CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202107Orig1s000
`
`MEDICAL REVIEW(S)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 1
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`

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 202107
`Priority or Standard Standard
`
`Submit Date(s)
`
`Received Date(s) April 18, 2011
`PDUFA Goal Date February 18, 2012
`Division / Office DMEP
`
`Reviewer Name(s) Zemskova Marina, MD
`Review Completion Date January 13, 2012
`
`Established Name Mifepristone
`(Proposed) Trade Name Korlym
`Therapeutic Class
`
`Applicant Corcept Therapeutics
`
`Formulation(s) Oral tablets
`Dosing Regimen 300-1200 mg once a day
`Indication(s) Endogenous Cushing’s
`syndrome
`Intended Population(s) Adults
`
`
`
`Template Version: March 6, 2009
`
`
`
`Reference ID: 3075278
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 2
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT.............................................. 9
`1.1 Recommendation on Regulatory Action .......................................................................... 9
`1.2 Risk Benefit Assessment .................................................................................................. 9
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies.............. 14
`1.4 Recommendations for Postmarket Requirements and Commitments ............................ 15
`INTRODUCTION AND REGULATORY BACKGROUND.......................................... 15
`2.1 Product Information........................................................................................................ 15
`2.2 Tables of Currently Available Treatments for Proposed Indications............................. 16
`2.3 Availability of Proposed Active Ingredient in the United States ................................... 18
`2.4
`Important Safety Issues With Consideration to Related Drugs...................................... 18
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ...................... 19
`2.6 Other Relevant Background Information ....................................................................... 22
`3 ETHICS AND GOOD CLINICAL PRACTICES ............................................................ 22
`3.1 Submission Quality and Integrity................................................................................... 22
`3.2 Compliance with Good Clinical Practices...................................................................... 22
`3.3 Financial Disclosures...................................................................................................... 24
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES...................................................................................................................... 24
`4.1 Chemistry Manufacturing and Controls ......................................................................... 24
`4.2 Clinical Microbiology..................................................................................................... 25
`4.3 Preclinical Pharmacology/Toxicology ........................................................................... 25
`4.4 Clinical Pharmacology ................................................................................................... 26
`4.4.1 Mechanism of Action .............................................................................................. 26
`4.4.2
`Pharmacodynamics.................................................................................................. 27
`4.4.3
`Pharmacokinetics..................................................................................................... 27
`5 SOURCES OF CLINICAL DATA..................................................................................... 31
`5.1 Tables of Studies/Clinical Trials .................................................................................... 31
`5.2 Review Strategy.............................................................................................................. 35
`5.3 Discussion of Individual Studies/Clinical Trials............................................................ 35
`5.3.1
`Study C1073-400 (Study 400)................................................................................. 35
`5.3.2
`Study C1073-415 (Study 415)................................................................................. 48
`5.3.3 Non-Cushing’s Corcept-sponsored studies.................................................................. 52
`6 REVIEW OF EFFICACY .................................................................................................. 62
`Efficacy Summary .................................................................................................................... 62
`6.1
`Indication........................................................................................................................ 62
`6.1.1 Methods................................................................................................................... 62
`6.1.2 Demographics.......................................................................................................... 62
`
`Reference ID: 3075278
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`2
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 3
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`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`Subject Disposition.................................................................................................. 70
`6.1.3
`6.1.4 Analysis of Primary Endpoint(s)............................................................................. 72
`6.1.5 Analysis of Secondary Endpoints(s) ....................................................................... 83
`6.1.6 Other Endpoints....................................................................................................... 90
`6.1.7
`Subpopulations ........................................................................................................ 96
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .............. 97
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects............................. 98
`6.1.10 Additional Efficacy Issues/Analyses....................................................................... 98
`7 REVIEW OF SAFETY ..................................................................................................... 102
`Safety Summary...................................................................................................................... 102
`7.1 Methods ........................................................................................................................ 102
`7.1.1
`Studies/Clinical Trials Used to Evaluate Safety.................................................... 103
`7.1.2 Categorization of Adverse Events......................................................................... 103
`7.1.3
`Pooling of Data across Studies/Clinical Trials to Estimate and Compare Incidence
`............................................................................................................................... 103
`7.2 Adequacy of Safety Assessments................................................................................. 103
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
`Populations ............................................................................................................ 104
`7.2.2 Explorations for Dose Response ........................................................................... 107
`7.2.3
`Special Animal and/or In Vitro Testing ................................................................ 109
`7.2.4 Routine Clinical Testing........................................................................................ 110
`7.2.5 Metabolic, Clearance, and Interaction Workup..................................................... 110
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .......... 110
`7.3 Major Safety Results .................................................................................................... 110
`7.3.1 Deaths.................................................................................................................... 110
`7.3.2 Nonfatal Serious Adverse Events.......................................................................... 113
`7.3.3 Dropouts and/or Discontinuations......................................................................... 122
`7.3.4
`Significant Adverse Events ................................................................................... 126
`7.3.5
`Submission Specific Primary Safety Concerns..................................................... 126
`7.4 Supportive Safety Results............................................................................................. 151
`7.4.1 Common Adverse Events...................................................................................... 151
`7.4.2 Laboratory Findings .............................................................................................. 156
`7.4.3 Vital Signs ............................................................................................................. 167
`7.4.4 Electrocardiograms (ECGs) .................................................................................. 168
`7.4.5
`Special Safety Studies/Clinical Trials ................................................................... 169
`7.4.6
`Immunogenicity..................................................................................................... 175
`7.5 Other Safety Explorations ............................................................................................ 175
`7.5.1 Dose Dependency for Adverse Events.................................................................. 175
`7.5.2 Time Dependency for Adverse Events.................................................................. 175
`7.5.3 Drug-Demographic Interactions............................................................................ 177
`7.5.4 Drug-Disease Interactions ..................................................................................... 177
`7.5.5 Drug-Drug Interactions ......................................................................................... 178
`7.6 Additional Safety Evaluations...................................................................................... 180
`
`Reference ID: 3075278
`
`3
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 4
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`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`7.6.1 Human Carcinogenicity......................................................................................... 180
`7.6.2 Human Reproduction and Pregnancy Data ........................................................... 180
`7.6.3
`Pediatrics and Assessment of Effects on Growth.................................................. 181
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound................................ 182
`7.7 Additional Submissions / Safety Issues........................................................................ 182
`7.7.1
`120-day safety update............................................................................................ 182
`7.7.2 Literature review........................................................................................................ 186
`8 POSTMARKET EXPERIENCE...................................................................................... 189
`9 APPENDICES.................................................................................................................... 190
`9.1 Literature Review/Reference........................................................................................ 190
`9.1.1 Literature Review....................................................................................................... 190
`9.1.2 References.................................................................................................................. 197
`9.2 Labeling Recommendations ......................................................................................... 200
`9.3 Advisory Committee Meeting......................................................................................... 200
`
`
`
`Reference ID: 3075278
`
`4
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 5
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`Table of Tables
`
`Table 1. Adrenal-blocking Drugs ................................................................................................. 18
`Table 2. Research Sites for the DSI audition............................................................................... 22
`Table 3. Number (%) of Patients with Protocol Violations.......................................................... 24
`Table 4. Mifepristone Cmax and AUC following Single Doses of 300, 600, and 1200 mg in
`Healthy Adults in the Fasted State (Source: Table 44 Clinical Pharmacology Summary) .......... 28
`Table 5. Summary of Plasma PK Parameters of Mifepristone and its Metabolites following a
`Single dose of 600 mg or Multiple doses of 600 mg/day of Mifepristone for 7 days (Study C-
`1073-05)........................................................................................................................................ 29
`Table 6. Corcept’s Safety and Efficacy Studies in Patients with Cushing’s syndrome................ 31
`Table 7. Corcept's Clinical Studies in non-Cushing’s syndrome indication / patients................. 31
`Table 8. Korlym Dosing Regimen................................................................................................ 37
`Table 9. Patients Disposition and Reasons for the Withdrawal in Study 415 .............................. 52
`Table 10. Non-Cushing’s Corcept's Studies That Provided the Supportive Safety Data for
`Mifepristone.................................................................................................................................. 54
`Table 11. Demographics and Body Measurements at Baseline (ITT/Safety Population) ............ 63
`Table 12. Medical Therapy of Hypercortisolemia (ITT/Safety Population) ................................ 64
`Table 13. Cushing’s Syndrome History and Signs/Symptoms at Screening (Safety Population) 65
`Table 14. Summary of Subjects with > 80% Compliance with Study Drug by Analysis
`Population and Cohort .................................................................................................................. 67
`Table 15. Concomitant Medications Used by ≥ 20% or More of the Overall Study Population
`(ITT/Safety Population)................................................................................................................ 68
`Table 16. Concomitant Medications Used to Treat Diabetes (ITT/Safety Population)................ 69
`Table 17. Concomitant Medications Used to Treat Hypertension (ITT/Safety Population) ........ 70
`Table 18. Patient Disposition by Populations and Study Cohort (n (%)) ..................................... 71
`Table 19. Cumulative Distribution Function for Percent Reduction in AUCglucose at Week 24/ET
`in C-DM Subjects (mITT population) .......................................................................................... 74
`Table 20. Reduction in AUCglucose e in C-DM Subjects by Visit (mITT Population) .................. 76
`Table 21. Cumulative Distribution Function for Change in Diastolic Blood Pressure at Week
`24/ET in C-HT Subjects (mITT Population) ................................................................................ 78
`Table 22. Summary of Diastolic Blood Pressure in C-HT Subjects by Visit (mITT Population) 80
`Table 23. Diastolic Blood Pressure at Baseline and Week 24 Visit for Subjects with and without
`Spironolactone Treatment: C-HT Cohort mITT Population......................................................... 81
`Table 24. Systolic and Diastolic BP Changes and changes in dose and/or number of
`antihypertensive medications in C-HT cohort (mITT population)............................................... 83
`Table 25. HbA1C and % of AUCglucose Changes from Baseline to Week 24 Visit in Patients with
`Elevated HbA1C at Baseline in C-DM Cohort (mITT Population)............................................... 85
`Table 26. Reduction in Antidiabetic Medications (mITT Population)......................................... 86
`Table 27. Percent Change in Body Weight from Baseline to Week 24 (mITT Population) ........ 87
`Table 28. Summary of Change from Baseline in SBP: All Subjects with Hypertension at
`Screening (mITT population) ....................................................................................................... 88
`Table 29. Median Scores of Data Review Board for Clinical Improvement by Visit.................. 90
`Table 30. Summary of Changes from Baseline in AUCinsulin by Visit (Population)..................... 91
`
`Reference ID: 3075278
`
`5
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 6
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`Table 31. Summary of HOMA-IR Results by Visit and Population (C-HT subjects and C-DM
`Subjects Not Taking Insulin) ........................................................................................................ 92
`Table 32. Summary of Change from Baseline in Waist Circumference (mITT Population) ....... 92
`Table 33. Summary of Change from Baseline in Body Composition by Visit............................. 93
`Table 34. Demographics and Disease characteristics in Patients Included in Published Reports of
`Mifepristone for the Treatment of Cushing's syndrome ............................................................... 99
`Table 35. Efficacy Observations during Mifepristone Treatment of Cushing's syndrome ........ 100
`Table 36. Demographic Characteristics in the Primary and Extension Studies (Study 400 and
`415) ............................................................................................................................................. 104
`Table 37. Extent of Exposure in Study 400 (ITT/Safety Population)......................................... 105
`Table 38. Extent of Cumulative Exposure (Study 400 and 415) ................................................ 106
`Table 39. Summary of TEAEs by Dose Levels in Safety population (Study 400) .................... 108
`Table 40. Listing of deaths in supportive Corcept’s studies in other indications....................... 112
`Table 41. Listing of SAEs in Patients Who Received Mifepristone in Non-Cushing’s Studies.121
`Table 42. Patients Disposition and Reasons for the Withdrawal in studies 400 and 415........... 122
`Table 43. Summary of AEs that Led to the Study Withdrawal in Non-Cushing’s Syndrome
`Studies......................................................................................................................................... 125
`Table 44. Summary of Subjects Who Experienced AI in Studies 400 and/or 415..................... 127
`Table 45. Summary of Subjects with Suspected AI, but Not Reported as AI in Study 400....... 128
`Table 46. Summary of Subjects Who Experienced Vaginal Bleeding in Studies 400 and/or 415
`..................................................................................................................................................... 131
`Table 47. Potassium Values and Korlym Doses in Subjects with Hypokalemia in Study 400 .. 135
`Table 48. Potassium Values and Korlym Doses in Subjects with Hypokalemia in Study 415 .. 137
`Table 49. Summary of Subjects with an Elevation in TSH in Study 400................................... 139
`Table 50. Summary of Subjects with an Elevation in TSH in Study 415................................... 139
`Table 51. ECG Intervals (Change from Screening to Day 14 Summary Statistics)................... 143
`Table 52. Summary of Subjects with QTcF ≥ 450 msec or an Increase in QTcF ≥ 30 msec
`(original NDA data) .................................................................................................................... 143
`Table 53. Listing of Subjects with QTcB ≥ 450 msec or a Change in QTcB ≥ 30 msec ........... 144
`Table 54. Summary of Treatment-emergent Adverse Events Occurring in > 5% Subjects in Study
`400............................................................................................................................................... 152
`Table 55. Treatment-emergent Adverse Events Occurring in Three (10%) or More Subjects by
`System Organ Class and Preferred Term (Safety Population) in Study 415 .............................. 155
`Table 56. Summary of Hematology Parameter Values (Study 400) .......................................... 158
`Table 57. Summary of Hematology Parameter Values (Study 415) .......................................... 160
`Table 58. Clinical Chemistry Parameter (Study 400)................................................................. 161
`Table 59. Clinical Chemistry Parameter (Study 415)................................................................. 163
`Table 60. Summary of Lipid Data (Study 400; Safety Population)............................................ 164
`Table 61. Summary of Lipids Values (Study 415) ..................................................................... 165
`Table 62. Summary Statistics for Vital Signs values (Study 415).............................................. 168
`Table 63. The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for
`mifepristone (600 mg and 1800 mg, Day 7) and the Largest Lower Bound for Moxifloxacin (Day
`14) (FDA Analysis)..................................................................................................................... 171
`
`Reference ID: 3075278
`
`6
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 7
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`Table 64. Comparison of Treatment-emergent Adverse Events (Occurring in Three or More
`Subjects) Starting in Study 400 and Study 415 by System Organ Class and Preferred Term
`(Safety Population) ..................................................................................................................... 176
`Table 65. Mifepristone Doses Used in the Treatment of Patients with Cushing's syndrome..... 187
`Table 66. Safety Observations during Mifepristone Treatment of Cushing's syndrome............ 188
`
`
`Reference ID: 3075278
`
`7
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 8
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`Table of Figures
`
`Figure 1. Structural Formula......................................................................................................... 15
`Figure 2. Cumulative Distribution Function for Percent Change in AUCglucose from Baseline to
`Week 24/ET: C-DM Cohort (mITT Population) .......................................................................... 74
`Figure 3. Plot of the Individual AUCglucose Values versus Time Profile (Responders in C-DM
`Cohort of mITT Population) ......................................................................................................... 75
`Figure 4. Plot of Mean AUCglucose values versus Time Profile (C-DM Cohort, mITT Population)
`....................................................................................................................................................... 76
`Figure 5. Cumulative Distribution Function for mm HG in DBP from Baseline to Week 24/ET:
`C-HT Cohort (mITT Population).................................................................................................. 78
`Figure 6. Mean DBP values Versus Time Profile: C-HT Cohort (mITT Population).................. 79
`Figure 7. Mean SBP values Versus Time Profile: All Patients with Hypertension at baseline
`(mITT Population) ........................................................................................................................ 88
`
`
`Reference ID: 3075278
`
`8
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 9
`
`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`1 Recommendations/Risk Benefit Assessment
`Mifepristone (Korlym) is a glucocorticoid receptor antagonist that is proposed by Corcept
`Therapeutics for the treatment of clinical and metabolic effects of hypercortisolemia in patients
`with endogenous Cushing’s syndrome. Mifepristone is currently marketed in the US by another
`company under the brand name Mifeprex™ for the indication of early termination of pregnancy.
`Corcept submitted this NDA (20705) to the Division under Section 505(b)(2) on April, 2011 .
`The proposed starting dose for Korlym is 300 mg; the dose may be escalated further in 300-mg
`increments to a maximum of 1200 mg once daily based on the assessment of clinical response
`and tolerability.
`
`Currently there is no approved medical therapy to reduce the effects of hypercortisolemia in
`patients with Cushing’s syndrome in the US.
`
`1.1 Recommendation on Regulatory Action
`
`According to my review of clinical data, I recommend approval of the use of Korlym 300 -1200
`mg in patients with Cushing’s syndrome and glucose intolerance or diabetes induced by
`hypercortisolemia.
`
` A
`
` daily administration of Korlym was not effective in producing a clinically meaningful
`improvement of hypertension induced by hypercortisolemia in patients with Cushing’s
`syndrome. Therefore, Korlym should not be recommended for the treatment of hypertension in
`patients with Cushing’s syndrome.
`
`1.2 Risk Benefit Assessment
`
`Korlym (Mifepristone) is a potent and specific antagonist of the type II nuclear glucocorticoid
`receptor (GR-II) and competes with cortisol for the binding to the receptor, preventing the
`biological effect of cortisol. Importantly, it does not decrease cortisol level. Given that the
`Sponsor has demonstrated the drug product’s efficacy and acceptable safety in patients with
`Cushing’s syndrome, Korlym can play a useful role in this population.
`
`Efficacy
`The Sponsor conducted a single Phase 3 pivotal study, Study C1073-400 (referred to as “Study
`400” in this review), in support of the proposed indication. The study was an open label study
`conducted in subjects with clinically significant hypercortisolemia who had not responded
`adequately to surgical or radiation treatment for Cushing's disease, and in subjects with the other
`forms of ACTH-dependent and ACTH-independent endogenous Cushing’s syndrome. An open
`label design was chosen because of the lack of an approved comparator drug. Fifty patients were
`enrolled in the study and received treatment with Korlym for 6 months. The initial dose of
`Korlym was 300 mg orally once a day that was titrated up to 1200 mg once a day based on
`efficacy and safety every 4 weeks or more frequently, if necessary. Patients’ enrollment in the
`
`Reference ID: 3075278
`
`9
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`(b) (4)
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 10
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`

`

`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`study was based on the presence of two major complications associated with hypercortisolemia:
`impaired glucose tolerance/diabetes mellitus (the so called “C-DM cohort”) or hypertension (the
`“C-HT cohort”). There was no randomization to the any of these 2 cohorts; patients were
`assigned based on baseline characteristics The study demonstrated that administration of Korlym
`to the 25 subjects in C-DM cohort resulted in a significant improvement in glycemic
`abnormalities: 87% of patients demonstrated an improvement in glycemic control as assessed by
`the percent decrease in the area under the two-hour blood glucose response curve (AUCglucose) at
`the end of the study, and 60% (15/25 subjects) of patients had a reduction in AUCglucose of more
`than 25% (co-primary efficacy endpoint). Because the lower bound of the 1-sided 95%
`confidence interval (CI) was greater than 20% (42%), this response rate of 60% was statistically
`significant. When standard 2-sided 95% CI was applied, the lower CI was 40.4%, still
`statistically significant. The mean change from baseline in AUCglucose was -8722 mg/dL*2hrs (2-
`sided 95% CI = (-13184, -4260), p=0.0009) from a baseline mean of 30670 mg/dL*2hrs. The
`improvement in glycemic control occurred early during the study - at Week 6 visit. Although the
`AUCglucose is not a standard endpoint in the assessment of the glucose control and may be
`affected by the other factors such as diet, exercise, and stress, the improvement in this primary
`efficacy parameter was supported by a significant reduction of HbA1C levels, a secondary
`efficacy endpoint. HbA1C provides a more reliable and validated measure of long-term glycemic
`control. There was a clear improvement in HbA1C by the end of the study: mean values
`decreased by 1.1% (2-sided 95% CI = (-1.56, -0.65), p=0.0001). Of the 12 subjects in the C-DM
`cohort with baseline HbA1C values > 7% (mean 8.5%), nine had reductions in HbA1C values to
`less than 7% at the end of the study. Of these, six subjects had HbA1C values within the normal
`range (< 6%) at the end of the study. Moreover, seven of 19 subjects who were treated with
`antidiabetic medications at baseline had a reduction in the number and/or doses of antidiabetic
`medications by the end of the study; five of 12 subjects who were on insulin therapy had a dose
`reduction of 50% or more by the end of the study. The majority of patients with impaired glucose
`tolerance or diabetes responded to the doses < 600 mg (9 of 15 patients).
`
`Other efficacy findings were supportive of the primary findings of the efficacy of Korlym in the
`cohort of patients with impaired glucose tolerance or diabetes induced by hypercortisolemia.
`Decrease in insulin levels and increase in insulin sensitivity (as evaluated by the homeostatic
`model assessment of insulin resistance (HOMA-IR)), decrease in body weight and waist
`circumference, and improvement in body composition with decrease in total and abdominal fat
`content was consistent with the improvement in glycemic control.
`
`The study met the other primary endpoint and demonstrated that 38% (8/21 subjects) of the
`subjects in C-HT cohort had an improvement in diastolic blood pressure (DBP) by 5 mm Hg or
`more. This result was statistically significant because the lower bound of the one-sided 95% CI
`was greater than 20%, the pre-specified margin of clinical significance. The clinical significance
`of the improvement in blood pressure control in these patients has to be called into question
`because of the following:
`• Hypertension was defined at baseline as systolic blood pressure (SBP) ≥ 140 mmHg and/or
`diastolic blood pressure > 90 mmHg. Thus patients with normal DBP (but elevated SBP)
`
`Reference ID: 3075278
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`10
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2069, Page 11
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`Clinical Review
`Marina Zemskova, M.D
`NDA 202107
` (Mifepristone Tablets)
`
`
`
`•
`
`were eligible for the study. Further decrease of normal DBP is of unknown clinical
`significance.
`• The median DBP values in all C-HT cohort patients were normal at baseline and decreased at
`the end of the study by 6 mm Hg (from 87 mmHg to 81 mmHg, respectively). The mean
`DBP values did not change at the end of the study as compared to baseline values.
`• The overall improvement in DBP was less striking than improvement in glycemic control:
`only 50% of patients in C-HT had some improvement in DBP. Moreover, the other 50% of
`patients had worsening of DBP control (in contrast only 3 patients (13 %) in C-DM cohort
`had worsening of glycemic control).
`• The Sponsor was advised to apply 95% 2-sided or 97.5% 1-sided confidence intervals. The
`sponsor applied 1-sided CI instead. Thus, biostatistician reviewer computed 95% 2-sided
`confide