CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202107Orig1s000
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`CROSS DISCIPLINE TEAM LEADER REVIEW
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`Cross Discipline Team Leader Review
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`Cross-Discipline Team Leader Review
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`udrome Recommended:
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`Feb .
`
`13, 2012
`
`Dra os Roman MD
`Cross-Disci I line Team Leader Review
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`NDA -202107
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`Corce t Thera o eutics Inc.
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`A ril 15, 2011; received Aril 18, 2011.
`
`Fe u
`.
`17, 2012
`Korlym Imifepristone
`
`Tablet/300 :- ;
`Treatment of hypercortisolism in patients with endogenous
`Cushin ; ’s
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`NDAIBLA #
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`Slln nlement#
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`A n nlicant
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`Date of Submission
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`PDUFA Goal Date
`Proprietary Name I
`Established
`S A
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`names
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`Dosa_e forms / Stren_ h
`Proposed Indication(s)
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`1 . Introduction
`
`On April 15, 2011 Corcept Therapeutics submitted a New Drug Application for Korlym
`(mifepristone) under Section 505(b)(2) of the Federal Food, Drug and Cosmetics Act in
`support of the following indications: treatment of clinical and metabolic efl'ects of
`hypercortisolism in patients with endogenous Cushing’s syndrome including, specifically,
`
` . Mifepristone is a glucocorticoid receptor (GR-II) antagonist and the rationale for
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`being used to treat hypercortisolism in Cushing’s syndrome is based on its ability to compete
`with endogenous cortisol at the receptor level, and block the biological activity of cortisol.
`Korlym is manufactured as a 300 mg tablet and is intended for use once a day orally.
`Treatment with Korlym is initiated at 300 mg once a day and titrated up to 1200 mg daily
`based on clinical response and tolerability. Korlym is intended for chronic use. Currenfly
`there are no approved drug products for the treatment of Cushing’s syndrome; several products
`are used 011' label alone or in combination with variable efficacy results.
`
`The mifepristone clinical program for Cushing’s syndrome was developed under IND 76,480,
`which was 0
`ed on An
`t 2, 2007 in the Division of Metabolism and Endocrinolo
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`. It should be noted that at the time of opening IND
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`76,480 for Cushing’s syndrome, the Korlym pharmacology/toxicology and clinical
`pharmacology programs had been quite extensive, and human exposure across a variety of
`indications and doses exceeded 1100 subjects/patients. The IND was in fact opened with what
`was planned to be the registration clinical trial (Study C1073-400), the results of which are
`submitted in the current NDA. This study was planned as a 24-week, open-label, uncontrolled
`(single-arm), Phase 3 clinical trial to be conducted in 50 patients with Cushing’s syndrome and
`glucose intolerance or diabetes (29 patients in the end) and hypertension (21 patients).
`Cushing’s disease is a rare disease and Corcept has received orphan indication on July 5, 2007
`for the “treatment of clinical manifestations of endogenous Cushing's syndrome”. At the time
`when the IND was opened, DMEP provided answers to a series of questions submitted by the
`sponsor regarding the development program for the Cushing’s syndrome indication. In
`summary:
`• The Division agreed that the toxicology studies conducted up to that time, along with
`ongoing carcinogenicity studies, would be sufficient for a Cushing’s syndrome
`indication.
`• Given the rarity of the disease and the ethical issues raised by conducting a placebo
`controlled trial in a condition of such severity when there is preliminary evidence of
`efficacy from published reports, submission of a single Phase 3 clinical study using a
`single-arm, open-label design was found to be acceptable for an NDA submission.
`• The Division provided advice regarding efficacy endpoints selected to be evaluated in
`the pivotal study, and specifically indicated that, due to the fact that cortisol levels
`cannot be used as a measure of efficacy in the case of mifepristone, the primary
`efficacy endpoints should be clinical, i.e. change in blood pressure and/or glycemic
`control. The Division also advised to use of area under the time vs. concentration curve
`for glucose during an oral glucose tolerance test as a study endpoint. In the end it was
`selected as one of the two primary endpoints.
`• Following review of the dosing information accumulated in healthy volunteers and
`across various patient populations studied under mifepristone INDs, the Division
`recommended that Korlym doses should not exceed a maximum of 20 mg/kg/day.
`• The Division also advised that every woman with an intact uterus undergo transvaginal
`ultrasound at baseline and completion of the study.
`
`
`In subsequent correspondence (September, 2, 2009) the Division added a request to obtain
`baseline and end-of-trial endometrial biopsy in order to evaluate the proliferative effect of the
`drug on the endometrium. In doing so, the Division decided that, given the severity of the
`condition being studied and the lack of an approved therapy, the potential effects of
`mifepristone on reproduction should be studied in the registration clinical trial rather than in a
`dedicated reproductive study that will slow the Korlym clinical program.
`
`In a communication dated March 3, 2010, DMEP asked the sponsor to add baseline and end-
`of-trial ophthalmological exams to the safety evaluations of the pivotal trial. This request was
`triggered by the observation of retinal atrophy in the preclinical program in a single animal
`species (Sprague Dawley rats) that was not confirmed in a second species (i.e. not observed in
`mouse or dog). As was the case with endometrial biopsies, this request and the subsequent
`implementation in the clinical trial were made while the trial was in progress.
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`It should be mentioned that after the initiation of the pivotal trial the sponsor noticed that the
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`and its implications will be discussed in detail in the efficacy section of this memorandum
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`DIVIEP granted Corcept Therapeutics 3 pre—NDA meeting that took place on September 14,
`2010. Issues discussed at the meeting included Corcept’s program for the Cushing’s syndrome
`indication in general, the sponsor’s intention to follow a 505(b)(2) regulatory path, the format
`and content of the NDA, the proposed stability program, and a proposed REMS. With respect
`to the plan to submit an NDA under Section 505(b)(2) of the FD&C Act, the sponsor
`expressed their intension to cross reference the nonclinical data from another mifeprestone
`product (Mifeprex) as the listed drug. They were advised that the nonclinical toxicology
`studies conducted under IND 76,480 were sufficient to bridge to the nonclinical findings in the
`already-approved Mifeprex label. During the meeting, the Agency also provided advice to
`standard CMC, biopharmaceutics, and clinical pharmacology questions. There were no areas
`of disagreement and DMEP agreed with sponsor’s overall plan.
`
`2. Background
`
`Important for establishing an accurate risk/benefit analysis for Korlym in Cushing’s syndrome
`is a clear understanding of the patient population for which Korlym is intended for use, and the
`complex medical context in which the decision of adding Korlym to the management of
`patients with Cushing syndrome is made. Cushing’s syndrome is a multisystem disorder of
`cortisol excess. Korlym aims at treating patients with endogenous hypercortisolism
`(exogenous hypercortisolism, the most frequent cause of Cushing’s syndrome, is almost
`exclusively an iatrogenic condition and is treated by dose reduction or optimization). The
`hypercortisolism in endogenous Cushing’s syndrome (further referred to in this memorandum
`simply as Cushing’s syndrome), results from inappropriate activation of the hypothalamic-
`pituitary—adrenal (HPA) axis at either the hypothalamus or pituitary level, excess cortisol
`secretion originating from the adrenal gland (tumors, hyperplasia), or from ectopic sources of
`corticotropin releasing factor (CRF), adrenocorticotropic hormone (ACTH), or cortisol. By far
`the most common type of Cushing’s syndrome is Cushing’s disease, a condition which is due
`to excessive secretion of ACTH from a pituitary micro- or macroadenoma (it accounts for up
`to 80% of all cases of Cushion’s syndrome).
`
`(Endogenous) Cushing’s syndrome11s a rare disease. The incidencern the US ranges from 0.7
`to 2.4 per 1 million persons per year- With an estimated prevalence of approximately 20,000
`patients, Cushing’ s syndrome meets the regulatory definition of a rare disorder, and, in fact,
`
`I Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006 May 13;367
`(9522):l605-17.
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`Korlym has received orphan designation. A disease of adult age mostly (peak incidence is
`between 25 and 40 years of age) that affects women more than men (8-fold higher rate of
`pituitary tumor and 5-fold higher rate of cortisol-secreting adrenal tumors in women with
`Cushing syndrome than in men), Cushing’s syndrome, if left untreated, has an extremely poor
`prognosis: a mean duration from presentation to death of 4.7 years in Cushing’s original series
`and a mortality rate that is 5-fold higher than that of age and gender-matched subjects2.
`Medical treatment of Cushing’s syndrome is secondary to surgical management that can be
`curative. However, a significant proportion of patients is not cured by surgery. For instance,
`remission rates following initial surgery for Cushing’s disease due to microadenomas of the
`pituitary are between 70-90% and smaller (50-65%) if due to macroadenomas3. Patients who
`fail surgery have several therapeutic options that include repeat surgery at the original site
`(pituitary or ectopic) or removal of the adrenals, radiotherapy, or medical therapy. Medical
`therapy may also be used rarely in some patients who are not candidates for surgery or
`radiotherapy (including patients with metastatic disease), or when immediate control of the
`hypercortisolemia is required prior to surgery due to the severity of the disease.
`
`Currently there are no approved medical therapies for Cushing’s syndrome. Several drugs that
`reduce cortisol secretion (adrenal-directed therapy) are used off label in clinical practice
`(metyrapone, etomidate, ketoconazole) with the goal of reduction or normalization of cortisol
`secretion. In many respects mifepristone stands alone in the context of the above-mentioned
`steroidogenesis inhibitors, because it does not reduce cortisol synthesis. Rather, mifepristone
`reduces the biological effects of the existing endogenous cortisol by competing effectively
`with it for binding to the type II nuclear glucocorticoid receptors for which mifepristone has an
`18-fold higher affinity than cortisol.
`
`The fact that the potential efficacy of mifepristone cannot be measured by quantifying
`endogenous cortisol secretion (e.g. measuring urinary free cortisol, an important efficacy
`measure in clinical practice and an equally relevant endpoint in clinical trials) has had direct
`consequences in the way clinical trials with Korlym have been planned and conducted. In
`absence of any other qualified biomarkers of disease improvement, the applicant had to select
`clinical endpoints. Of the many clinical manifestations of Cushing’s disease (glucose
`intolerance and diabetes, hypertension, obesity, myopathy, bone loss, decreased quality of life,
`gonadal dysfunction, dermatological changes, compromised immune function, psychiatric
`symptoms, and fluid and electrolyte disturbances) glucose intolerance and diabetes, on one
`hand, and hypertension, on the other hand, were selected as primary measures of efficacy for
`the Korlym phase 3 clinical trial.
`
`Thus, central to this application is whether the Korlym clinical program has provided
`substantial evidence of effectiveness in adults with Cushing syndrome who have not
`adequately responded to surgical treatment. This determination is a particularly challenging
`task for a variety of reasons. First and foremost, Korlym has been studied in a single-arm
`clinical trial with no comparator; since there are no approved medical therapies for this
`
`2 Etxabe J, Vazquez JA 1994 Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin
`Endocrinol (Oxf) 40:479–484
`3 Blevins LS et al. An approach to the management of patients with residual Cushing’s disease. J Neurooncol
`(2009) 94; 313-319.
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`indication to compare with, and since the use of a placebo arm in a disease of such severity
`would be unethical. Such a design in which patients serve as their own control is acceptable
`because the disease is not expected to show spontaneous improvement, and favorable changes
`observed at the end of the trial relative to baseline can be presumed to be treatment-related if
`there are no major confounders. Even so, additional challenges in interpreting the results of
`the Phase 3 clinical trial are posed by the small size of the study (50 patients), the confounding
`effects of concomitant medications such as antihypertensive drugs and glucose lowering
`medications that may interfere with the metrics of the primary efficacy variables, the expected
`biochemical and clinical variability of the patients enrolled, their relatively diverse surgical,
`radiological and medical history, and the heterogeneity in Cushing’s syndrome etiology
`(although most patients having pituitary disease, a few had ectopic forms of Cushing’s
`syndrome). Last but not least, methodological shortcomings appear to have been generated in
`one of the primary analysis cohorts, the “hypertension” cohort, which enrolled patients on the
`basis of elevated systolic and/or diastolic blood pressure, while diastolic blood pressure only
`was selected as primary efficacy variable. This memorandum will thus focus on the
`aforementioned limitations and on the interpretability of the Phase 3 program results with
`respect to efiicacy, in addition to discussing the standard safety findings.
`
`3. CMC/Device
`
`The CMC review (DARRTS 1/12/2012 and 1/17/2012) recommends approval of this
`application. There are no recommendations for Phase 4 studies. The Office of Compliance has
`issued on January 12, 2012 an “acceptable” recommendation for the manufacturing facilities.
`
`The active in
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`em in Korl
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`mifepristone, has a molecular weight of 429.60 g/mol. It is a
`made to be structurally similar to progesterone and
`is man actured as immediate-release tablets and formulated to
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`
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`ucocort1c01
`. Kor
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`mifepristone
`contain 300 m of
`sodium starch
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`silicified microcrystalline
`hydroxypro lcellulose NF
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`sodium lauryl sulfate
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`
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`magnesium stearate
`film coating
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`. A11 exci ients meet compendial requirements. Mifepristone in Korlym was
`formulatedh because ofits poor solubility. Korl
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`
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`density
`two packaging configurations: a 28-count bottle is acka ed in
`, and a 280-
`polyethylene bottle with a child-resistant closure
`count bottle acka ed in a
`hi
`density polyethylene bottle with a child-resistant
`
`
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`will be packaged in
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`hi
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`closure“-
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`The CMC review indicates that Corcept has authorization to the relevant DMFs for the drug
`substance, ingredients, container-closure system, and manufacturing processes. The drug
`specifications were reviewed and found to be acceptable. Impurities and dcgradants met ICH
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`requirements. Based on the stability data submitted, an expiry of 24 months is granted at room
`temperature.
`
` categorical exclusion from an Environmental Assessment was granted.
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` A
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`4. Nonclinical Pharmacology/Toxicology
`
`
`The nonclinical pharmacology/toxicology reviews (DARRTS, 1/20/2012 and 2/7/2011)
`recommend approval. They do not make any recommendations for additional studies.
`
`The applicant submitted in this NDA a 12-month toxicology study in dogs and a 2-year
`carcinogenicity study in the mice and rats. Both studies were conducted at the request of the
`Agency and were in addition to a wide range of preclinical studies previously submitted under
`IND 76,480. The applicant did not submit any reproductive and developmental toxicology
`studies of their own; instead they are referencing the nonclinical fertility and genotoxicity data
`in the Mifeprex® label (Danco Laboratories). Reliance on Danco’s data was found to be
`scientifically valid by the toxicology/pharmacology team on the basis of the demonstration
`that the active ingredient in Korlym is mifepristone and that the pharmacological/toxicological
`studies conducted with Korlym demonstrate pharmacodynamic effects consistent with the
`known effects of mifepristone.
`
`Relevant safety findings of the pharmacology/toxicology program (other then those related to
`the known pharmacodynamic effect of the drug) include liver toxicity4, thyroid tumors5, retinal
`atrophy, and QT prolongation. The liver and thyroid findings have been attributed to
`induction of enzyme activity in the liver (mainly CYP3A) that results in hyperplasia and
`eventually neoplasia, as well as increased thyroid hormone metabolism in the liver. In clinical
`studies LFT elevation has not been a problem (there were no cases that met the definition of
`Hy’s law, and LFT outlier values were rare, transient, of moderate magnitude, and resolved
`without intervention or could be explained by underlying liver disease. Thyroid laboratory
`changes have been minimal (transient TSH elevations with minimal changes in free T4) and
`are all monitorable (See also Section 8 for clinical discussion). The retinal atrophy (single
`species observation) and the QTc prolongation observed in dogs will also be discussed in
`Section 8 of this memorandum.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
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`
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`The clinical pharmacology review (DARRTS 1/13/20012) finds the data submitted in the
`NDA acceptable. However, due to the fact that mifepristone, the active ingredient in Korlym,
`
`4 Elevated liver function tests (LFTs), hepatocellular hypertrophy (especially in rat), hepatocellular toxicity in
`mouse at doses of about 5X clinical exposure; hepatocellular adenomas (rat-specific).
`5 Thyroid follicular cell adenomas, carcinomas in female rats.
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`is a CYP 3A4 substrate, and due to the potential pharmacokinetic interaction between
`mifepristone and ketoconazole (a strong CYP3A4 inhibitor used commonly off label for the
`medical management of patients with Cushing’s syndrome), the clinical pharmacology team
`recommended a drug-drug interaction study between Korlym and ketoconazole as a post-
`marketing requirement.
`
`The clinical pharmacology review includes an extensive description of the pharmacokinetics
`and metabolism of mifepristone, including information collected from Corcept’s 18 clinical
`pharmacology studies6, as well as information described in other sources such as the Mifeprex
`label. The pharmacokinetics of mifepristone has been characterized and is relatively well
`known. Mifepristrone has an absolute bioavailability that varies between 40% and 70% and,
`due to low solubility, it is believed that absorption at higher doses would be limited. The Tmax
`is 1-4 hours and delayed with food for approximately 1 hour after single and multiple doses.
`The T1/2 of mifepristone is 40.7 hours after a single dose and 84.6 hours after multiple dose
`administration of a clinical average dose 600 mg. Once absorbed, mifepristone is metabolized
`hepatically by CYP3A4. Six metabolites have been identified, three of them being also active
`metabolites with peak concentrations reached around 4, 6, and 36 hours, respectively. Both
`the parental product and its metabolites are protein bound (99% for mifepristone and 96-98%
`for metabolites). Major binding proteins are α1-acid glycoprotein (which is saturable within
`the therapeutic dose range) and albumin. Approximately 90% of drug is eliminated in bile and
`<10% in urine.
`
`The review indicates that the pharmacokinetics of mifepristone is not proportional with dose;
`following oral administration of a single mifepristone dose of 300 mg to 1800 mg there is an
`increase in exposure that is not proportional to the increase in dose. Since there is no evidence
`for facilitated transporter(s) responsible for absorption for mifepristone, which could account
`for the nonlinear PK, the reviewer proposes that this observation could be explained by the
`low solubility of mifepristone. Of interest, in the Phase 3 trial, the pre-dose concentrations did
`not increase significantly as the dose was increased above 600 mg.
`
`Mifepristone is not only a substrate of CYP 3A4 but also an inhibitor. This feature may be
`responsible for the observation that mifepristone concentrations tends to decrease over time.
`The clinical relevance of this observation is not clear at this time.
`
`The clinical pharmacology reviewer points out that the effect of strong CYP3A4 inhibitors on
`the pharmacokinetics of mifepristone has not been evaluated. Ketoconazole is such an
`inhibitor and is particularly relevant in clinical practice because both ketoconazole and
`mifepristone are used in the medical treatment of Cushing’s syndrome. Although the applicant
`proposes
`,
`understanding the effects that ketoconazole may have on the pharmacokinetics of mifepristone
`(and labeling appropriately this information) is of particular clinical importance. Therefore I
`agree fully with the postmarketing recommendation to conduct a drug-drug interaction study
`with ketoconazole.
`
`6 The 18 clinical pharmacology studies include 13 studies in which the pharmacokinetics of mifepristone has
`been evaluated in different patient populations (healthy subjects, patients with severe renal impairment, moderate
`hepatic impairment), five in vitro studies and a thorough QTc study.
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`No justification for a body weight cut-off of 60 kg was found despite the use of such a dosing
`threshold by the applicant in the Phase 3 clinical trials.
`
`Food effect studies conducted with 1200 mg single dose, 1200 mg multiple doses, and 600 mg
`single dose indicate that food increases Cmax and AUC of mifepristone (e.g. an increase of
`19% in Cmax and 29% in AUC following a single dose of 600 mg of mifepristone).
`Mifepristone is recommended to be taken with food.
`
`Results from a study conducted in patients with severe renal impairment showed no significant
`change in the pharmacokinetics of mifepristone following administration of 1200 mg of
`mifepristone.
`
`Finally, based on the known metabolism of mifepristone and the drug-drug interaction studies
`conducted, the clinical pharmacology reviewer makes the following recommendations:
`• No dose adjustment is necessary for patients with hepatic impairment, but doses in
`excess of 600 mg should not be used in patients with moderate hepatic impairment, and
`the drug should not be used in patients with severe impairment.
`• Concomitant use of Korlym with simvastatin or lovastatin should be contraindicated.
`• When given concomitantly with Korlym, substrates of CYP2C8/9 should be used at the
`smallest recommended doses and closely monitored for adverse effects.
`• Other oral drugs with CYP3A mediated metabolism may need the lowest or a reduced
`dose when used with Korlym.
`• Concomitant use of strong inhibitors of CYP3A is contraindicated.
`• Mild to moderate inhibitors of CYP3A do not require dose adjustment of Korlym.
`• Use of moderate inhibitors of CYP3A4 should be avoided.
`• Use of midazolam should be contraindicated.
`• Use of CYP2B6 substrates should be avoided.
`
`
`
`
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`6. Clinical Microbiology
`
`
`Not applicable.
`7. Clinical/Statistical- Efficacy
`
`
`The main source of clinical data for the Cushing’s syndrome indication is Study C1073-400
`(further referred to as Study 400), a 24-week, single-arm, multicenter (17 US sites) open-label
`study conducted in 50 adult patients with Cushing’s syndrome. Patients who completed the
`study and benefited from Korlym were allowed participation in an extension trial, Study
`C1073-415 (further referred to as Study 415) following a 6-week period of observation off
`mifepristone. Study 415 is ongoing.
`
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`Study 400 enrolled adult patients with a diagnosis of endogenous Cushing’s syndrome who
`had clinical evidence of hypercortisolemia7, biochemical evidence of cortisol excess8, and who
`required medical treatment in the opinion of the investigator. There was no specific metric
`associated with the clinical determination that a patient was a candidate for medical treatment
`or not; instead, not unlike a clinical practice scenario, the decision appears to have been based
`on the best judgment of the caring physician/investigator9. Not surprisingly, given the
`heterogeneity of Cushing’s syndrome in general, the etiology of Cushing’s syndrome among
`the patients enrolled in Study 400 was quite diverse, and included Cushing’s disease (most
`patients), ectopic sources of ACTH, or excess of cortisol secretion due to adrenal sources
`(adrenal carcinoma).
`
`Mifepristone treatment was started in all patients with a dose of 300 mg once a day. This was
`followed by dose escalations of 300 mg at a time, which were done at several weeks interval in
`absence of clinical improvement, provided that the drug was well tolerated. The highest
`allowed doses were 900 mg for patients with weights < 60 kg (this dose could be reached as
`early as Week 6) and 1200 mg for those with weights > 60 kg (this was achieved as early as
`Week 10). No patients received doses in excess of 1200 mg (although the protocol allowed
`exceptions under certain circumstances) and no dose was allowed to exceed 20 mg/kg/day.
`Dose reductions were also permitted for safety or poor tolerability. If Korlym treatment
`resulted in oversuppression of cortisol activity and evidence of adrenal insufficiency (an event
`anticipated based on prior experience with this drug and its known mechanism of action)
`mifepristone was to be interrupted for ≥ 7 days (given the long half-life of the drug) and
`treatment with exogenous corticosteroid was to be initiated; if Korlym treatment was re-
`initiated it had to be done with the initial starting dose of 300 mg.
`
`Two inclusion criteria deserve special attention because they are related in a fundamental way
`to the clinical endpoints selected for the primary efficacy analysis (glucose control and
`reduction in diastolic blood pressure). As designed, patients were to be enrolled in Study 400
`in two distinct cohorts: a cohort of patients who had either glucose intolerance or type 2
`diabetes (from now on referred to, for simplicity, as the “diabetes” cohort because 83% of
`patients in this cohort had diabetes) and a cohort of patients with hypertension (from now on
`referred to as the “hypertension” cohort). Please note that there was no randomization to any
`of these two groups, and patients were assigned to each of them simply according to pre-
`specified baseline characteristics. Of the 50 patients enrolled, 29 were assigned to the diabetes
`cohort and 21 to the hypertension cohort. Each cohort had a different prespecified primary
`
`7 Patients had to have two or more of the following signs and symptoms: Cushingoid appearance (moon facies,
`dorsal-cervical fat pad, plethora), increased body weight or central obesity, proximal muscle weakness, low bone
`mass (DXA T-score < -1.0), psychiatric symptoms (including depression or psychosis), hirsutism and/or
`violaceous striae and/or acne.
`8 This consisted in above-normal urinary free cortisol (UFC) on at least two complete 24-hour urine collections
`collected within 4 months of the baseline visit with at least one done during the screening period which was 6
`weeks in length (all UFC collections were accompanied by concomitant measuring of urine creatinine to ensure
`appropriate collection of the urine specimens).
`9 The applicant specifically states that “the study enrolled subjects for whom the investigator had determined that medical
`treatment of endogenous hypercortisolemia was needed. Medical treatment could have been intended to treat the effects of
`persistent or recurrent hypercortisolemia after surgery and/or radiation for Cushing’s disease, to bridge the period of time for
`radiation to become effective, when surgery was not feasible, or in subjects with non-pituitary based ACTH-dependent and
`ACTH-independent disorders” (CSR C1073-400, page 21).
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`efficacy endpoint and primary efficacy analysis. As such, Study 400 could didactically be
`seen as two different small trials, one conducted in patients with glucose intolerance or
`diabetes and the other in patients with hypertension. In these two “trials”, the primary efficacy
`assessments were different but the safety evaluations were identical.
`
`To be enrolled in the diabetes cohort, patients had to show evidence of glucose intolerance10 or
`diabetes11 based on the results of a baseline oral glucose tolerance test or based on standard
`diabetes diagnostic criteria. Of note, there criteria were not applied to those patients who had
`previously been diagnosed with diabetes mellitus and were on anti-hyperglycemic medications
`prior to study initiation (i.e. these patients were allowed enrollment on the basis of prior
`diagnosis of diabetes). Such patients, however, had to be on stable doses of antidiabetic
`medications prior to enrollment and no changes in antidiabetic medication(s) were allowed
`from 2 weeks prior to the initiation of the study drug through its completion12. No new
`antihyperglycemic medications were allowed once enrolled, and patients who required and
`received additional antihyperglycemic medications during the study were to be discontinued.
`The primary efficacy analysis for the diabetes cohort was a responder analysis; a responder
`was defined as a patient who had a ≥ 25% reduction in the serum glucose area under the time
`vs. concentration curve at end of trial relative to baseline following an oral glucose tolerance
`(oGTT) test.
`
`The blood pressure criterion required for assignment to the hypertension group included a
`systolic blood pressure ≥ 140 mmHg and/or a diastolic blood pressure > 90 mmHg; patients
`were also allowed enrollment if they had a history of hypertension caused by or aggravated by
`hypercortisolemia and were currently receiving antihypertensive medication(s); such patients
`had to be on stable doses of antihypertensive medications, and no changes were allowed for 4
`weeks prior to enrollment. No new antihypertensive medications were allowed during the
`trial; if used, patients were to be discontinued13. The primary efficacy analysis for the
`hypertension cohort was also a responder analysis, a responder being a patient that experienced
`a ≥ 5 mm reduction in diastolic blood pressure. It should be mentioned from the start (and this
`issue will be further expanded with the actual presentation of the clinical efficacy results) that
`there is some degree of disconnect between the blood pressure inclusion criterion and the
`primary efficacy analysis for this cohort in that the above-described inclusion criterion allowed
`patients to be enrolled with normal diastolic blood pressure, and in fact the mean diastolic
`blood pressure at baseline (82.9±11.42 mm Hg) was within the normal range.
`
`
`
`10 Evidence of impaired glucose tolerance was to consist in a plasma glucose level between 140 mg/dL and 199
`mg/dL after a 2-hour 75-gram oral glucose load.
`11 Diabetes mellitus had to be confirmed by a fasting plasma glucose ≥ 126 mg on two measurements OR a 2-
`hour plasma glucose level ≥ 200 mg/dL after a 75-gram oral glucose load.
`12 19/29 (65.5%) of the patients in the diabetes group fell in this category and used glucose lowering drugs during
`the trial, including exenatide, sulphonylureas, metformin, DPP-IV inhibitors, or various insulins.
`Thiazolidinediones were not allowed during the study and for 4 months prior to enrollment.
`