CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
` 202107Orig1s000
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`PHARM/TOX SUPERVISORY MEMO
`
`
`
`
`Food and Drug Administration
`
`Memorandum
`
`Date: 7 Feb 2012
`RE: Korlym NDA 202107, 505(b)(2) application
`Sponsor: Corcept Therapeutics
`Drug/Indication Mifepristone / Hyperglyemia in Cushing’s Syndrome
`
`
`
`Corcept Therapeutics is seeking approval of Korlym for the treatment of hyperglycemia
`secondary to metabolic complications of endogenous Cushing’s syndrome. Korlym is the
`proposed trade name for mifepristone which is a receptor antagonist for the glucocorticoid and
`progestin receptors. Anti-androgen activity is also a known effect of mifepristone. The intended
`therapeutic target for the proposed indication is the glucocorticoid receptor, though inhibition of
`the progestin receptor is certain to occur at therapeutic drug concentrations.
`
`Corcept cites Mifeprex (NDA 20687) as the listed drug upon which to rely for part of the
`toxicological assessment of Korlym (i.e., 505b2), specifically the reproductive and
`developmental studies as described in the Pregnancy and related sections of the approved
`Mifeprex drug label. Reliance on Mifeprex for this information is scientifically valid based on
`studies conducted by Corcept that chemically identified Korlym as mifepristone, the same active
`ingredient in Mifeprex. Further, the toxicological profile of Korlym observed in two-year rodent
`bioassays and a twelve-month dog assay, along with associated dose-ranging studies, also
`conducted by Corcept, are consistent with the known pharmacology of mifepristone as a
`glucocorticoid and progestin receptor antagonist. Confirmation that the chemical identity and
`pharmacological/toxicological activity of Korylm is consistent with mifepristone provides
`sufficient information to bridge to Mifeprex as the listed drug.
`
`As Mifeprex is approved for single-dose use, Corcept was obligated to characterize the chronic
`toxicology of Korlym in new studies to support the chronic clinical indication sought in
`Cushing’s patients. Thus, the pivotal studies included a twelve-month dog study and two-year
`bioassays in rats and in mice. As described in Dr. Brundage’s review, these animal species did
`not tolerate mifepristone at doses that were tolerated by human subjects in clinical trials. The
`absence of endocrine disruption at baseline in the test species likely explains the inability to test
`doses of mifepristone much above the intended clinical dose. At the doses tested, the
`observations made were consistent with the anticipated pharmacology and toxicology of an anti-
`glucocorticoid, anti-progestin, anti-androgen agent. The extensive and complex hepatic
`metabolism noted in animals likely underlies the treatment-related liver effects which ranged
`from hepatocellular enlargement and ALT elevation in rodents and dogs in shorter-term studies
`to liver adenomas and follicular cell thyroid adenoma and carcinoma in female rats exposed to
`mifepristone for two years. Complex hepatic metabolism is also seen in human subjects, and
`periodic transaminase monitoring may be a reasonable safety measure. Within the dosing
`
`Reference ID: 3083735
`
`

`

`limitations discussed above, results of these studies adequately addressed the lack of chronic
`toxicology data with mifepristone and adequately support, in part, its proposed clinical use in
`Cushing’s patients.
`
` concur with Dr. Brundage’s recommendation of ‘approval’ for NDA 202107.
`
` I
`
`Reference ID: 3083735
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TODD M BOURCIER
`02/07/2012
`P/T recommends AP
`
`Reference ID: 3083735
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application Number:
`Supporting Document/s:
`Applicant’s Letter Date
`CDER Stamp Date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`202107
`SDN 1
`15 April 2011
`18 April 2011
`Korlym (Mifepristone Immediate-Release Tablet)
`Reduction of the effects of hypercortisolism in
`patients with endogenous Cushing's Syndrome
`Corcept Therapeutics
`Division of Metabolism and Endocrinology Products
`(HFD-510)
`Patricia Brundage, Ph.D.
`Todd Bourcier, Ph.D.
`Mary Parks, M.D.
`Jena Weber
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of NDA 202107 are owned by Corcept Therapeutics or are data for which Corcept
`Therapeutics has obtained a written right of reference. Any information or data necessary for
`approval of NDA 202107 that Corcept Therapeutics does not own or have a written right to
`reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of
`safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries of a
`previously approved application is for descriptive purposes only and is not relied upon for
`approval of NDA 202107.
`
`Reference ID: 3074344
`
`1
`
`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`1
`
`TABLE OF CONTENTS
`EXECUTIVE SUMMARY ......................................................................................................3
`INTRODUCTION................................................................................................................3
`1.1
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ................................................................3
`1.3
`RECOMMENDATIONS .......................................................................................................5
`1.3.1 Approvability..............................................................................................................5
`1.3.3 Labeling.....................................................................................................................5
`2 DRUG INFORMATION .........................................................................................................7
`2.1
`DRUG .............................................................................................................................7
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS......................................................................8
`2.3
`DRUG FORMULATION.......................................................................................................8
`2.4
`COMMENTS ON NOVEL EXCIPIENTS .................................................................................8
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN...................................................8
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN................................................9
`2.7
`REGULATORY BACKGROUND ...........................................................................................9
`STUDIES SUBMITTED.........................................................................................................9
`3.1
`STUDIES REVIEWED ........................................................................................................9
`3.2
`STUDIES NOT REVIEWED...............................................................................................10
`PHARMACOLOGY.............................................................................................................10
`4.1
`PRIMARY PHARMACOLOGY ............................................................................................11
`4.3
`SAFETY PHARMACOLOGY ..............................................................................................13
`Effects on hERG Inhibition Assay using HEK293 Transfected Cells (500331-1/T-013)
`....................................................................................................................................13
`Effects of Mifepristone and Three Metabolites (RU42633, RU42698 and RU42848),
`on Cloned hERG Potassium Channels Expressed in Human Embryonic Kidney Cells
`(101115.DPT/T-025) ...................................................................................................14
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...........................................................16
`5.1
`PK/ADME ....................................................................................................................16
`5.2
`TOXICOKINETICS ...........................................................................................................24
`6 GENERAL TOXICOLOGY..................................................................................................26
`6.2
`REPEAT-DOSE TOXICITY ...............................................................................................26
`12-Month Oral Toxicity Study of C1073 in Dogs (T-012/950-004) ..............................28
`7 GENETIC TOXICOLOGY ...................................................................................................43
`8 CARCINOGENICITY ..........................................................................................................46
`A 2-Year Oral Gavage Carcinogenicity Study of C-I073 in the Albino Rat (T-022) .....47
`104-Week Oral Oncogenicity Study of C1073 in Mice (T-014/950-005) .....................63
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.............................................74
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION.............................................74
`12
`REFERENCES................................................................................................................74
`
`3
`
`4
`
`5
`
`Reference ID: 3074344
`
`2
`
`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`1 Executive Summary
`1.1
`Introduction
`This is a 505(b)(2) application for the immediate release (IR) formulation of mifepristone
`(Korlym®) to treat the clinical and metabolic effects of hypercortisolism in patients with
`endogenous Cushing’s syndrome. As an anti-glucocorticoid, mifepristone blocks the
`biological effects of cortisol centrally and peripherally by competing with cortisol's binding
`to the glucocorticoid receptor type II (GRII), which reduces the clinical and metabolic
`manifestations of hypercortisolism.
`
`Mifepristone is approved for the acute indication of pregnancy termination (single dose
`administration) under NDA 20687 (Danco Laboratories/Population Council). To support the
`proposed chronic use indication for the treatment of hypercortisolism in patients with
`endogenous Cushing’s syndrome, the sponsor conducted a 12-month toxicology study in
`the dog and 2-year carcinogenicity studies in the mouse and rat at the request of the
`Agency. The sponsor is referencing the nonclinical fertility and genotoxicity data in the
`Mifeprex® label (Danco Laboratories/Population Council) as allowed under this 505(b)(2)
`application.
`1.2
`Brief Discussion of Nonclinical Findings
`In addition to the chronic nonclinical studies in the mouse, rat, and dog, the sponsor
`conducted two in vitro hERG studies, pharmacokinetic studies in the dog and monkey,
`pivotal repeat dose toxicology studies in the mouse, rat, and dog, and two in vitro
`genotoxicity studies (bacterial mutation and chromosome aberration) in support of this
`application.
`
`Mifepristone is metabolized primarily by CYP3A4 into the metabolites RU42633, RU42848,
`and RU42698, which are each greater than 10 percent of total drug-related exposure and
`are pharmacologically active. All three metabolites are formed in humans and all
`nonclinical species studied.
`
`Repeat dose studies were conducted in the mouse (up to 3 months), rat (up to 3 months),
`and dog (up to 12 months) in an effort to identify potential toxicities associated with
`long-term use of mifepristone. Tolerability was exceeded in all species such that evaluating
`doses much above clinical exposure was not feasible. Consequently, the nonclinical
`evaluation of mifepristone’s toxicity is somewhat limited by the low exposure achieved in
`animals. Causes for the general signs of moribundity (e.g., reduced activity/ataxia,
`inappetence, hunched posture and prostration, dehydration) were not clearly established.
`However, patients with Cushing’s syndrome appeared to tolerate mifepristone at doses
`resulting in moribundity in non-diseased, healthy animals. The difference in the metabolic
`state of Cushing’s patients (e.g., hypercortisolism) versus the healthy animals used in the
`toxicology studies likely underlies the apparent discordant response to mifepristone.
`
`Despite the dosing limitations in the nonclinical studies, adverse findings not clearly related
`to the pharmacodynamic activity of mifepristone were identified in the liver, thyroid, and
`retina of animals.
`
`Liver and Thyroid
`Treatment-related adverse liver effects were noted in all three nonclinical species at doses
`comparable to clinical exposure. Increased liver weight and hepatocellular hypertrophy,
`
`Reference ID: 3074344
`
`3
`
`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`especially in the rat, are likely due to enzyme induction. However, chronic administration in
`rats resulted in single cell necrosis, multinucleated hepatocytes, basophilic cell foci, and
`increased pigmentation. Elevated ALT levels (up to 11X ↑) and hepatocellular pigmentation
`also occurred in the chronic dog study at exposures equal to or less than clinical exposure.
`Signs of hepatocellular toxicity in the mouse were also noted at doses marginally above
`(~5X) clinical exposure. Based on this data, consideration should be given to periodic
`monitoring of liver transaminase levels in patients exposed to mifepristone for a chronic
`duration.
`
`Over a two-year dosing period, hepatocellular adenomas, as well as thyroid follicular cell
`adenomas, carcinomas, and pooled adenomas/carcinomas were identified in female rats.
`A trend of increased thyroid adenoma with thyroid enlargement was also seen in male rats.
`The sponsor attributes the hepatocellular and follicular cell tumors to a rat-specific chronic
`induction of enzyme activity in the liver and subsequent increase in thyroid hormone
`metabolism resulting in thyroid hyperplasia and eventually neoplasia. Though plausible, the
`sponsor did not conduct any mechanistic studies to assess thyroid activity/function or
`hepatic enzyme activity. Moreover, clinically, chronic administration of mifepristone has
`caused elevations in serum TSH and transient decreases in T4 in Cushing’s patients as
`well as in patients with meningioma. It is unclear to what extent these might be related to
`liver enzyme induction. There was no treatment-related increase in the incidence of any
`tumor in mice. However, the ‘negative’ tumor finding is tempered by the limited exposure
`(≤1X MRHD of 1200 mg/day; AUC basis) achieved in the study. Overall, the relevance of
`the liver and thyroid tumors observed in rats to humans is equivocal and cannot be
`excluded.
`
`
`Retina
`Treatment-related retinal atrophy in albino rats at clinically relevant exposures (~1X MRHD
`of 1200 mg/day; AUC basis) appears to be species-specific and therefore not relevant to
`human subjects chronically exposed to mifepristone. FDA ophthalmology reviewers
`commented that it is difficult to tell if these nonclinical findings present additional clinical
`risk beyond that known when glucocorticoids are perturbed in human subjects. Eye exams
`at entry and every six months for clinical studies longer than 6 weeks in duration requested
`by the Agency have detected no treatment-related retinal atrophy to date.
`
`Other Observations
`In the mammary gland, there was a marked decrease in fibroadenomas in all dose groups
`(≥5 mg/kg) in the 2-year rat study, but an increase in adenomas/adenocarcinomas up to
`the mid dose (25 mg/kg; <1X MRHD). Although a decrease in body weight at the high dose
`may have contributed to the broken dose-response for the increase in mammary
`adenomas/adenocarcinomas, the pharmacology of the drug (i.e., anti-progesterone) does
`not strongly support a treatment-related increase in mammary tumors.
`
` concentration-related inhibition of hERG mediated IKr current caused by mifepristone and
`its three major active metabolites, as well as a slight QTc prolongation (6-8 msec) postdose
`in the chronic dog study at a clinically relevant exposure (~1X the MRHD of 1200 mg/kg;
`AUC basis) indicate possible cardiac effects. The sponsor conducted a thorough QT study
`in healthy males, which was determined to be inconclusive by the Agency’s
`Interdisciplinary Review Team.
`
`Other adverse findings of note from the nonclinical program were considered reasonably
`related to the pharmacodynamic activity (i.e., anti-glucocorticoid, anti-progestin, and
`
` A
`
`Reference ID: 3074344
`
`4
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`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`anti-androgen) of mifepristone. Changes in the pituitary and adrenal gland are attributable
`to perturbations of the HPA axis. However, they are not of significant concern in the
`Cushing’s patient population. Inflammation in the lungs in dogs and pulmonary histiocytosis
`in rats following chronic administration is also likely due to GRII blockade.
`
`At exposures below clinical exposure (<1X MRHD), there were adverse effects in the male
`and female reproductive systems that are attributable to the anti-androgen and
`anti-progesterone activity of mifepristone. Although these changes do not appear to result
`in neoplastic lesions, the lack of neoplastic findings is tempered by the limited drug
`exposure in rats and mice. The reversibility of these findings was not determined,
`especially in males.
`
`The use of Korlym® is contraindicated in women who are pregnant or may become
`pregnant because of the possibility of pregnancy termination due to mifepristone’s potent
`anti-progestational effect. No nonclinical reproductive studies were required.
`1.3
`Recommendations
`
`1.3.1 Approvability
`AP (Approval)
`
`1.3.2 Additional Non Clinical Recommendations
`None.
`
`Labeling
`1.3.3
`The sponsor used language from the approved Mifeprex® label (Danco
`Laboratories/Population Council) to describe the nonclinical genotoxicity and fertility data
`as allowed under this 505(b)(2) application. The section describing the carcinogenicity data
`was revised and teratology data from the approved Mifeprex® label were added under
`section 8.1 Pregnancy. Changes/additions to the proposed label are underlined.
`
`
`Reference ID: 3074344
`
`5
`
`(b) (4)
`
`1 PAGE OF DRAFT LABELING HAS BEEN WITHHELD IN FULL
`AS B4 (CCI/TS) IMMEDIATELY FOLLOWING THIS PAGE
`
`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`2 Drug Information
`2.1
`Drug
`CAS Registry Number
`84371-65-3
`
`•
`
`
`Code Name
`C1073, RU38486, EP10778
`
`Chemical Name
`• 11 ß-( 4-dimethylaminophenyl)-17ß-hydroxy-17 a-(1-propynyl)estra-4,9-dien-3-
`one (IUPAC)
`(11 ß, 17ß)-11 (( 4-dimethylaminophenyl))-17ß-hydroxy-17 -(l-propynyl)-estra-
`4,9-dien-3-one (chemical abstracts name)
`
`Molecular Formula/Molecular Weight
`C29H35NO2/429.58 (mifepristone)
`C28H33NO2/415.57 (RU42633)
`C29H35NO3/445.59 (RU42698)
`C27H31NO2/401.54 (RO42848)
`Structure or Biochemical Description
`
`
`Pharmacologic Class
`Glucocorticoid/progesterone receptor antagonist
`
`
`
`Reference ID: 3074344
`
`7
`
`

`

`NDA 202107
`
`Patricia Brundage
`
`2.2
`
`Relevant INDs, NDAs, BLAs and DMFs
`
`
`
` NDA 20687 (mifepristone; induction of abortion; Danoo Laboratories/Population Council;
`Mifeprex0
`DMF
`
`2.3
`
`Drug Formulation
`
`Korlymo tablets are immediate release (IR) tablets containing 300 mg of the active
`component mifepristone. The tablets are light yellow to yellow, oval, film coated, and
`debossed with "CORCEPT" on one side and "300" on the other. The tablets are roduced
`
`
`
`2.4
`
`Comments on Novel Excipients
`
`There are no novel excipients in the drug product. Each oompendial excipient to be used in
`the proposed commercial drug product meets the requirements of the respective current
`USP or NF monograph.
`
`Exci
`
`- ients S . onsor’s Table
`
`Excipient
`
`Amount per Tablet
`(mg)
`
`% in Core Tablet
`
` Hyd-oxypropylccllulosc
`
`Sodium Starch Glycolatc
`
`Silicifiod Microcrystallinc
`Cellulose
`
`Sodium Lauryl Sulfate
`
`Sodium Starch Glycolate
`
`Magnesium Stearaie
`
`Total Core Tablet Weight
`
`300 mg mifepristone)
`
`Film Coating
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`Impurities
`
`was established for individual unspecified impurities, which meets the
`A limit of NMT
`ICH Q3A(R2) i en Ication threshold based on the maximum daily clinical dose of 1200 mg
`
`Reference ID: 3074344
`
`

`

`NDA 202107
`
`Patricia Brundage
`
`m4)
`mifepristone. A limit of NMT 9"” is proposed for the impurity
`of mifepristone. This equates to a maximum total daily
`(“3mg based on the maximum 1200 mg/day clinical dose. Although this exceeds
`intake of
`the ICH Q3A(R2) impurity qualification threshold,
`m4) is present in all nonclinical
`species and humans generally at concentrations similar to or higher than concentrations of
`the parent drug, mifepristone and is therefore considered qualified.
`
`Degradants
`
`A limit of NMT 0"“) was established for individual unspecified degradants, which is in
`accordance with ICH QBB(R2).
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`300 mg/day initially and titrated up to 600 mg/day based on assessments of the response
`and tolerability. Further escalation in 300 mg increments up to a maximum dose of
`1200 mg/day may be appropriate in some patients (>60 kg) with increased monitoring for
`risk factors associated with the drug.
`
`Exposure at the proposed maximum recommended human dose (MRHD) of 1200 mg/day
`was established in healthy male volunteers administered mifepristone (1200 mg/day) once
`daily for 7 days (Study C-1 073-19). Exposure at the MRHD was not established in patients
`with Cushing’s syndrome.
`
`PK Parameters of Mifepristone and its Metabolites following Repeat Dosing
`'
`onsor’s Table' Stud C-1 073-19
`
`28133i6613
`
`AUCo-u
`(ng*l1/mL)
`
`3120 11199
`
`44932 $14048
`
`50.3 :r 33.5
`
`RU4269S m 672i2-40
`Ru4234s
`12931318
`
`8938:5931
`
`535-1283
`
`2.7
`
`Regulatory Background
`
`Under NDA 20687, FDA approved mifepristone (Mifeprex®) for the termination of early
`intrauterine pregnancy in September 2000. The FDA-approved regimen consists of taking
`600 mg (three 200 mg tablets) of mifepristone orally on Day 1 and 400 pg (two 200 pg
`tablets) of misoprostol orally on Day 3.
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`Most studies were previously submitted and reviewed unde
`
`“M"
`
`Summaries of
`nonclinical reviews from the INDs are included in this NDA review. Nonclinical studies
`reviewed/summarized in this submission include:
`
`0 Effects on hERG Inhibition Assay using HEK293 Transfected Cells
`(500331-1/T-013)
`
`Reference ID: 3074344
`
`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`• Effects of Mifepristone and Three Metabolites (RU42633, RU42698 and RU42848),
`on Cloned hERG Potassium Channels Expressed in Human Embryonic Kidney
`Cells (101115.DPT/T-025)
`• Protein Binding of C-1073 by Equilibrium Dialysis and Ultracentrifugation
`(PK-C0173-001)
`• Pharmacokinetic Study of C-1073 in Dogs Following an Oral and a Subcutaneous
`Dose (PK-C0173-005)
`• 4-Week Toxicity Study of C1073 in Female Mice (T-003)/GLP/ reviewed under
`IND59737
`• 13-Week Oral Toxicity Study in Mice (T-007)/GLP
`• A 28-Day Toxicokinetic Study with C-1073 When Administered Once by Oral
`Gavage in Sprague-Dawley Rats (T-004)
`• A 13-Week Oral Gavage Toxicity Study of C-1073 in the Albino Rat
`• 4-Week Oral Toxicity Study of C-1073 in Dogs (PK-007)
`• 12-Month Oral Toxicity Study of C1073 in Dogs (T-012)
`• 28-day Toxicokinetic Study with C-1073 When Administered Once daily by Oral
`Gavage to Cynomolgus Monkeys (T-006)
`• C-1073 Bacterial Mutation Test (T-009)
`• C-1073 Chromosome Aberration test (T-010)
`• 104-Week Oral Oncogenicity Study of C1073 in Mice
`• A 2-Year Oral Gavage Carcinogenicity Study of C-I073 in the Albino Rat
`The following in vitro pharmacokinetic studies were submitted to clinical pharmacology for
`review, but are briefly summarized within this review.
`•
`In Vitro Evaluation of the Binding of Mifepristone and Three Metabolites to Human
`Plasma Proteins (PK-C1073-002)
`• Determination of the Inhibition Potential (Ki) of C-1073, RU42633, RU42698, and
`RU42848 using Human Liver Microsomes (PK-C0173-003)
`• Determination of the Inhibition Potential (IC50) of C-1073, RU42633, RU42698, and
`RU42848 using Human Liver Microsomes (PK-C0173-004)
`In Vitro Interaction Studies of Mifepristone (RU486) with Human MDR1, MRP1,
`MRP2, MRP3, BCRP Transporters, and with Human OATP1B1, OATP1B3,
`OATP2B1, OCT1, OAT1, and NTCP Uptake Transporters (PK-C0173-006)
`Studies Not Reviewed
`
`3.2
`None
`4 Pharmacology
`In support of this 505(b)(2) new drug application, two safety pharmacology study were
`conducted to assess the effects of mifepristone on the rapidly activating inward rectifying
`potassium current (IKr) conducted by hERG channels. No other nonclinical pharmacology
`
`•
`
`Reference ID: 3074344
`
`10
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`

`

`NDA 202107
`
`Patricia Brundage
`
`studies were conducted for this 505(b)(2) application. The review relied upon the
`pharmacology information in the published literature.
`
`4.1
`
`Primary Pharmacology
`
`No new nonclinical primary pharmacology studies were conducted for this 505(b)(2)
`submission.
`
`Mechanism of Action
`
`Mifepristone acts as an antagonist at the progesterone receptor (PR), glucocorticoid
`receptor type II (GRII), and androgen receptor (AR) (Schreiber et al., 1983; Wagner et al.,
`1999; Song et al., 2004; Moguilewsky and Philibert, 1985). In binding displacement assays,
`mifepristone binds with a relatively high affinity to the GRII, PR, and AR (Heikinheimo et al.,
`1987a; Morgan et al., 2002). Mifepristone binds to the human GRII with an affinity
`3—4 times higher than that of dexamethasone and about 18 times higher than that of
`cortisol (Sartor and Cutler, 1996). Mifepristone’s three major metabolites, which obtain
`relatively high serum levels, also demonstrated binding affinities to the GRII and PR
`(Heikinheimo et al., 1987a). Mifepristone does not bind appreciably to either the estrogen
`(ER) or mineralocorticoid receptor (MR) (Moguilewsky and Philibert, 1985; Morgan et al.,
`2002).
`
` 0.24 :1 0.02
`
`15 i 2.6
`
`4.6 : 0.41
`
`44% at 10.131
`
`92% at 101th
`
`Reported as Kis :t SEM (n=3) in nM or percent inhibition at close. [3H]-dexamethasone (10 nM) for GR.
`[3H]-dihydrotestosterone (1 nM) for AR
`
`Relative Binding Affinities of Mifepristone and Its Three Metabolites for Human
`Uterine M ometrial and Endometrial PR Heikinheimo et al. 1987
`
`Relative Bindin
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`-—_E_
`
`
`—-—
`
`Relative Binding Affinities of Mifepristone and Its Three Metabolites for Human
`Placental GR Heikinheimo et al. 1987
`
`Relative Binding
`
`__
`Mifepristone
`Monodemeth lated metabolite RU 42633 _i_
`I-__--_
`
`Reference ID: 3074344
`
`1 1
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`

`

`NDA 202107
`
`
`
`Patricia Brundage
`
`Several studies have demonstrated that mifepristone functions as an active antagonist at
`the GRII and PR. In addition to competitively inhibiting agonist binding at the GRII,
`mifepristone causes the translocation of the ligand-GRII complex into the nucleus where it
`blocks the agonist-GRII complex from interacting with its DNA-target site (Wagner et al.,
`1999). Mifepristone also has a slow dissociation rate from the intracellular GRII relative to
`other endogenous or synthetic glucocorticoids (Philibert, 1984). At the PR, mifepristone
`promotes the PR dimerization and binding to specific progesterone response elements
`(PREs) of target DNA, which effectively competes with binding of agonist-bound PR to the
`DNA (Leonhardt and Edwards, 2002). However, mifepristone induces an altered
`conformation in the PR that is distinct from that induced by the hormone agonist rendering
`the receptor transcriptionally inactive as a result of the recruitment of co-repressors instead
`of co-activators (Jackson et al., 1997; Zhang et al., 1998; Wagner et al., 1998).
`
`Mifepristone has been shown to inhibit the actions of exogenous and endogenous
`glucocorticoids and progestins (Philibert et al., 1985). The anti-glucocorticoid activity of
`mifepristone occurs at slightly higher doses than does the anti-progestational activity
`(Cadepond et al., 1997; Sitruk-Ware and Spitz, 2003; Peeters et al., 2004). While doses
`above 1.5 mg/kg interrupted pregnancies (more than 40% of embryos lost) in rats
`demonstrating its anti-progestational effect, doses of 5 mg/kg and greater effectively
`blocked the effects of the glucocorticoid dexamethasone (5 mg/day) on body-, adrenal-,
`spleen-, and thymus-weight (Peeters et al., 2004). The three main metabolites of
`mifepristone also were shown to have anti-progestational (induction of abortion) and
`anti-glucocorticoid (inhibition of thymolytic effect) activity (Deraedt et al., 1985).
`
`As an anti-androgen, mifepristone has been shown to cause an interaction between the AR
`and co-repressors suggesting it could be a selective receptor modulator (Song et al.,
`2004). According to the approved Mifeprex® label, anti-androgenic activity was observed in
`rats following repeated administration of doses from 10 to 100 mg/kg. Mifepristone has also
`been shown to have a low level of AR agonist activity in vitro (Kemppainen et al., 1992).
`
`Drug Activity Related to Proposed Indication
`Cortisol is secreted from the cortical cells of the adrenal glands and is normally under the
`control of the pituitary hormone ACTH (Glucocorticoid/progesterone receptor antagonist
`hormone). Production of cortisol by the adrenal gland is stimulated by the ACTH produced
`by the pituitary. Under normal conditions, pituitary ACTH secretion is then inhibited by
`increasing levels of cortisol through negative feedback regulation.
`
`In animals (dogs and monkeys) and humans with an intact, functioning
`hypothalamic-pituitary–adrenal (HPA) axis, mifepristone antagonizes the negative pituitary
`feedback of cortisol by blocking central GRIIs (Bertagna et al., 1994; Bertagna et al., 1984;
`Healy et al., 1983; Spitz et al., 1993). In healthy males, mifepristone (200 mg/day;
`8 consecutive days) significantly increased the circulating concentrations of ACTH and
`cortisol that was reversible within 4 days after the end of treatment (Bertagna et al., 1994).
`Long-term administration of mifepristone (100 mg/day; 1 year) also produced persistent
`elevations of ACTH and cortisol; however, the response to CRH and the circadian rhythm
`of ACTH and cortisol secretion were not affected indicating that the central regulatory
`mechanisms remain intact (Lamberts et al., 1991). In addition to increases in cortisol and
`ACTH, long term administration of mifepristone (200 mg/day; ≥1 year) also caused
`elevations in TSH, androstenedione, estrone, testosterone and estradiol (Lamberts et al.,
`1991; Heikinheimo et al., 1997; Heikinheimo et al., 2000).
`
`Reference ID: 3074344
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`12
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`NDA 202107
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`
`
`Patricia Brundage
`
`Cushing's syndrome is a multisystem disorder caused by excess cortisol levels. Cushing's
`syndrome results from elevated cortisol levels due either to autonomous production of
`cortisol from the adrenal gland or over-stimulation of the adrenal gland by ACTH.
`Endogenous Cushing's syndrome results from the body's increased production of cortisol,
`whether it is due to an ACTH-dependent or ACTH-independent cause.
`
`With regards to the treatment of Cushing’s syndrome, mifepristone acts at the cellular level
`to prevent the biological effects of cortisol by competing with cortisol's binding to the GRII.
`Although mifepristone does not decrease cortisol production, it is expected to reduce the
`clinical impact of hypercortisolism.
`4.3
`Safety Pharmacology
`Effects on hERG Inhibition Assay using HEK293 Transfected Cells (500331-1/T-013)
`Study #:
`500331-1/T-013
`Study Report Location: Module 4; Volume 1.1
`Conducting Laboratory and
`Location:
`Date of Study Initiation:
`8 June 2005
`GLP Compliance:
`Yes
`QA Statement:
`Yes
`Drug, Lot #, and % Purity: Mifepristone, 70295AA008, 100%
`
`Key Study Findings
`(cid:131) Using the whole-cell patch-clamp technique, mifepristone (3-143 µg/mL
`[~7-326 µM]) produced no appreciable inhibition of hERG tail potassium current.
`
`Methods
`
`HEK293 cells stably transfected