` Manama.ll’-
`
`
`
`ORIGINAL CONTRIBUTION
`
`PETITIONER’S
`,EXHIBIT
`
`/‘< Htf/l/ L
`H ’7'3fl/
`
`
`
`
`
`Mifepristone Plasma Level and Glucocorticoid Receptor
`Antagonism Associated With Response in Patients With
`Psychotic Depression
`
`Thaddeus Block. MD. *f Georgios Petrides, MDHZL Harvey Kushner, PhD,§ Ned Kalin, MD,//
`Joseph Belanofif MD, *7‘ and Alan Schatzberg, MD7"
`
`Abstract:
`Background: Psychotic depression has no Food and Drug Administration—
`approved treatment. Patients demonstrate significant dysrcgulation of the
`hypothalamic-pituitary-adrenal axis providing a biologically targeted treat»
`ment opportunity. The purpose ofthis study was to explore the clinical and
`biological effects of short-duration (7-day) glucocorti coid receptor antago-
`nism with mifepristone and the role of mifepristone plasma levels in pa-
`tients with psychotic depression.
`Methods: This double-blind, randomized study took place at 34 US clin-
`ical research centers and included patients with a diagnosis of Diagnostic
`and Statislr'cal Manual ofMental Disorders. Fow1h Edition. major depres-
`sive disorder, severe, with psychotic features. Patients underwent daily, ob-
`served, in-clinic administration of oral study drug (mifepristone 1200 mg or
`placebo) for days 1 to 7 ofthe 56-day trial, followed by treatment with a sin-
`gle Food and Drug Administrationeapprm'ed antidepressant on days 8 to 56.
`The following scales were administered on days 0, 7, 14, 28, 42, and 56:
`Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale,
`Hamilton Rating Scale for Depression, and Colrunbia-Suicide Severity Rat-
`ing Scale. The primary end point was a categorical analysis evaluating the
`proportion ofpatients with 50% or greater reduction from baseline in BPRS
`Positive Symptom Subscale score on both days 7 and 56, demonstrating early
`and durable response. Cortisol and adrenooorticotropic homrone were mel-
`sured on days 0, 7, 28, and 56. Mifepristone plasma levels were assesed
`on days 0 and 7.
`
`From ‘Corcept Therapeutics, Menlo Park; TStanford University, Stanford, CA;
`IZucker Hillside Hospital, Glen Oaks, NY; §the Biomedical Computer Re—
`search Institute, Inc, Philadelphia, PA; and “the University ofWisconsin School
`of Medicine and Public Health, Madison, WI.
`Received December 22, 2016; accepted afier revision April 28, 2017.
`Dr Block had full access to all the data in the study and takes responsibility for
`the integrity ofthe data and the accuracy of the data analysis.
`Corcept Therapeutics had a role in the design and conduct of the study; the
`collection, management, analysis, and interpretation of the data,-
`preparation, review, or approval ofthe manuscan and decision to submit
`the article for publication.
`Drs Block and Belanoff contributed to the study concept and design and the
`acquisition, analysis, or interpretation ofdata. Dr Kushner contributed to the
`statistical analysis. Dr Belanoff obtained fimding. Dr Block contributed to
`the study supervision. All authors contributed to drafting ofthe manuscript
`and critical revision ofthe manuscript for important intellectual content.
`Reprints: Thaddeus Block, MD, Clinical Development, Corcept Therapeutics,
`149 Commonwealth Dr, Menlo Park, CA 94025
`(e—mail: tblock@corcept.com).
`This study was firndcd by Corcept Therapeutics.
`Supplemental digital content is available for this article. Direct URL citation
`appears in the printed text and is provided in the HTML and PDF versions
`of this article on the journal's Web site (wwwpsychophannacologycom).
`Copyright © 2017 The Authoris). Published by Welters Kluwer Health, Inc.
`This is an open-access article distributed under the terms ofthe Creative
`Commons Attribution-Non Commercial-No Derivatives License 4.0
`(CCBY—NC—ND), where it is permissible to download and share the work
`provided it is properly cited. The work cannot be changed in any way or
`used commercially wiflrout permission from the journal.
`ISSN: 0271-0749
`DOI: 10.1097/JCR0000000000000744
`
`Results: An interim analysis indicated that the primary efficacy end point
`was unlikely to be met, and the study was stopped early with 292 of the
`planned 450 patients enrolled. Although the primary end point was not met,
`in a secondary prespecified analysis, patients who attained a mifepristone
`plasma level of 1637 nymL or greater (defined a priori and termed the hiyr
`plasma level; 66.7% of patients) demonstrated statistically significant reduc-
`tions in psychotic symptoms compared with patients who received placebo
`starting on day 28. This group also showed nonsignificant numeric superior—
`ity on Hamilton Rating Scale for Depression improvement No signifiwnt im-
`provements were observed in the low-mifepristone group (<1637 ng/mL)
`versus the placebo group. There were no significant differences in Columbia-
`Suicide Severity Rating Scale suicidality ratings between groups.
`Conclusions: Mifepristone 1200 mg daily for 7 days was safe and well
`tolerated, allowing most treated patients to achieve the a priori defined ther-
`apeutic plasma level of 1637 ngan, the mifepristone level associated with
`biological effect and clinical benefit.
`Key Words: mifepristone, plasma level, psychotic depression,
`glucocorticoid receptor antagonism, cortisol, HPA axis
`
`(J Clin Psychophamtacol 2017;37: 505—5 1 1)
`
`N early 20% ofpatients with major depression develop nihilis-
`tic. paranoid, guilty. or somatic delusions lithat is. major de-
`pressive disorder with psychotic features. Psychotic depression
`{PD} has serious consequences for both patients and their care-
`givers.” It is associated with cognitive problems. including impair—
`ment in attention. working memory, and executive functioning.4
`Patients are likely to be hospitalized and have elevated suicide risks
`Longer—term consequences include elevated all—cause mortality.
`mostly from cardiovascular and metabolic illness.n Such patients
`can have excellent interepisode function. There are no Food and
`Drug Administration (FDAl—approved treatments of PD.
`Disruption of the hypothalamic-pituitary-adrenal axis has
`been implicated in the pathophysiology of PD. Cortisol binds to
`the glucocorticoid receptor (GR), which is found in all tissue types,
`including the central nervous system. Although cortisol is critical
`for maintaining homeostasis, excess stimulation of GR adversely
`afiects metabolism, cardiovascular and immune fiinction, cognition,
`and mood. Chronic use of high-dose prednisonc can lead to severe
`depression or mania. psychosis, and impaired cognitive issues in
`susceptible patientsl Ctrshing syndrome.
`the classic example of
`GR overstimulation, is characterized by obesity, infections, diabe-
`tes, cardiovascular problems, depression, and psychosiss‘9
`Patients with PD demonstrate dysregulation in cortisol activ-
`ity. rhythm. and production, as evidenced by (a) high rates of non—
`suppression on the dcxzrme'thnsonc suppression cerium ('b] reduced
`diurnal fluctuation of cortisol, (c) high plasma cortisol and adreno-
`corticotropic hormone [ACTH] levels, and (11) increased excretion
`of 24—hour urinary free cortisol.L 1“:
`Mifepristone, a competitive GR antagonist, was first pro—
`posed as a therapy for patients with PD based on the observation
`
`[ournal of Clinical Psychopharmacology - Volume 37, Number 5, October 2017
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`www.psychopharmacology.com l 505
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`Black et al
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`loumal of Clinical Psychophannacology . Volume 37, Number 5, October 2017
`
`that these patients have prominent cortisol dysregulation.13 In addition,
`mifepristone had been observed to reverse the psychiatric symptoms of
`psychosis and depression in patients with Cushing syndrome.“1
`Although many pharmacologic studies in depression focus
`on daily drug administration for 8 weeks, the proposed regimen
`with mifepristone is different. Some clinical trials in which mifep-
`ristone was dosed daily foronly 1 week have been short-"n to signif—
`icantly reduce psychotic symptoms at week 1,]5'1“ with sustained
`effects noted for up to 8 weeks,” However, other clinical trials
`have failed to demonstrate statistically significant 5
`oration of
`mifepristone from placebo on primary end points.” R Interest-
`ingly, these studies have consistently identified a reproducible
`and statistically significant association between plasma level of
`mifepristone (herein referred to as high PL) and clinical response
`as measured by reduction in psychotic symptomsdug High—PL
`patients significantly outperformed both the group ofpatients with
`plasma levels less than the identified threshold (herein referred to
`as low PL). as well as those administered with placebo.“ Al-
`though the pharrnacokinetics of mifepristone is complex and non—
`linear, higher mifepristone plasma levels can be achieved with
`higher mifepristone doses. Most data fi-om earlier studies were
`based on a mifepristone dose of 600 mg daily for 7 days, in which
`the therapeutic plasma level of high PL was achieved in only half
`of those patients treated with mifepristone. In 1 study that in-
`cluded a 1200—mg mifepristone treatment arm,
`(17“:‘u of patients
`at that dose attained high PL. 1“ in addition to high PL, a high de-
`gree of GR antagonism (inferred by increase in posttreatment cor—
`tisol and ACTH levels) has also been associated with significantly
`greater likelihood (P< 0.003) of sustained clinical response. I“ Mi-
`fepristone blocks negative feedback of cortisol in the hypothalamus
`and pituitary, leading to increased circulating ACTH and cortisol
`while antagonizing GR more globally. Demonstrable biological me-
`diators of treatment response are rare in psychiatry, particularly
`changes in levels or function of specific pharmacologic targets.
`Applying experience fi'om earlier studies in PD, this study
`was designed and conducted to test (a) the efficacy of 1200 mg
`of mifepristone per day for 7 days versus placebo for reducing
`psychotic symptoms atboth days 7 and 56, (b) the hypothesis that
`the a priori defined high-PL group is associated with significantly
`greater clinical response than both low-PL and placebo groups,
`and (c) the relationships among mifepristone plasma level, degree
`of GR antagonism as measured by posttreatment increases in
`plasma ACTH or serrnn cortisol, and treatment response.
`
`METHODS
`
`Study Design and Participants
`The protocol, consent forms, and all amendments were appmved
`by the institutional review board or ethics committee ofthe partic-
`ipating study center. The investigator or designee obtained from each
`patient a signed and dated written informed consent/authorization
`consistent with FDA/International Council for Harmonization
`regulations, the HIPAA Privacy Rule (if applicable), and applica-
`ble state and local laws. This study was posted on clinicaltrialsgov
`(Clinicaltrialsgov identifier: NCT0063 7494).
`This was an 8-week, multisite (34 sites), double—blind, ran—
`domized clinical trial conducted in the Uniwd States fiom April 2008
`to June 2014. Randomization was 1:] mifepristone 1200 mg/d
`or placebo daily for 7 days. The primary objective was to evaluate
`the safety and efi'rcacy of short-duration treatment with mifepris—
`tone (followed by an antidepressant for 7 weeks) for reducing psy-
`chotic symptoms in patients with PD.
`A total of 292 patients (men or nonpregnant women, age 2
`22 y) with 3 Diagnostic and Statistical Manual of Mental
`
`Disorders, Fourth Edition, diagnosis ofmajor depressive disorder,
`severe, with psychotic features (ie, PD) and who had not been tak-
`ing antidepressants or antipsychotics for at least 7 days were en-
`rolled. Entry criteria at baseline included Brief Psychiatric Rating
`Scale (BPRS) Positive Symptom Subscale (PSS) unadjusted score
`of 12 or greater, BPRS total unadjusted score of 38 or greater,
`and Hamilton Rating Scale for Depression (HAMD-24) total score
`of 20 or greater. All patients were hospitalized for at least 3 nights
`on days 0, l, and 2 with hospital discharge on day 3 if clinically ap-
`propriate. Observed dosing with study drug (mifepristone or pla-
`cebo) took place on days 1 to 7 of the 56—day study, followed by
`treatment with a single FDA-approved antidepressant on days 8 to
`56. Ninety-five percent (277/292) of the patients received study
`drug for all 7 days,
`
`Study Assessments and End Points
`Alter completion of a psychiatric evaluation by the study
`physician, 3. Structured Clinical Interview for Diagnosis was per-
`formed by a blinded certified centralized rater to confirm the PD
`diagnosis. Centralized diagnosis and ratings over encrypted l'P
`VPN videoconference systems were used to reduce potential site
`bias. Patients were clinically assessed by the site staff during
`screening and on days 0 to 7, 14, 28, 42, and 56 or early termina-
`tion with the following scales:
`
`- HAMD-24: A 24-item patient questionnaire comprising the
`HAMD—l7 and 7 additional items.
`- BPRS: An 18—item evaluation to assess psychopathology; each
`item is scored on a numeric scale ranging from 1 (“not present”)
`to 7 (“extremely severe”).
`- BPRS-PSS: A subset of the BPRS of 4 items to assess the de-
`gree ofpsychosis and symptom severity: conceptual disorganiza-
`tion, suspiciousness, hallucinatory behavior, and unusual thought
`content. The BPRS-PSS score was rescaled by subtracting 4
`from the sum ofthe individual symptom scores and ranges from
`0 to 24.
`- Colurnbia—Suicide Severity Rating Scale (C—SSRS): A 12-item
`scale that measures the degree of suicide ideation or behavior.
`
`Plasma trough mifepristone samples were collected on day 7,
`before administration of the last dose of study drug. All doses of
`study medication were observed by appropriately trained study staff.
`An a priori receiver operating characteristic curve analysis, based on
`data from previous clinical trials with mifepristone,18 determined that
`the mifepristone plasma concentration of 1637 ng/mL was the opti-
`mal therapeutic plasma level threshold for differentiating responders
`from nonresponders. Patients with a trough day 7 mifepristone level
`of 1637 ng/mL or greater are referred to as the "high~P]j’ group,
`whereas those with a level less than 1637 ng/mL are referred to as
`the “low—PL group.”
`The primary efficacy end point was the proportion ofpatients
`with 50% or greater reduction from baseline in BPRS-PSS at both
`days 7 and 56. A secondary efl'icacy analysis was the prespecified
`comparison of a 50% or greater reduction in BPRS—PSS at days 7
`and 56 in the high-PL and placebo groups.
`The safety of mifepristone was evaluated using reported ad-
`verse events (AEs) coded using the Medical Dictionary for Regu-
`latory Activities, standard clinical laboratory tests (hematology,
`chemistry, and urinalysis), physical examinations, vital signs,
`and electrocardiograms. Samples for laboratory analyses were col-
`lected at screening and on days 7, 28, and 56. Electrocardiogram
`(lZ—lead) were obtained at screening and on day 7. Samples for cortisol
`and ACTH were collected at study baseline (day 0) and on days 7, 28,
`and 56. The samples were collected in the moming before dosing
`with study drug and processed by l centralized laboratory.
`
`506 I www.psychopharmaco|ogy.com
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`Mifepristone Plasma Level Effect
`loumal of Clinical Psychopharmacology . Volume 37, Number 5, October 2017
`
`An antidepressant (fluoxetine, citalopram, bupropion, or
`venlafaxine) was provided on study days 8 to 56. Limited doses
`of benzodiazepines for anxiety or zolpidem for sleep disturbance
`were used ifclinically indicated Changes in the selection of study
`antidepressant required sponsor approval. Other antidepressants,
`antipsychotics, and mood stabilizers were prohibited during the
`7-day screening process and throughout the 56-day study.
`
`STATISTICAL ANALYSIS
`
`interim analysis, the study was stopped by the independent, external
`Data Monitoring Committee based on the low probability of
`reaching statistical significance on the primary,» efficacy end point:
`mifepristone, 39f110 [35.5'Jr'ir), and placebo, 36/116 [31.0“4r), x2
`P = 0.5. The study stopped enrolling new patients but did allow
`all enrolled patients to complete the study.
`The present report and analysis is based on the final number
`of N = 292 enrolled ITT patients (mifepristone, n = 141;
`placebo, n = 151).
`
`All numerically continuous data are summarized using mean
`(SD) unless otherwise specified. All categorical data are presented
`using percentages. A prospective statistical analysis plan was
`followed for all analyses. For the primary end point and all cate—
`gorical end points, a Fisher exact test was used to compare propor-
`tions, and a 95% confidence interval for differences in 2 binomial
`proportions is presented. For categorical measures (with or with-
`out efl‘ect of plasma level) involving the proportion of patients
`with a BPRS-PSS of 50% or greater change from baseline, last—
`observation-carried-forward (LOCF) imputation was used. For
`continuous measures of efl‘icacy (with or without effect ofplasma
`level), comparisons are based on a mixed model
`repeated-
`measures analysis of covariance of the changes from baseline at
`each visit, with treatment and visits as fixed effects and intercept
`and subject as random effects, and a Treatment x Visit interaction
`term, with the baseline value as a covariate. For all analyses in-
`volving plasma levels, plasma level group was also included in
`the mixed model repeated-measures analysis of covariance model
`as a fixed effect Mixed model repeated-measures analyses were
`performed based on observed data, and imputation methods were
`not used.
`The intent-to-treat (ITT) population included all randomized
`patients who took at least 1 dose of drug. All analyses were per-
`formed using the ITT population and SAS version 9.2 (Cary,
`NC). The analysis of the primary end point was based on an
`LOCF imputation model. The safety evaluation was performed
`using all ITT patients who took at least 1 dose of mifepristone
`or placebo.
`
`RESU LTS
`
`Each site enrolled between 1 and 47 patients. As shown in
`Table l, the baseline demographics and characteristics were well
`balanced across groups. The mean age was 46 years; 55% were fe—
`male; and two thirds (66%) were black, and one third (32%) were
`white. Ofthe 292 patients randomized, 75 discontinued early fi'orn
`the trial (43 placebo, 32 mifepristone) (Supplemental Fig. 1, http://
`linkslwwcorn/JCP/A455).
`
`Efficacy
`Primary Outcome
`As indicated in Table 2, statistically significant diiferences
`were not observed between mifepristone and placebo on the cate-
`gorical primary measure of response of the percentage ofpatients
`who demonstrated a 50% or greater reduction in BPRS-PSS
`scores at both days 7 and 56 (36% for mifepristone vs 32% for pla-
`cebo, P = 0.5). On day 7, an unexpectedly high placebo response
`rate (44%) occurred versus mifepristone (47%) (P = 0.6). A sig—
`nificant difference in response rate was observed on day 28 (mi-
`fepristone, 60%; placebo, 48%; P = 0.03).
`
`Mifepristone Plasma Level
`Of the mifepristone patients, 66.7% (94/141) were in the a
`priori defined high-PL group (mean [SD], 2815 [102l]ng/mL),
`24.8% (35/141) were in the low-PL group (mean [SD], 1257
`[297]ng/mL), and 8.5% (12/141) had missing values. A second-
`Interim Analysis
`ary prespecified analysis of the high—PL group demonstrated sta—
`A prespecified interim analysis for efficacy and firtility was
`tistically significant improvement versus placebo at individual
`time points on days 28, 42, and 56 (Fig. 1). By day 56, 69% of
`conducted when 50% of the patients were enrolled (n = 226/450).
`The study was powered at 80% to detect a diiference of 13%
`the high-PL group, 57% ofthe low-PL group, and 56% ofthe pla-
`cebo group met the BPRS-PSS response criterion (P = 0.04,
`(37% vs 24%) in response rate between the mifepristone and pla—
`high-PL vs placebo).
`cebo groups for 1-tailed CL of 0.025 with 450 patients. After the
`
`
`TABLE 1. Baseline Characteristics of A" Study Patients
`
`Characteristic
`
`Age, mean (SD), y
`Sex, female, “/0
`Race, %
`White
`Black
`Other
`BPRS total score, adjusted mean (SD)
`BPRS-PSS score, adjusted mean (SD)
`HAMD—24 score, mean (SD)
`HAMD suicide question score, mean (SD)
`*t Test.
`1“Fisher exact test.
`
`Mifepristone (N = 141)
`
`
`Placebo (N = 151)
`Total (N = 292)
`
`P
`
`45.4 (9.0); range, 22—62
`54
`
`47.0 (9.5); range, 25—69
`56
`
`46.2 (9.3); range, 22—69
`55
`
`34
`64
`2
`32.9 (6.6); range, 20—49
`11.5 (2.6); range, 8—18
`38.0 (6.0); range, ZWSZ
`1.1 (1.2); range, 0—3
`
`29
`68
`3
`33.2 (6.2); range, 20—51
`11.9 (2.6); range, 8719
`37.7 (6.0); range, 23—58
`1.1 (1.2); range, 0—3
`
`32
`66
`2
`33.1 (6.4); range, 20—51
`11.7 (2.6); range, 8—19
`37.9 (6.0); range, 20—58
`1.1 (1.2); range, 0—3
`
`0.1*
`0.7T
`0.3T
`—
`—
`—
`0.4““
`0.1‘
`0.7“
`0.7*
`
`© 201 7 Walters Kluwer Health, Inc. All rights reserved.
`
`www.psychopharmacology.com I 507
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`
`TABLE 2. BPRS-PSS: Proportion With 50% or Greater Reduction at Visit From Baseline (LOCF)
`
`Proportion With 250% Reduction at Visit From Baseline, n (%)
`Mifepristone
`
`Fisher Exact Test, 2-Tailed P
`
`All Mifepristo ne
`High PI.“
`Low PL“
`Placebo
`All Mifepristone High PL“
`Low PLl
`
`Study Day
`(N = 141)
`(N = 94, 66.7%)
`(N = 35, 24.8%)
`(N = 151)
`vs Placebo
`vs Placebo
`vs Placebo
`
`Primary efi‘icacy end point
`Days 7 and 56
`51 (36.17)
`Individual study days
`Day 7
`Day 14
`Day 28
`Day 42
`Day 56
`
`66 (46.81)
`78 (55.32)
`85 (60.28)
`86 (60.99)
`90 (63.83)
`
`37 (39.36)
`
`10 (28.57)
`
`48 (31.79)
`
`0.5
`
`0.3
`
`45 (47.87)
`56 (59.57)
`59 (62.77)
`62 (65.96)
`65 (69.15)
`
`16 (45.71)
`19 (54.29)
`21 (60.0)
`21 (60.0)
`20 (57.14)
`
`0.6
`66 (43.71)
`0.3
`75 (49.67)
`0.03
`72 (47.68)
`0.2
`80 (52.98)
`
`84 (55.63)
`0.2
`
`0.6
`0.1
`0.03
`0.047
`0.04
`
`0.8
`
`0.8
`0.7
`0.3
`0.6
`1.0
`
`*High PL, mifepristone 2 1637 nngL.
`
`*Low PL, mifepristone < 1637 ng/mL.
`
`Figure 1 shows the results for the individual time points for
`cortisol, ACTH, and change from baseline in end points of
`BPRS-PSS, BPRS total, HAMD-24, and C-SSRS across the en—
`tire study. Brief Psychiatric Rating Scale measures reveal statisti-
`cally significant effects for the high-PL group when compared
`with placebo; however, the data did not show statistical separation
`on the HAMD-24. The low-PL group was not significantly differ-
`ent from the placebo group on any measure at any time point.
`
`ACTH and Cortisol Effects
`
`We explored whether the attainment ofa higher mifepristone
`plasma level was associated with a greater degree of GR antago-
`nism, as measured by elevations in ACTH or cortisol levels, and
`whether the measurable biological efi‘ects of GR antagonism were
`related to the clinical antipsychotic effects of mifepristone. In pa—
`tients receiving mifepristone, both cortisol and ACTH were ele-
`vated on day 7 and returned to baseline by day 28 (Figs. 1A, B).
`Significant correlations were observed among mifepristone-
`treated patients on day 7 for log mifepristone level and log in—
`creases in cortisol (r = 0.28, P = 0.002, n = 130) and ACTH
`(r = 0.17, P = 0.06, n = 125). As indicated in Figure 1, both the
`high— and low—PL groups were associated with significantly
`higher ACTH and cortisol levels at day 7 than the placebo group,
`with high-PL effect demonstrating the greatest effect.
`
`Safety
`Treatment—emergent AEs occurred in 114 (80.8%) and 103
`(68.2%) mifepristone and placebo patients, respectively (Table 3).
`The only serious AEs occurred in 3 mifepristone patients who
`required hospitalization; the events resolved and were judged by
`the investigator to be unrelated to study drug. Two patients treated
`with mifepristone and 4 patients treated with placebo discontinued
`because of an AB.
`No clinically relevant differences in laboratory measures, vi-
`tal signs, physical findings, or electrocardiograms were observed
`between the mifepristone and placebo patients.
`No statistically significant differences were observed among
`the 3 groups on suicidality as measured by the C-S SRS (Fig. 1D).
`
`DISCUSSION
`
`In the interim analysis, statistical significance was not met on
`the primary efiicacy end point, and the study was stopped early
`
`with enrolment of 292 of a planned 450 patients. Despite the neg-
`ative primary outcome, this study provides valuable insights:
`
`1. On the basis of a secondary prespecified analysis ofthe a priori
`mifepristone plasma threshold, this study demonstrated a clear
`Tl'll‘FEpI'lStOl‘tC plasma loveliresponse relationshigp, thereby repli-
`cating similar findings in previous studies.”1
`2. Biological markers of GR antagonism (cortisol and ACTH) were
`found to be mediators of antipsychotic effect of mifepristone.
`
`Low-PL patients responded much like the patients who were
`administered with placebo, also confirming previous studies. ' “R
`We hypothesize that a therapeutic mifepristone plasma level must
`be reached to develop a cerebrospinal fluid concentration suffi—
`cient to antagonize GR in the brain. Because patients were ob—
`served during study drug administration, the pharmacokinetics
`variability was not a function of treatment adherence.
`Plasma ACTH levels and, to a lesser degree, plasma cortisol
`levels on day 7 were substantial mediators of clinical response. Al-
`though statistically significant correlations were observed among
`mifepristone—treated patients on day 7 for both cortisol and ACTH,
`the degree of correlation points to a limited amount of variance of
`change in cortisol or ACTH because of rnifepristone plasma level.
`These data suggest that there may be other biological determinants
`of GR responsiveness (eg, GR genetic variation).
`This study incorporated several design changes from previ-
`ous studies, including increasing the dose of mifepristone from
`600 to 1200 mg and incorporating centralized ratings. Centralized
`ratings were implemented to attempt to reduce the placebo re-
`sponse rate. However, the placebo response rate at day 7 (44%)
`was higher than expected and higher than in previous mifepristcne
`PD studies, none of which used centralized ratings. It is plausible
`that conducting remote interviews over videoconference technol-
`ogy, for patients with PD, contributed to—rather than lessened—
`the placebo response rate. The third party who provided central-
`ized ratings rotated raters within a patient's course of treatment,
`which may have intensified the problem.
`We note that all patients enrolled in the study were admin-
`istered a single antidepressant for 7 weeks after 1 week of mifep-
`ristone or placebo. The degree of improvement noted in both
`groups by study end may reflect positive effects of antidepres-
`sant monotherapy in this population. Benefits of monotherapy
`with selective serotonin reuptake inhibitors in PD have been
`
`508 l www.psychopharmacology.com
`
`© 2017 Whiter: Kluwer Health, Inc. All rights reserved.
`
`NEPTUNE GENERICS - Ex. 1040
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`journal of Clinical Psychophormacology . Volume 37, Number 5, October 2017 Mifepristone Plasma Level Effect
`
`A
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`
`High plasma mifepristone level 21637 ng/mL, n = 94/141 (66.7%): low plasma inifepristone level
`<l637ng/mL, n=35li4l (24.8%); placebo: n = 151 (100%). In c, imputations are LDCF. In 6 and f.
`P—values are based on mixed modeI repeated measures of analysis of variance.
`SE bars are presented.
`* Statistically significant difference (P 5 05) between high plasma level and placebo groups.
`** Statistically significant difference (P S .05) between low plasma level and placebo groups.
`Abbreviations: BPRS, Brief Psychiatric Rating Scale; C—SSRS. Columbia Suicide Severity Rating Scale;
`HAMD-24, Hamilton Rating Scale for Depression; LOCF, last observation carried forward; PSS, Positive
`Symptom Subscale.
`
`FIGURE 1. Effects of mifepristone plasma level and antidepressant therapy in patients with PD.
`
`reported.20 Although such treatment may help explain the high
`response rates observed afler day 7,
`it does not explain the
`high placebo response rate seen on day 7 before antidepressant
`therapy started.
`
`Clinical trials with placebo response rates greater than 30%
`have diminished ability to statistically separate drug From pla-
`coho.” Despite the 44% placebo response rate on llie BPRS~
`PSS observed at day 7, a robust signal oftreatment effect on BPRS
`
`© 20) 7 Walters Kluwer Health, Inc. All rights reserved.
`
`www.psychopharmacology.com l 509
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`NEPTUNE GENERICS - Ex. 1040
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`Block et al
`[oumal of Clinical Psychophannaco/ogy . Volume 37, Number 5, October 2017
`
`
`
`TABLE 3. AB Occurring in 5% of Patients or Greater in Any Group
`
`Mifepristone
`
`All Mifepristone
`High PL‘t
`Low PL)r
`Placebo (Based All Patients (Based
`
`AE
`(N = 141)
`(N = 94, 66.7%) (N = 35, 24.8%) on N = 151), % on N = 292), %
`No. (11) patients who discontinued because of AB
`2
`1
`l
`4
`76
`Patients reporting AEs, %
`74.2
`68.2
`82.9
`91.5
`80.8
`Patients with any AE
`21.2
`19.2
`17.1
`27.7
`23.4
`Headache
`15.1
`12.6
`8.6
`21.3
`17.7
`Nausea
`10.6
`9.3
`8.6
`14.9
`12.1
`Constipation
`8.6
`9.3
`0
`11.7
`7.8
`Diarrhea
`8.2
`6.0
`8.6
`12.8
`10.6
`Dry mouth
`8.2
`10.6
`8.6
`4.3
`5.7
`Insomnia
`7.9
`6.0
`0
`13.8
`9.9
`Dyspepsia
`6.8
`6.0
`8.6
`7.4
`7.8
`Dizziness
`6.5
`5.3
`2.9
`8.5
`7.8
`Vomiting
`5.8
`6.0
`11.4
`4.3
`5.7
`Anxiety
`5.8
`3.3
`11.4
`8.5
`8.5
`Pollakiun'a
`5.1
`4.0
`8.6
`6.4
`6.4
`Rash
`4.5
`2.6
`5.7
`7.4
`6.4
`Fatigue
`
`Abdominal pain 3.4 5.0 7.4 0 2.0
`
`
`
`
`
`*High PL, mifepristone 2 1637 ngmL.
`TLow PL, mifepristone < 1637 nymL.
`
`and positive trends on HAMD-24 in patients in the high—PL group
`were seen on days 28, 42, and 56 (Fig. 1).
`Mifepristone 1200 mg daily for 7 days was safe and well tol-
`erated when compared with placebo. confirming earlier safely find“
`ings.J3 Placebo— and mifepristone-treatcd patients discontinued the
`trial because of ABS at comparable rates (Supplemental Fig. l,
`http://linkslwwicom/JCP/A455). At
`the mifepristone dose of
`1200 mg, approximately two thirds ofthe mifepristonc patients attained
`the a priori therapeutic plasma level (1637-ng/mL mifepristone).
`There are no FDA-approved medications for the treatment
`of PD. Targeting the specific biology of hypothalamic—pituitary-
`adrenal axis dysregulation in these patients could be a welcome
`advance for the field ofpsychiatry. A safe and tolerable side effect
`profile, coupled with a therapeutic plasma level and measurable
`biological effects associated with treatment response, makes GR
`modulation :1 reasonable line of inquiry in this disabling and po-
`tentially lethal illness. Future research should target the ability to
`stratify which patients would achieve high PL in advance oftreat—
`ment with mifepristone with the hopes of improving the benefit—
`risk profile.
`
`ACKNOWLEDGMENTS
`The authors thank the study participants, without whom this
`study would never have been accomplished, and the investigators
`for theirparticipation in this study. Agility Clinical, Inc, adminis-
`tered the interim analysis and received compensation from
`Corcept Therapeutics. The authors also thank Dat Nguyen,
`PharmD, andRuth Ann Gover ofCorcept TherapeuticsfiJr admin-
`istrative assistance in review and submission of the manuscript
`and Caren Rickhofif MWC, qf'rI-ichr-aphica Medical Writing Ser-
`vicesfor providing editorial assistance.
`
`AUTHOR DISCLOSURE INFORMATION
`Dr Block is an employee and shareholder ofCorcept Them-
`peutics. Dr Belanofi"is a cofounder: employee, and shareholder of
`
`Corcept Therapeutics. Dr Petrides r‘t’C't’lt t-rl compensation as a prin—
`cipal investigatorfizr this study. Dr Kushner ricochet! compensation
`as a consultantfiar Corcept Therapeutics. Dr Kalin has received com-
`pensation as a consultantfor Corcept Thertnreutics. Dr Schatzberg is
`a cofounder and shareholder ofCorcept Therapeutics.
`
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