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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`MEMORANDUM
`
`(Addendum to the orig'nal review dated to 1/13/2012)
`
`NDA:202107
`Brand Name
`Generic Name
`Reviewer
`
`Submission Date: April 18, 2011
`KorlymTM
`Mifepristone
`Jee Eun Lee, Ph.D.
`
`Team Leader (Acting)
`
`Jayabharathi Vaidyanathan, Ph.D.
`
`OCP Division
`0ND Division
`Sponsor
`Relevant IND, NDA
`Submission Type
`Formulation; Strength(s)
`Route of Administration
`
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`Corcept Therapeutics
`NDA 20687 (Mifeprex); IND 76480 (Korlym)
`Original NDA 505(b)(2)
`Tablets for immediate release; 300 mg
`Oral
`
`Indication
`
`Cushing's syndrome for patients who have not
`ade uatel
`
`res onded to sur e
`
`This is an addendum to the Clinical Pharmacology Review for NDA 202107 dated
`1/ 13/2012 and includes recommendations on the sponsor’s proposed labeling.
`
`Summary of Labeling Recommendations
`
`‘Strikethrough red’ text is for statements recommended to be deleted and ‘blue color’ text
`is for statements recommended to be added.
`
` 1
`
`Reference ID: 3075281
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEE E LEE
`01/23/2012
`
`JAYABHARATHI VAIDYANATHAN
`01/23/2012
`
`Reference ID: 3075281
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`MEMORANDUM
`
`(Addendum to the original review dated to 1/13/2012)
`
`NDA:202107
`Brand Name
`Generic Name
`Reviewer
`
`Submission Date: April 18, 2011
`KorlymTM
`Mifepristone
`Jee Eun Lee, Ph.D.
`
`Team Leader (Acting)
`
`Jayabharathi Vaidyanathan, Ph.D.
`
`Division Director
`OCP Division
`0ND Division
`Sponsor
`Relevant IND, NDA
`Submission Type
`Formulation; Strength(s)
`Route of Administration
`
`Chandrahas Sahajwalla, Ph.D.
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`Corcept Therapeutics
`NDA 20687 (NIifeprex); IND 76480 (Korlym)
`Original NDA 505(b)(2)
`Tablets for immediate release; 300 mg
`Oral
`
`Cushing's syndrome for patients who have not
`adequately responded to surgery
`m4)
`
`Indication
`
`Background:
`
`to Clinical Pharmacology review dated 1/ 13/ 12 in DARRTS for Clinical
`Refer
`Pharmacology details of mifepristone. The purpose of this addendum is to summarize the
`Clinical Pharmacology related post marketing study requirement.
`
`1. Phase IV Requirements
`
`Mifepristone is a substrate of CYP 3A4 and its three major active metabolites are formed
`Via CYP3A4-mediated metabolism. Sponsor conducted a drug-drug interaction study
`with cimetidine, a mild CYP3A inhibitor. There was no effect of cimetidine on
`mifepristone exposure. The effect of moderate or strong CYP3A inhibitors on the
`nharmaenkinptir's nf mifpnristnm: has not linen evaluated Signfior has proposed to
`. Since ketoconazole,
`nical management of
`Cushing’s disease, there is a high potential of its concomitant use with mifepristone. The
`degree of change in exposure of mifepristone when co-administered With strong CYP3A
`inhibitors is unknown and may present a safety risk or deprive the patients on strong
`inhibitors the use of Mifepristone due to lack of accurate knowledge of this potential drug
`
`Reference ID: 3074721
`
`

`

`interaction. Thus, the quantitative data for effect of ketoconazole on the pharmacokinetics
`of mifepristone would be beneficial to the target populations. A drug-drug interaction
`study with ketoconazole is recommended as a Post Marketing Requirement (PMR). The
`goal of this study is to get a quantitative estimate of the change in exposure of
`mifepristone following co-administration with ketoconazole. Based on the results of this
`study, the effect of moderate CYP3A inhibitors on mifepristone pharmacokinetics may
`need to be addressed. This will help provide more therapeutic options available to
`Cushing’s patients and appropriate labeling of mifepristone when co-administered with
`CYP3A inhibitors.
`
`
`
`
`
`
`Reference ID: 3074721
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEE E LEE
`01/20/2012
`
`JAYABHARATHI VAIDYANATHAN
`01/20/2012
`
`CHANDRAHAS G SAHAJWALLA
`01/20/2012
`
`Reference ID: 3074721
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA:202107
`
`Brand Name
`
`Submission Date: April 18, 2011
`
`KorlymTM
`
`Generic Name
`
`Mifepristone
`
`Reviewer
`
`Jee Eun Lee, Ph.D.
`
`Team Leader (Acting)
`
`Jayabharathi Vaidyanathan, Ph.D.
`
`OCP Division
`
`Clinical Pharmacology II
`
`0ND Division
`
`Metabolism and Endocrinology Products
`
`Sponsor
`
`Corcept Therapeutics
`
`Relevant IND, NDA
`
`NDA 20687 (Nlifeprex); IND 76480 (Korlym)
`
`Submission Type
`
`Original NDA 505(b)(2)
`
`Formulation; Strength(s)
`
`Tablets for immediate release; 300 mg
`
`Route of Administration
`
`Oral
`
`Indication
`
`Cushing's syndrome for patients who have not
`adequately responded to surgery
`M“)
`
`
`
`Table of Contents
`
`EXECUTIVE SUMJMARY.................................................................................. 3
`1
`1.1 Recommendation ...................................................................................................................................................... 4
`
`1.2 Phase IV Requirements ............................................................................................................................................ 4
`
`QUESTION BASED REVIEW ........................................................................... 6
`2
`2.1 General Attributes .................................................................................................................................................... 6
`
`2.1.1 What the chemistry and physicochemical properties of the drug substance? ...................... 6
`2.1.2 What is the proposed mechanism of action and therapeutic indication? .............................. 7
`2.1.3 What are proposed dosage and routes of administration? ..................................................... 8
`2.1.4
`Is there any DSI inspection requested for any of the clinical studies? ................................... 8
`
`2.2 General Clinical Pharmacology............................................................................................................................... 8
`
`Reference ID: 3072217
`
`1/1 00
`
`

`

`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to
`support dosing? .......................................................................................................................... 9
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints)?................................................................................................................................ 10
`2.2.3 What are characteristics of the exposure-response relationships (dose-response,
`concentration-response) for efficacy/safety?.......................................................................... 11
`2.2.4 What are the pharmacokinetic characteristics?.................................................................... 15
`2.3 Intrinsic factors....................................................................................................................................................... 23
`2.3.1 What intrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety response?........................................................ 23
`2.3.2
`Should dose of mifepristone be adjusted in patients with severe hepatic impairment?..... 24
`Should dose of mifepristone be adjusted in patients with renal impairment?.................... 25
`2.3.3
`2.3.4
`Is there any effect of gender or race on mifepristone PK? ................................................... 25
`2.4 Extrinsic factors...................................................................................................................................................... 25
`2.4.1 What extrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety responses? ...................................................... 26
`2.4.2
`Should dose of mifepristone be adjusted with concomitant use of strong, moderate, and
`mild CYP3A4 inhibitors? ........................................................................................................ 31
`2.4.3 Are DDI studies with moderate and/or strong CYP3A4 inhibitors needed? ...................... 32
`Should CYP2B6 substrates such as bupropion and efavirenz be avoided? ........................ 32
`2.4.4
`2.4.5
`Should dose of CYP2C8/9 substrates be adjusted or use of CYP3A4 substrates be
`contraindicated with concomitant use of mifepristone? ....................................................... 33
`2.5 General Biopharmaceutics..................................................................................................................................... 33
`2.5.1 Based on the biopharmaceutics classification system principles, under which category is
`this drug classified?.................................................................................................................. 33
`2.5.2 What are protein-binding properties of the drug?................................................................ 34
`2.6 Analytical Section ................................................................................................................................................... 35
`2.6.1 What bioanalytical methods are used to assess the drug concentrations? .......................... 35
`
`REFERENCE:.................................................................................................................36
`
`3
`
`LABELING ......................................................................................................36
`
`APPENDIX ......................................................................................................36
`4
`4.1 Individual Clinical Study Review.......................................................................................................................... 36
`4.1.1 C-1073-05: Effect of Hepatic Impairment Study with Subjects with Child-Pugh B .......... 37
`4.1.2 C-1073-19: Effect of Renal Impairment Study...................................................................... 42
`4.1.3 C-1073-25: DDI with Simvastatin........................................................................................... 49
`4.1.4 C-1073-23: DDI with Digoxin.................................................................................................. 54
`4.1.5 C-1073-24: DDI with Alprazolam........................................................................................... 58
`4.1.6 C-1073-26: DDI with Cimetidine ............................................................................................ 65
`4.1.7 C-1073-16: DDI with Fluvastatin............................................................................................ 71
`4.1.8 C-1073-20: Food Effect Study with 1200 mg Dose ................................................................ 74
`4.1.9 C-1073-27: Food Effect with 1200 mg/day Multiple Dose .................................................... 81
`4.1.10 C-1073-12: Food Effect Study with 600 mg Dose .................................................................. 85
`4.1.11 C-1073-22: Bioavailability Comparison for Three Formulations........................................ 87
`4.1.12 C-1073-425: Multiple dose study at 600 mg/day to assess effects on high-density
`lipoproteins ............................................................................................................................... 90
`4.1.13 Summary of In Vitro Studies................................................................................................... 93
`4.2 Cover Sheet and OCP Filing.................................................................................................................................. 97
`
`
`
`Reference ID: 3072217
`
`2/100
`
`

`

`1
`
`Executive Summary
`
`Corcept Therapeutics submitted the NDA 20-2107 for Korlym with intended indication
`of the treatment of Cushin ’s
`drome for atients who have not ad uatel
`res nded
`
`to suriei#
`
`
`
`Mifepristone is approved in US (Mifeprex® tablet (200 mg strength), NDA 20-687) for
`use in termination of pregnancy (through 49 days’ pregnancy) in conjunction with
`misoprostol. The recommended dose for the termination of pregnancy is a single dose of
`600 mg.
`
`Mifepristone is a glucocorticoid receptor (GR-II) antagonist and acts as an antagonist of
`the progesterone receptor. Mifepristone likely competes with cortisol to its intracellular
`receptor, the GR—II, preventing the biological activity of cortisol. Cushing’s syndrome
`results from chronic exposure to excessive circulating levels of glucocorticoids. Patients
`with Cushing’s syndrome often show non-specific symptoms such as obesity, muscle
`weakness, and depression. High level of cortisol may cause diabetes and high blood
`pressure. The first line of treatment for Cushing’s syndrome is surgical removal of the
`pituitary tumor or the entire pituitary.
`
`The sponsor proposes the use of mifepristone for medical treatment for patients with
`
`
`
`To support the efficacy in Cushing’s syndrome, the sponsor conducted one 24—week,
`open-label, uncontrolled Phase 3 clinical trial in 50 patients with Cushing’s syndrome: 29
`patients with diabetes and 21 patients with hypertension. The Phase 3 clinical trial shows
`beneficial efl'ects of mifepristone in mitigating hypercortisolemia.
`
`The recommended dose titration scheme is the same as that used in the Phase 3 trial: 300
`
`mg to 1200 mg based on tolerability and dose cap of 900 mg for patients with body
`weight < 60 kg.
`
`The pharmacokinetics of mifepristone has been evaluated in thirteen studies with healthy
`subjects,
`subjects with severe renal
`impairment, moderate hepatic impairment.
`Mifepristone shows nonlinear pharmacokinetics and time-dependent pharmacokinetics.
`The major route of elimination is metabolism and three active metabolites produced by
`CYP3A4-mediated metabolism have been identified. In vitro studies submitted by the
`
`Reference ID: 3072217
`
`3/1 00
`
`

`

`sponsor indicate mifepristone is an inhibitor of CYP3A4 and CYP2C8, its metabolites are
`inhibitors of CYP3A4, CYP2C8/9, CYP2C19, and CYP 2A6. Furthermore, mifepristone
`is substrates for P-glycoprotein and breast cancer resistance protein GBCRP).
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology-11 (OCP/DCP-
`II) has reviewed the clinical pharmacology data submitted under NDA 202107 dated
`4/18/2011 and finds it acceptable.
`
`1.2 Phase IV Requirements
`
`Mifepristone is a substrate of CYP 3A4 and its three major active metabolites are
`products of CYP3A4-mediated metabolism. Mifepristone is also an inhibitor of CYP3A4.
`The effect of a strong CYP3A4 inhibitor such as ketoconazole on the harmacokinetics
`
`ofmifiristone has not been evaluated. Sfinsor proposesh
`
`Since ketoconazole is being used in the
`there is a potential of its concomitant use with
`management of Cushing’s disease,
`mifepristone. The need of conducting a drug-drug interaction study with ketoconazole as
`a PMR is being discussed internally and will be finalized following the wrap-up
`discussion with the review team and the decision will be reflected as an addendum to
`
`Clinical Pharmacology review.
`
`1.3 Clinical Pharmacology Summary
`
`The current submission consisted of 18 clinical pharmacology studies including a
`thorough QTc study and five in vitro studies. Mifepristone was approved as a single dose
`regimen for termination of pregnancy and its multiple-dose pharmacokinetics and drug-
`drug interactions with drugs that are frequently prescribed to the target population,
`patients with Cushing syndrome, are major parts of the clinical pharmacology programs
`in the current submission.
`
`The PK parameters of mifepristone following single dose of 600 mg are summarized in
`Table 1 and the PK profiles of mifepristone following single dose of 600 mg is shown in
`Figure 1 along with that of last dose of multiple doses of 600 mg of mifepristone for 7
`days in healthy volunteers. The detailed PK parameters and profiles of metabolites of
`mifepristone are summarized in 2.2.4.
`
`Table 1. Summary of Pharmaeokinetie Parameters of Mifepristone Following Single Dose of 600 mg
`in Health Sub'ects
`ean SD , Source: Reviewer’s Ana sis
`
`
`
`Reference ID: 3072217
`
`4/100
`
`

`

`AUC0-∞ (hr*ng/mL)
`AUC0-last (hr*ng/mL)
`Cmax (ng/mL)
`Tmax (hr)*
`t1/2 (hr)
`*Median with range
`
`
`170059 (61717)
`164816 (60913)
`2982.3 (1040)
`1.25 [0.5, 6]
`40.7 (14.6)
`
`369177 (205164)
`323797 (146061)
`3329.3 (1259)
`1 [0.5, 2]
`84.6 (60.9)
`
`
`Figure 1. Pharmacokinetics profiles of mifepristone following single dose of mifepristone 600 mg or
`multiple doses of mifepristone 600 mg/day for 7 days (source: C-1073-05)
`
`
`Simvastatin: The exposure of simvastatin and simvastatin acid (AUC) was increased
`greater than 10-fold and 15-fold, respectively following 80 mg of simvastatin co-
`administered with multiple doses of mifepristone (1200 mg/day) compared to that
`following 40 mg of simvastatin only.
`
`Fluvastatin: Following the first and last dose of mifepristone 1200 mg/day given for 7
`days, there was a 2.67-fold and 3.57 fold increase, respectively, in AUC0-24 of fluvastatin.
`
`Digoxin: The drug-drug interaction study with digoxin did not find significant effect of
`mifepristone on digoxin pharmacokinetics.
`
`Alprazolam: The exposure of alprazolam is expected to increase approximately 2-fold
`with concomitant administration of mifepristone.
`
`Cimetidine: No evidence for the effect of cimetidine, a mild inhibitor of CYP3A4, on the
`pharmacokinetics of mifepristone was observed.
`
`
`
`
`Reference ID: 3072217
`
`5/100
`
`

`

`Hepatic/renal impairment: No dose adjustment of mifepristone is recommended to
`subjects with renal impairment, but the sponsor set the maximum dose as 600 mg per day.
`No dose adjustment of mifepristone is recommended to patients with mild/moderate
`hepatic impairment, but the maximum dose should be set to 600 mg per day as it is to
`patients with renal impairment. The administration of mifepristone to patients with severe
`hepatic impairment is not recommended
`
`
`
` Question Based Review
`
` 2
`
`
`
`
`2.1 General Attributes
`
`
`2.1.1 What the chemistry and physicochemical properties of the drug substance?
`
`
`
`
`
`
`
`Chemical Structure:
`
`11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one
`(IUPAC)
`
`Mifepristone is derived from the naturally occurring material, estrone, and is structurally
`similar to progesterone and glucocorticoids. Mifepristone is an antagonist of the
`progesterone receptor at low doses and an antagonist of the glucocorticoid receptors at
`higher doses. Mifepristone has five chiral centers with the absolute stereochemistry 8S,
`11R, 13S, 14S, 17S. The sponsor claimed the absolute stereochemistry is believed to be
`preserved in vivo, which is preserved in the six metabolites. The CMC review team also
`confirmed that in vivo chiral conversion of mifepristone that generates altered
`pharmacological activity of the drug is not anticipated.
`
`Mifepristone is a weak base with a pKa of approximately 5.0 and demonstrates a pH-
`dependent solubility profile. At pH=1.5, the solubility is ~25 mg/mL and declined as pH
`increases. At pH=2.5 and above, the solubility is less than 1 mg/mL. The logarithm of the
`partition coefficient between n-octanol and water of mifepristone is 5.13.
`
`
`
`
`Reference ID: 3072217
`
`6/100
`
`

`

`
`Figure 2. pH- dependent solubility profile of mifepristone at ~25°C
`
`
`
`2.1.2 What is the proposed mechanism of action and therapeutic indication?
`
`
`The proposed indication of the current NDA of oral administration of mifepristone is to
`treat clinical and metabolic effects of hypercortisolism with endogenous Cushing’s
`syndrome.
`
`Glucocorticoid cortisol, secreted from the zona fasciculate and reticularis of the adrenal
`gland under the stimulus of adrenocorticotropic hormone (ACTH) from the pituitary
`gland is the end product of the hypothalamo-pituitary-adrenal (HPA) axis. ACTH is then
`secreted in response to corticotropin releasing hormone (CRH) and vasopressin from the
`hypothalamus. Cortisol exerts negative feedback control on both CRH and vasopressin in
`the hypothalamus, and ACTH in the pituitary. In normal individuals, cortisol is secreted
`in a circadian rhythm; levels fall during the day from a peak in the morning to a ground at
`midnight; they then begin to rise again in the afternoon. If this circadian rhythm is lost
`along with
`the feedback mechanism, excessive
`levels of cortisol may render
`“endogenous” Cushing’s
`syndrome. Administration of excessive quantity of
`glucocorticoid may lead to similar symptoms, which is called “exogenous” Cushing’s
`syndrome.
`
`Pituitary-dependent Cushing’s syndrome, known as Cushing’s disease, is the most
`common, which accounts for 60-80% of the cases. It is usually due to a monoclonal
`corticotroph adenoma. ACTH-independent causes of Cushing’s syndrome apart from
`exogenous glucocorticoids are various. The most common cause is an adrenal adenoma
`or carcinoma.
`
`The treatment of choice for Cushing’s disease is trans-sphenoidal surgery. The overall
`remission rate is about 70%, and ~25% of them have a recurrence within 10 years of
`post-surgery. The mortality rate associated with the surgery is about 2% and other major
`complications occur at 15% rate. The treatment of choice for all cases of ACTH-
`independent Cushing’s syndrome is adrenalectomy. Patients with adrenal adenomas show
`
`
`
`Reference ID: 3072217
`
`7/100
`
`

`

`100% recovery rate following the surgery, with low morbidity and mortality.
`Conventional radiotherapy is also accompanied.
`
`In patients who failed in responding surgery and/or radiotherapy, medical management is
`recommended prior to bilateral adrenalectomy. Inhibitors of steroid biosynthesis in the
`adrenal cortex are used, and the most commonly used agents are metyrapone,
`ketoconazole, and mitotane (BA Gross et al., 2007). Ketoconazole is believed to have a
`direct effect on ACTH secretion from a thymic carcinoid tumor.
`
`Mifepristone is a cortisol receptor blocker and it is suggested to treat the clinical and
`metabolic effect of hypercortisolism in patients with endogenous Cushing’s syndrome,
`including:
`• patients with Cushing’s disease who have not adequately responded to or relapsed
`after surgery
`• Patients with Cushing’s disease who are not candidates for surgery
`
`
`Mifepristone has a high affinity for the receptors of glucocorticoids (cortisol) and
`progesterone, and competes with these endogenous steroids for binding sites (Philibert et
`al,, 1985). The glucocorticoid-blocking effects of mifepristone occur at doses that those
`required to block progesterone. Mifepristone does not decrease cortisol production.
`Glucocorticoids modulate gene expression by interacting with a glucocorticoid receptor,
`followed by “transformation” of the steroid-receptor complex into a form capable of
`nuclear binding. Mifepristone appears to exert its antiglucocorticoid effects both by
`preventing complete glucocorticoid receptor transformation and by altering a step
`subsequent to binding of the glucocorticoid receptor with DNA.
`
`
`2.1.3 What are proposed dosage and routes of administration?
`
`
`Mifepristone is orally administered with recommended initial dose of 300 mg once daily.
`Further escalation in 300-mg increments to a maximum of 1200 mg once daily may be
`appropriate in some patients, with increased monitoring for risk factors associated with
`the drug. Korlym should be given as a single daily dose and recommended to be given
`with a meal for more consistent exposure.
`
`
`2.1.4 Is there any DSI inspection requested for any of the clinical studies?
`
`
`No. The Phase 3 study used the final to-be-marketed formulation.
`
`
`2.2 General Clinical Pharmacology
`
`
`
`
`Reference ID: 3072217
`
`8/100
`
`(b) (4)
`
`

`

`2.2.1 What are the design features of the clinical pharmacology and clinical
`studies used to support dosing?
`
`
`One Phase 3 clinical efficacy trial (C-1073-400) in patients with Cushing’s syndrome has
`been completed and a long-term extension study (C-1073-415) is ongoing. Study C-1073-
`400 was a 24-week, open-label study where 50 subjects were assigned to receive an
`initial dose of 300 mg mifepristone once daily (QD) following screening period. In search
`of the optimal dose, dose escalation was undertaken under clinical monitoring. After 14
`days of dosing at 300 mg QD, dose escalations in 300-mg increments were made every
`four weeks if no clinical improvement was seen and if the drug was well tolerated. Dose
`escalation was not required to patients who showed significant clinical improvement at
`the current dosing level. The primary endpoints were glucose homeostasis in diabetes
`cohort and blood pressure in hypertensive cohort. The secondary endpoints for clinical
`improvements included body weight, body composition, body strength, and psychiatric
`symptoms etc. The maximum dose to be used was 1200 mg QD (or 900 mg QD for
`subjects weighing < 60 kg). In cases of severe hypercortisolism, the dose of mifepristone
`could have been increased further with the approval of the medical monitor; however, the
`dose was not to be increased beyond a weight-adjusted dose of 20 mg/kg per day.
`Subjects who completed the study were to enter the extension study (C-1073-415) for
`evaluation of long-term safety of mifepristone of the signs and symptoms of endogenous
`Cushing’s syndrome and persistence of therapeutic benefit of mifepristone treatment. The
`initial dose of mifepristone for the extension study was the same dose that was being
`administered at the Week 24 visit in study C1073-400.
`
`Thirteen clinical pharmacology studies have been submitted under the current NDA.
`
`
`• C-1073-05 PK (single and multiple dose) in hepatically impaired and healthy
`subjects
`• C-1073-12 Food effect for a 600 mg single dose
`• C-1073-16 Drug interaction study: fluvastatin (CYP2C9 substrate)
`• C-1073-19 PK (multiple dose) in renally impaired and healthy subjects
`• C-1073-20 Food effect for a 1200 mg single dose: Dose effect for single doses of
`300, 600, or 1200 mg
`• C-1073-22 Bioavailability study of effect of formulation change
`• C-1073-23 Drug interaction study: digoxin (P-gp substrate)
`• C-1073-24 Drug interaction study: alprazolam (CYP3A substrate)
`• C-1073-25 Drug interaction study: simvastatin (CYP3A substrate)
`• C-1073-26 Drug interaction study: cimetidine (CYP3A inhibitor)
`• C-1073-27 Food effect for multiple doses of 1200 mg/day
`• C-1073-300 Thorough QT study in healthy volunteers - multiple doses of 600 or
`1800 mg/day
`• C-1073-425 Multiple dose study at 600 mg/day to assess effects on high-density
`lipoproteins
`
`
`Dose recommendations in the proposed labeling are in agreement with Phase 3 clinical
`trial for general population and results obtained from clinical pharmacology studies are
`
`
`
`Reference ID: 3072217
`
`9/100
`
`

`

`in sections for contraindications, drug-drug
`reflected
`populations.
`
`The dose recommendations proposed by the sponsor are:
`
`interactions, and specific
`
`
`During the pre-NDA meeting on September 4, 2010, recommendations from clinical
`pharmacology were made to the sponsor, which included:
`• DDI studies as guidance recommends including with a strong inhibitor of
`CYP3A4
`• PK sampling in Phase 3 trial was recommended for covariate analysis
`• Evaluation of hepatic impairment at all stages
`
`
`The sponsor did not conduct any additional DDI studies after the meeting. Instead, they
`briefly addressed the interaction potential using concentrations of mifepristone in one
`patient who was on ketoconazole (400 mg TID). Samples were collected for PK
`evaluation in Phase 3 trial but no population pharmacokinetic analysis was performed.
`Non-parametric covariate analysis was performed with pre-dose concentrations only.
`
`
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or
`surrogate endpoints)?
`
`
`The primary endpoints in the Phase 3 protocol are (1) change in AUCglucose during the
`oral glucose tolerance test (OGTT) in diabetes (DM) cohort (2) change in diastolic blood
`pressure in hypertensive (HT) cohort. The success of the study was evaluated by the
`responder analysis: subjects were defined as responders if they had (1) greater than 25%
`
`
`
`Reference ID: 3072217
`
`10/100
`
`(b) (4)
`
`

`

`decrease in AUCglucose in DM cohort (2) greater than 5 mmHg decline in diastolic blood
`pressure in HT cohort. A key secondary endpoint was an assessment of clinical
`improvement determined at every visit by the Data Review Board.
`
`
`2.2.3 What are characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy/safety?
`
`
`In study C-1073-400, mifepristone doses of 300, 600, 900, and 1200 mg were
`administered based on tolerability and clinical response. To determine how mifepristone
`exposure changes as dose changes, reviewer’s analysis was performed using the data of
`patients in DM cohort. As seen in Figure 3, there is no strong indication for increase in
`exposure in both responders and non-responders whose dose was increased from 300 mg
`to 1200 mg over time (top left panel in Figure 3). The distribution of responders is close
`to the central tendency (lowess line) and the exposure of non-responders was higher than
`average in patients whose maximum escalated dose was 300 mg (lower right panel in
`Figure 3).
`
`
`
`
`
`Reference ID: 3072217
`
`11/100
`
`

`

`Figure 3. Trough concentrations of mifepristone over time in patients whose maximum dose was 300,
`600, 900, and 1200 mg in Study C-1074-400 (two patients who received 150 mg as protocol deviation
`were excluded)
`
`Since mifepristone metabolites are also active, similar analysis were performed, to see if
`there is any exposure-response with respect to each metabolite. Figure 4 below shows
`that similar to the parent, there is a lack of any exposure-response relationship for the
`three metabolites.
`
`
`
`
`
`
`Reference ID: 3072217
`
`12/100
`
`

`

`n0t.BrwHM
`
`n
`
`a.mmDS
`
`3maUR
`
`a.mmm
`
`DoomgnawDoomgnawcan:D
`
`
`
`um.HW
`
`
`
`RU 42698 in “SD 300 mg
`
`
`|_|_|_|_|_|_|
`
` fiver-x
`XI”!
`xxx:
`
`DoomgnawDoomDoomDDS.D
`
`8%838%8889D
`
`
`
`
`
`SEER.529E850$2.72.”.
`
`
`
`
`
`SEES5:25.950$3.2m
`
`
`
`
`
`SEESEEEESEU$3.2m.
`
`
`
`
`
`3555Ezmhcmucou$3.2m
`
`um.mw
`
` DoomBowDoomDoomBE.D
`
`
`RU 42848 in "SD 300 mg
`
`
`xixwfi
`
`‘10
`
`‘15
`
`20
`
`Week
`
`(a)
`(a)
`
`‘10
`
`15
`
`20
`
`Week
`
`
`
`Reference ID: 3072217
`Reference ID: 3072217
`
`13/100
`13/100
`
`
`
`

`

`(b)
`
`
`Figure 4. . Trough concentrations of mifepristone and its metabolites over time in patients whose
`maximum dose was 300 mg (a) or 1200 mg (b) in Study C-1074-400
`
`To evaluate if body weight is a covariate for the PK exposure of mifepristone, trough
`concentrations were plotted against body weight of individual patients. As seen in figure
`5, body weight does not contribute to the PK exposure of mifepristone.
`
`
`
`
`
`Reference ID: 3072217
`
`14/100
`
`

`

`150 mg
`300 mg
`600 mg
`900 mg
`1200 mg
`
`4000
`
`3000
`
`2000
`
`1000
`
`0
`
`Pre-Dose Concentration at Week 24 (ng/mL)
`
`60
`
`80
`
`100
`
`160
`
`180
`
`200
`
`120
`140
`Body Weight (kg)
`
`Figure 5. Trough concentrations of mifepristone at Week 24 in patients whose maximum dose was
`300, 600, 900, and 1200 mg in Study C-1074-400 (two patients received 150 mg as protocol deviation)
`
`Although the sponsor specified 60 kg body weight for dosing cap of 900 mg, there is no
`justification for the body weight cut-off. The recommendation was based on dosing cap
`for 20 mg/kg. No subjects included in Phase 3 study had body weight below 60 kg and
`the clinical experience above 20 mg/kg is rare according to literature study summary.
`Thus, this recommendation for dosing seems reasonable.
`
`
`2.2.4 What are the pharmacokinetic characteristics?
`
`
`
`2.2.4.1 What are single- and multiple-dose PK parameters of mifepristone and i