plasma erate’’ severity rating on hallucinations and concentration–time curve of BI 409306 from delusions, positive formal thought disorder and zero extrapolated to infinity after a single dose negative symptoms, and minimal extrapyrami- (AUC ); area under the plasma concentra- 0-? dal and depressive symptoms. All patients were tion–time curve of BI 409306 in plasma at genotyped for cytochrome P450 2C19 steady state over a uniform dosing interval tau (CYP2C19). (AUC ); maximum measured concentration tau,ss Patients were excluded if they were treated of BI 409306 in plasma following a single dose with [ 1 antipsychotic agent, not stabilized on (C ) and at steady state (C ); time from max max,ss antipsychotic treatment, or had electroconvul- dosing to maximum measured concentration of sive therapy within the last 30 days, or if the BI 409306 in plasma following a single dose severity of their cognitive impairment would (t ) and at steady state (t ); and terminal max max,ss affect the study outcome in the clinical judg- elimination half-life of BI 409306 (t ). 1/2 ment of the investigator. In addition, patients with any of the following were excluded from Cognitive Outcomes the study: suicidal behavior within the past Additional secondary endpoints included mea- 2 years or type 4 or 5 suicidal ideation on the surement of the total score on the Hopkins Columbia Suicide Severity Rating Scale (C-SSRS) Verbal Learning Test–Revised (HVLT-R) and within the past 3 months; findings from medi- total score on the Brief Visuospatial Memory cal examination or laboratory values deviating Test–Revised (BVMT-R). from normal limits and of clinical relevance; planned elective surgery; a history or diagnosis Statistical Analyses of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, car- Dose proportionality was explored after a single diovascular, metabolic, immunological, dose (day 1, C and AUC ) and after max 0-? 132 Neurol Ther (2018) 7:129–139 multiple dosing (day 14, C and AUC ) completed the study and two withdrew consent max,ss tau,ss using a linear regression model with log-trans- (Fig. 2). There were four important protocol formed dose as an independent variable applied deviations: one patient in the 25-mg group to log-transformed data. Two-sided 95% confi- received a prohibited medication (lorazepam) on dence intervals (CIs) for the slope were com- day 7; one patient in the 50-mg group tested puted from this model. For PK endpoints positive for cocaine on day -1, but had initiated AUC and AUC , a linear model with treatment before the drug screen results were 0-? tau,ss patient and order as fixed effects was applied to available; another patient had a prior suicide log-transformed data to assess linearity for each attempt; and one patient in the placebo group dose separately. Attainment of steady state was declined to provide informed consent for the assessed using a linear model with patient as a optional pharmacogenetic sample collection for fixed effect, time as a repeated effect, and DNA banking. However, none of these patients log-transformed pre-dose concentration from were excluded from the study analysis. Patients days 1 to 14 as the dependent variable for each were predominantly male (87.5%) and African dose separately. American (52.5%) or white (47.5%), with a mean Changes in HVLT-R and BVMT-R total scores (standard deviation [SD]) age of 40.2 (9.0) years. were compared between doses of BI 409306 and Demographics and baseline characteristics were placebo using an analysis of covariance model well balanced across all treatment groups, with with treatment as a fixed effect and baseline as a the exception of cognition (HVLT-R and covariate. Safety analyses were performed for all BVMT-R; Table 1). As BI 409306 oxidative meta- patients who received C 1 dose of the study bolism is dependent on CYP2C19, CYP2C19 drug; the results are summarized descriptively. phenotype was predicted for each patient based on genotype. Of the 40 randomized patients, 16 (40.0%) were predicted to be ultra-rapid metab- RESULTS olizers (UM) for CYP2C19; 11 (27.5%), extensive metabolizers (EM); and 8 (20.0%), intermediate Patient Characteristics metabolizers (IM). No patients were predicted to be poor metabolizers (PM) for CYP2C19. For five Of the 50 patients enrolled, 40 were randomized patients, the predicted CYP2C19 phenotype to receive either BI 409306 or placebo; 38 patients could not be determined based on genotype. Fig. 2 Patient disposition Neurol Ther (2018) 7:129–139 133 Table 1 Patient demographics and baseline characteristics BI 409306 Placebo (n 5 10) Total (N 5 40) 25 mg (n 5 10) 50 mg (n 5 10) 100 mg (n 5 10) Mean age (SD), years 37.9 (9.5) 42.5 (9.0) 42.5 (8.4) 37.8 (9.5) 40.2 (9.0) Gender, n (%) Male 10 (100.0) 7 (70.0) 10 (100.0) 8 (80.0) 35 (87.5) Female – 3 (30.0) – 2 (20.0) 5 (12.5) Race, n (%) African American 5 (50.0) 4 (40.0) 7 (70.0) 5 (50.0) 21 (52.5) White 5 (50.0) 6 (60.0) 3 (30.0) 5 (50.0) 19 (47.5) BMI, kg/m 26.0 (5.6) 31.5 (4.3) 29.1 (6.1) 28.7 (5.2) 28.8 (5.5) HVLT-R score 17.9 (5.5) 18.4 (3.7) 16.9 (6.4) 19.5 (5.2) 18.2 (5.2) BVMT-R score 9.2 (10.3) 17.5 (3.8) 12.9 (7.9) 16.2 (10.3) 14.0 (8.8) Smoking status, n (%) Never smoked – 1 (10.0) 1 (10.0) 3 (30.0) 5 (12.5) Ex-smoker – 1 (10.0) 3 (30.0) – 4 (10.0) Current smoker 10 (100.0) 8 (80.0) 6 (60.0) 7 (70.0) 31 (77.5) Alcohol status, n (%) Non-drinker 10 (100) 9 (90.0) 9 (90.0) 10 (100.0) 38 (95.0) Drinks–no interference – 1 (10.0) 1 (10.0) – 2 (5.0) Treated set includes all patients who received at least 1 dose of study medication Data are presented as mean (SD), unless indicated otherwise BMI body mass index, BVMT-R Brief Visuospatial Memory Test–Revised, HVLT-R Hopkins Verbal Learning Test–Re- vised, SD standard deviation Safety spontaneously without medical treatment. All but three events (blurred vision in one patient each in the 25-mg and 50-mg groups, and visual Table 2 summarizes the AEs. BI 409306 was well field defect in one patient in the 100-mg group) tolerated; treatment-emergent AEs were repor- were assessed as related to treatment. There ted in 23 (57.5%) patients. All AEs were mild in were no deaths, serious AEs or discontinuation intensity, and no apparent dose-related trends due to AEs. The incidence of treatment-emer- were observed for any AE. Eleven (27.5%) gent AEs was similar between BI 409306 and patients reported a total of 13 eye-related AEs, placebo. No clinically relevant or dose-related including blurred vision (n = 8), photopsia changes were observed in laboratory parame- (flashing lights; n = 2), visual impairment ters, vital signs, or ECGs in patients receiving BI (n = 2), and visual field defect (n = 1). The 409306 or placebo. number of patients reporting eye-related AEs CGI-I indicated no change or minimal was similar across all BI 409306 dose groups and improvement in the patients’ overall disease the placebo group. All eye-related AEs were status. The mean change from baseline in total non-serious and mild in intensity, and resolved 134 Neurol Ther (2018) 7:129–139 Table 2 Summary of adverse events System organ class/preferred term BI 409306 Placebo Total (n 5 10) (N 5 40) 25 mg 50 mg 100 mg n (%) n (%) (n 5 10) (n 5 10) (n 5 10) n (%) n (%) n (%) Total with adverse events 4 (40.0) 9 (90.0) 6 (60.0) 4 (40.0) 23 (57.5) Infections and infestations – 1 (10.0) 1 (10.0) – 2 (5.0) Furuncle – 1 (10.0) – – 1 (2.5) Tooth infection – – 1 (10.0) – 1 (2.5) Psychiatric disorders 1 (10.0) – 2 (20.0) 1 (10.0) 4 (10.0) Agitation – – 1 (10.0) 1 (10.0) 2 (5.0) Anxiety 1 (10.0) – 1 (10.0) – 2 (5.0) Nervous system disorders 1 (10.0) 1 (10.0) 2 (20.0) – 4 (10.0) Dizziness 1 (10.0) – – – 1 (2.5) Headache – 1 (10.0) 1 (10.0) – 2 (5.0) Tremor – – 1 (10.0) – 1 (2.5) Visual field defect – – 1 (10.0) – 1 (2.5) Eye disorders 2 (20.0) 4 (40.0) 2 (20.0) 2 (20.0) 10 (25.0) Vision blurred 2 (20.0) 3 (30.0) 1 (10.0) 2 (20.0) 8 (20.0) Photopsia – 1 (10.0) 1 (10.0) – 2 (5.0) Visual impairment 1 (10.0) 1 (10.0) – – 2 (5.0) Gastrointestinal disorders 2 (20.0) – 1 (10.0) – 3 (7.5) Gastroesophageal reflux disease 1 (10.0) – – – 1 (2.5) Nausea 1 (10.0) – – – 1 (2.5) Toothache – – 1 (10.0) – 1 (2.5) Vomiting 1 (10.0) – – – 1 (2.5) Musculoskeletal and connective tissue – 3 (30.0) – – 3 (7.5) disorders Musculoskeletal pain – 2 (20.0) – – 2 (5.0) Back pain – 1 (10.0) – – 1 (2.5) General disorders and administration site – – 1 (10.0) 1 (10.0) 2 (5.0) conditions Pain – – 1 (10.0) – 1 (2.5) Pre-existing condition improved – – – 1 (10.0) 1 (2.5) Injury, poisoning, and procedural – 1 (10.0) 1 (10.0) – 2 (5.0) complications Excoriation – 1 (10.0) 1 (10.0) – 2 (5.0) Percentages are calculated using total number of patients per treatment as the denominator PANSS scores for the 25-, 50-, and 100-mg BI visual acuity were reported intermittently for a 409306 and placebo groups were -0.1, -0.2, few patients across all treatment groups. Color -1.4, and -0.9, respectively, at day 7, and 2.3, discrimination was reported as normal at max- 0.0, -3.6, and 0.0, respectively, at day 13, sug- imum time points in all the patients. Visual gesting no deterioration in disease symptoms or examination of box-plots of C of BI 409306 max,ss clinical status. Mild suicidal ideation after or its major metabolites did not suggest any treatment initiation (C-SSRS score = 1) was association between higher exposure and wors- reported in one patient each in the 50-mg ening of visual acuity or color vision. BI 409306 and placebo groups. Changes in Neurol Ther (2018) 7:129–139 135 Administration of BI 409306 had a negligible Cognitive Outcomes effect on the mean pupil diameter relative to placebo. No significant treatment differences were observed with 25-, 50-, or 100-mg BI 409306 in Pharmacokinetics HVLT-R total scores (p = 0.0867, p = 0.2011, and p = 0.4103, respectively) or BVMT-R total scores (p = 0.5791, p = 0.605, and p = 0.7171, PK profiles of BI 409306 following single- and respectively) compared with placebo. multiple-dose administration were character- ized by a rapid increase in plasma concentration and rapid elimination. Table 3 shows the PK DISCUSSION endpoints after single- and multiple-dose administration of BI 409306. After single-dose In this study, BI 409306 at a dosage of 25, 50, or administration, BI 409306 was rapidly absorbed, 100 mg per day for 14 days was well tolerated in reaching C within 30–45 min (Fig. 3). Fol- max patients with mild-to-moderate schizophrenia. lowing absorption, BI 409306 was rapidly The PK of BI 409306 following single- and eliminated, with geometric mean (gMean) t 1/2 multiple-dose administration was characterized ranging from 1.10 to 1.85 h. After multiple-dose by very rapid absorption followed by rapid administration, BI 409306 was rapidly absorbed, monophasic to biphasic elimination. No evi- with C attained within the first hour after max,ss dence of deterioration in schizophrenia symp- dosing. Total exposure at steady state was sim- toms, suicidality, or overall clinical status was ilar to that following a single dose, with an observed in this study. accumulation ratio close to 1 (ranges: AUC The safety results for BI 409306 in this study 0.758–1.13; C 0.768–1.40), indicating minor max are comparable to those from studies conducted to no accumulation with multiple dosing. in healthy male volunteers. In previous studies, Dose-normalized gMean C , C , max max,ss AEs were mild to moderate in intensity and of AUC and AUC values were similar for 0-? tau,ss short duration [11, 14]. The most frequently the 50- and 100-mg dose groups following sin- reported AEs were visual AEs. Consistent with gle- and multiple-dose administration, suggest- the present study, there was no apparent ing dose proportionality. However, dose-dependent increase in AEs [14]. In young dose-normalized parameters for the 25-mg dose and elderly healthy subjects administered 25, group were lower than expected, with approxi- 50, or 100 mg BI 409306 or placebo, a majority mately threefold lower C and AUC- max,ss,norm of the AEs were mild in intensity, with a compared with the higher dose tau,ss, norm dose-dependent increase in subjects reporting groups. Linearity with respect to multiple dose eye disorders such as photophobia (increased administration could not be established due to sensitivity to light), chromatopsia (change in high inter-individual variability in the linearity color perception), visual impairment, blurred index within each dose group. vision, abnormal sensation in the eye, asthe- Inter-individual variability in BI 409306 PK nopia, and eye pain [12]. Similarly, in healthy parameters was moderate to high. The geometric male Chinese and Japanese subjects, most AEs coefficient of variation (gCV) after a single dose were mild; the most frequently reported AEs in ranged from 98.4% to 108% for AUC and from 0-? subjects receiving BI 409306 were eye disorders 73.3% to 106% for C ; gCV at steady state ran- max (29.8%), which were resolved within 1–2 h [13]. ged from 86.8% to 112% for AUC and from tau,ss Visual side effects have been proposed to be 74.4% to 90.9% for C . Exposure was highest max,ss associated with PDE9A, which regulates the in patients with the CYP2C19 IM predicted phe- level of cGMP by hydrolyzing it and modulates notype, followed by EM and UM patients. How- inhibitory processes in the cone pathway of the ever, inter-individual variability was lower in the retina [15]. Given the results in healthy sub- IM patients than in the EM and UM patients, with jects, eye-related AEs were of interest in this gCV% of 48.4%, 152%, and 154%, respectively. study, and indeed, these were the most 136 Neurol Ther (2018) 7:129–139 Table 3 Pharmacokinetic endpoints after single- and multiple-dose administration of BI 409306 BI 409306 25 mg (n 5 10) 50 mg (n 5 10) 100 mg (n 5 10) AUC , nmol•h/L 217 (107) 770 (98.4) 2020 (108) 0-? AUC , nmol•h/L 147 (112) 969 (104) 2280 (86.8) tau,ss C , nmol/L 138 (91.9) 431 (73.3) 998 (106) max C , nmol/L 99.2 (86.8) 631 (90.9) 1290 (74.4) max,ss t ,h 0.63 (0.33–1.50) 0.63 (0.33–2.0) 0.75 (0.33–2.0) max t ,h 0.75 (0.33–1.0) 0.33 (0.33–1.5) 0.63 (0.33–1.5) max,ss t , h 1.10 (43.1) 1.57 (27.0) 1.85 (31.0) 1/2 RA, C 0.768 (42.5) 1.40 (23.9) 1.29 (61.4) max RA, AUC 0.758 (26.9) 1.13 (17.8) 1.13 (42.5) Pharmacokinetic (PK) set included all patients in the treated set who had no important protocol violation(s) relevant to the evaluation of PK parameters and who provided at least 1 evaluable observation for a PK endpoint Data are presented as geometric mean (% gCV) unless otherwise noted Median (min–max) AUC , area under the plasma concentration–time curve of the analyte from zero extrapolated to infinity after single 0-? dose; AUC , area under the plasma concentration–time curve of the analyte in plasma at steady state over a uniform tau,ss dosing interval tau; C , maximum measured concentration in plasma following a single dose (and at steady state); gCV, max,ss geometric coefficient of variation; RA, AUC, accumulation ratio of the analyte in plasma at steady state corresponding to the ratio of AUC to AUC ; RA, C , accumulation ratio of the analyte in plasma at steady state corresponding to tau,ss 0-? max the ratio of C to C ; t , time from dosing to maximum measured concentration in plasma following a single dose max,ss max max,ss (and at steady state); t , terminal elimination half-life 1/2 Fig. 3 Geometric mean plasma concentration–time profiles after single and multiple doses of BI 409306 (25, 50, and 100 mg) frequently reported AEs. Unlike previous stud- reported intermittently and with similar sever- ies, however, eye-related AEs in this study were ity and frequency by patients across treatment reported with similar frequency in all treatment groups, and were typically mild and transient. groups. Overall, changes in visual acuity were While some changes in visual acuity in BI Neurol Ther (2018) 7:129–139 137 409306-treated patients occurred around the with chronic schizophrenia, many of whom are anticipated time of peak plasma concentrations on multiple medications or on medications that of BI 409306, a consistent relationship between were excluded. Nevertheless, the study results changes in visual acuity and BI 409306 C was provide guidance for design of future trials with max not observed. Interestingly, the frequency of BI 409306. total AEs in this study is comparable to that of a study in which the selective PDE9A inhibitor CONCLUSION PF-04447943 was used in patients with mild-to-moderate probable Alzheimer’s disease Overall, BI 409306 showed satisfactory safety [16]. and tolerability at 25-, 50-, or 100-mg qd doses The PK of BI 409306 in this study is in line for 14 days in patients with mild-to-moderate with that observed in previous studies in heal- schizophrenia. The PK profile of BI 409306 was thy subjects, which is characterized by very characterized by rapid absorption, rapid rapid absorption and elimination, with minor monophasic to biphasic elimination, and minor accumulation. In the current study, exposure accumulation with multiple dosing. There were was dose-proportional from 50 to 100 mg and no apparent effects on cognitive function over was comparable to that observed in a previous 14 days of treatment with BI 409306. study [12]. However, exposure in the 25-mg dose group was lower than expected, resulting in a lack of dose proportionality over the 25- to 100-mg dose range. Linearity with respect to ACKNOWLEDGEMENTS multiple-dose administration could not be established due to the high inter-subject vari- The study and the article processing charges were ability in the linearity index within each dose funded by Boehringer Ingelheim Pharma GmbH group. This variability could be partly due to & Co. KG (Ingelheim am Rhein, Germany). All differences in CYP2C19 predicted phenotype, as authors had full access to all the data in this study exposure in IM was highest, followed by expo- and take complete responsibility for the integrity sure in EM and UM. of the data and accuracy of the data analysis. The A previous study reported that BI 409306 authors would like to thank Diana Brewer of crossed the blood–brain barrier, with the maxi- Community Clinical Research, Inc., Austin, TX, mum concentration in CSF reaching 28.31% of USA, for her significant assistance in the opera- the maximum plasma concentration [14]. BI tional conduct of this study, and Dr. Lauren Liss 409306 had no effect on the chosen cognitive for her help in drafting the Introduction sec- tests over the 14-day treatment period in tion. All named authors meet the International patients with schizophrenia; however, that Committee of Medical Journal Editors (ICMJE) study was not of sufficient power or duration to criteria for authorship for this manuscript, take adequately assess the overall effect on cognition responsibility for the integrity of the work as a [17]. In a phase II placebo-controlled study, whole and have given final approval of the ver- PF-04447943 reached maximal concentrations sion to be published. Writing, editorial support of approximately five times the IC50 [16]. and formatting assistance was provided by Moreover, the estimated median exposure Suchita Nath-Sain, PhD, of Cactus Communica- remained above the IC50 for the entire dosing tions, which was contracted and funded by duration. Treatment with PF-04447943 over a Boehringer Ingelheim for these services. Boeh- 12-week period was not more effective than ringer Ingelheim was given the opportunity to placebo in terms of cognition, behavior, or review the manuscript for medical and scientific clinician-rated global change. accuracy as well as intellectual property consid- A limitation of this study is that the popu- erations. The results presented in this paper were lation was drawn from a single center. Further- published in part at the 15th International more, the patients who participated in this Congress on Schizophrenia Research, 28 March study may not represent the larger population to 1 April 2015, Colorado Springs, CO, USA, and 138 Neurol Ther (2018) 7:129–139 the 70th Annual Scientific Meeting of the Society 2. Nabeshima T, Mouri A, Murai R, Noda Y. Animal model of schizophrenia: dysfunction of NMDA of Biological Psychiatry, 14–16 May 2015, Tor- receptor-signaling in mice following withdrawal onto, Ontario, Canada. from repeated administration of phencyclidine. Ann N Y Acad Sci. 2006;1086:160–8. Disclosures. David Brown received a fee 3. Salisbury DF, Shenton ME, Griggs CB, Bonner-Jack- from Boehringer Ingelheim for consulting ser- son A, McCarley RW. Mismatch negativity in chronic vices on the clinical trial protocol. Kristen schizophrenia and first-episode schizophrenia. Arch Daniels is employed by Boehringer Ingelheim. Gen Psychiatry. 2002;59:686–94. Michael Sand is employed by Boehringer 4. Schobel SA, Chaudhury NH, Khan UA, et al. Imag- Ingelheim. Solen Pichereau was an employee of ing patients with psychosis and a mouse model Boehringer Ingelheim at the time that the study establishes a spreading pattern of hippocampal was conducted but is now employed by Roche dysfunction and implicates glutamate as a driver. Neuron. 2013;78:81–93. (Basel, Switzerland). Solen Pichereau has no conflicts to declare. The authors received no 5. Medoff DR, Holcomb HH, Lahti AC, Tamminga CA. direct compensation related to the develop- Probing the human hippocampus using rCBF: ment of the manuscript. The journal’s article contrasts in schizophrenia. Hippocampus. 2001;11:543–50. processing charges will be funded by the sponsor. 6. Dorner-Ciossek C, Baum-Kroker KS, Rosenbrock H. CNS functions and diseases-Chapter 15: role of Compliance with Ethics Guidelines. All PDE9 in cognition. In: Zhang H, Xu Y, O’Donnell JM, editors. Advances in neurobiology, vol. 17. procedures followed in this study (ClinicalTri- Basel: Springer International Publishing; 2017. als.gov: NCT01892384) were in accordance with the protocol, ethical standards laid down in the 7. Reneerkens OA, Rutten K, Steinbusch HW, et al. Helsinki Declaration of 1964 (as revised in Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharma- 2013), the International Conference on Har- cology. 2009;202:419–43. monisation Harmonised Tripartite Guidelines for Good Clinical Practice and relevant Boeh- 8. Schmidt CJ. Phosphodiesterase inhibitors as ringer Ingelheim standard operating proce- potential cognition enhancing agents. Curr Top Med Chem. 2010;10:222–30. dures. Informed consent was obtained from all patients for inclusion in the study. 9. Dorner-Ciossek C, Giovannini R, Rosenbrock H. BI 409306, a novel phosphodiesterase 9A inhibitor, Open Access. This article is distributed part I: potency, selectivity and in vitro functional under the terms of the Creative Commons characterization on synaptic plasticity. Interna- tional Congress on Schizophrenia Research. Attribution-NonCommercial 4.0 International Schizophrenia Bull. 2015; p. S31. License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any noncommer- 10. Rosenbrock H, Marti A, Koros E, et al. BI 409306, a cial use, distribution, and reproduction in any novel phosphodiesterase 9A inhibitor, part II: in vivo characterization regarding target engage- medium, provided you give appropriate credit ment and cognition tasks in rodents. International to the original author(s) and the source, provide Congress on Schizophrenia Research. Schizophre- a link to the Creative Commons license, and nia Bull. 2015; p. S36. indicate if changes were made. 11. Moschetti V, Boland K, Feifel U, Hoch A, Zim- dahl-Gelling H, Sand M. First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A REFERENCES inhibitor, in healthy males. Br J Clin Pharmacol. 2016;82:1315–24. https://doi.org/10.1111/bcp. 1. Neill JC, Barnes S, Cook S, et al. Animal models of cognitive dysfunction and negative symptoms of 12. Moschetti V, Boland K, Hoch A, et al. Safety, tol- schizophrenia: focus on NMDA receptor antago- erability, pharmacokinetics, and pharmacodynam- nism. Pharmacol Ther. 2010;128:419–32. ics of multiple rising doses of BI 409306 film-coated Neurol Ther (2018) 7:129–139 139 tablets given orally once or twice daily for 14 days 15. Dhingra A, Tummala SR, Lyubarsky A, et al. PDE9A in young and elderly healthy volunteers. Poster is expressed in the inner retina and contributes to presented at: Alzheimer’s Association International the normal shape of the photopic ERG waveform. Conference, 18–23 Jul 2015, Washington, DC, USA. Front Mol Neurosci. 2014;7:60. https://doi.org/10. 3389/fnmol.2014.00060. 13. Wunderlich G, Kim JM, Yum S.-Y.A., et al. Safety, tolerability, and pharmacokinetics of BI 409306: a 16. Schwam EM, Nicholas T, Chew R, et al. A multi- randomized, placebo-controlled, double-blinded center, double-blind, placebo-controlled trial of the phase I study in Chinese and Japanese healthy male PDE9A inhibitor, PF-04447943, in Alzheimer’s dis- volunteers. Poster presented at: Alzheimer’s Asso- ease. Curr Alzheimer Res. 2014;11:413–21. ciation International Conference, 18–23 Jul 2015, Washington, DC, USA. 17. Brown A, Daniels K, Zhang S, et al. Safety, tolera- bility, pharmacokinetics and pharmacodynamics of 14. Boland K, Moschetti V, Dansirikul C, et al. A phase BI 409306 film-coated tablets given orally qd for I, randomized, proof-of-clinical-mechanism study 14 days in patients with schizophrenia. Interna- assessing the pharmacokinetics and pharmacody- tional Congress on Schizophrenia Research. Schizophrenia Bull. 2015; p. S04. namics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers. Hum Psychopharmacol. 2017;. https://doi.org/10.1002/hup.2569.

Journal

Neurology and TherapySpringer Journals

Published: Nov 24, 2017

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