CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
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`
`APPLICATION NUMBER:
`
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` 212801Orig1s000
`
`
`SUMMARY REVIEW
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`
`

`

`Cross Discipline Team Leader Review
`
`Date
`From
`Subject
` NDA/BLA # and Supplement#
`
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name
`Established or Proper Name
`Dosage Form(s)
`Applicant Proposed
`Indication(s)/Population(s)
`
` Applicant Proposed Dosing
`Regimen(s)
`Recommendation on Regulatory
`Action
`Recommended
`Indication(s)/Population(s) (if
`applicable)
`
`
`
`Cross-Discipline Team Leader Review
`
`3/2/2020
`Marina Zemskova, MD
`Cross-Discipline Team Leader Review
`NDA 212801
`Novartis
`3/7/2019
`3/7/2020
`Isturisa
`Osilodrostat
`film-coated tablets for oral use
`Treatment of patients with Cushing’s disease
`
`2 mg-30 mg to be administered orally twice a day
`
`Approval
`
`Treatment of adult patients with Cushing’s disease for
`whom pituitary surgery is not an option or has not been
`curative.
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`Reference ID: 4568946
`
`1
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`

`

`Cross Discipline Team Leader Review
`
` 1. Benefit-Risk Assessment
`
`Benefit-Risk Assessment Framework
`Cushing’s Disease (CD) is a rare disease caused by an ACTH-secreting pituitary adenoma, which results in excess cortisol secretion and is
`associated with increased morbidity and mortality. CD is the most common cause of endogenous Cushing’s syndrome (CS) and accounts for
`
`approximately 70% of cases of endogenous CS. Because of the significant morbidity associated with CD, early therapy is fundamental. Surgical
`resection of the adenoma is first-line therapy and the treatment of choice. Surgery is successful in 60-80% patients with CD caused by pituitary
`microadenoma (less than 1 cm in diameter). However, even in patients who respond to surgery, up to 25% will experience recurrence within 10
`years. Second-line therapy of CD includes pituitary radiation, medical therapy to reduce serum cortisol concentrations or block cortisol action,
`and bilateral adrenalectomy. Although not curative, medical therapy plays an important role in the management of CD. Medical therapy is
`employed in patients with persistence or recurrence of CD despite having undergone surgery, in patients with CD who undergo radiotherapy to
`control hypercortisolemia until the results of radiotherapy become effective, and in patients who are not candidates for radiation or surgery due to
`poor health. Lifelong medical treatment to suppress cortisol levels may be required if the primary cause of Cushing’s syndrome (CS) cannot be
`treated successfully with surgery and/or radiation.
`
`The U.S.-approved drugs indicated to treat one or more manifestations of CS/CD are: two injectable formulations of pasireotide, a somatostatin
`analog (Signifor, NDA 200677 and Signifor LAR, NDA 203255, Novartis), and mifepristone, a glucocorticoid receptor antagonist (Korlym,
`NDA 202107, Corcept Therapeutics). Pasireotide is approved for the treatment of patients with CD for whom surgery is not an option or has not
`
`been curative. Mifepristone is approved for the control of hyperglycemia in adult patients with endogenous CS with type 2 diabetes mellitus
`(T2DM) or glucose intolerance who have failed surgery or are not candidates for surgery. These drugs are associated with adverse events
`including QT interval prolongation, gastrointestinal adverse reactions, and adrenal insufficiency. For pasireotide, the need for injections can
`affect compliance or acceptability of the treatment. Registration trials have shown that pasireotide normalized or decreased urine cortisol by 50%
`in ⁓ 40% of patients. As already mentioned, mifepristone is approved only for a subgroup of CS patients - patients who have abnormalities in
`glucose metabolism - which include about 50-60% of all CS patients. Therefore, there is an unmet need for additional approved therapies for
`CS/CD.
`
`
`Current guidelines from professional societies list several unapproved drugs as part of the medical management of patients with CS or CD1 2.
`According to these guidelines, steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane and etomidate) are recommended and are the most
`
`widely used agents in the treatment of CS of any etiology; these drugs are effective in 75- 80% of patients3. Treatment with these drugs is
`
`1 Biller BM, Grossman AB, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62.
`
`
` 2 Nieman LK, Biller BM, et al. Endocrine Society Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015
`
`Aug;100(8):2807-31.
`
`3 Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology. 2010;92 Suppl 1:111-5
`
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`Reference ID: 4568946
`
`2
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`

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`Cross Discipline Team Leader Review
`associated with such adverse reactions as gastrointestinal adverse effects, adrenal insufficiency, liver toxicity (ketoconazole), edema,
`hypertension and hirsutism (metyrapone), etc. Thus, extensive clinical monitoring is required which may limit their use in patients with CS.
`
`Overall, therapeutic options for treatment of CS remain limited and many patients with CS remain undertreated.
`
`The Applicant has demonstrated in a single, multi-center, double-blind, randomized withdrawal (RW) study of osilodrostat following a 24-week,
`single arm, open-label dose titration period (study C2301) that treatment with osilodrostat in patients with non-surgical or recurrent CD is
`effective in reducing mean 24-hour urinary free cortisol (mUFC) levels from baseline. In this study, 137 patients were initially treated with
`osilodrostat for 24 weeks in a dose titration open-label single arm period. The starting dose was 2 mg BID; the dose was titrated based on mUFC
`levels every 2 weeks to maximum dose 30 mg bid to achieve normalization of mUFC. The prespecified titration schedule was 2 mg, 5 mg, 10
`mg, 15 mg, 20 mg and 30 mg; however, some subjects were titrated more slowly than was prespecified or had doses decreased during the study
`because of drug tolerability and adverse events including adrenal insufficiency. After the first 24 weeks of treatment, 70/137 patients who were
`responders at week 24 (defined as patients who had normal mUFC and did not require a dose increase during the previous 12 weeks) were
`randomized to receive osilodrostat or placebo in the RW period. Those who were not eligible for randomization continued the study with open-
`label osilodrostat.
`
`The primary endpoint was the proportion of patients whose mUFCs remained in the normal range after withdrawal of treatment between the
`osilodrostat and placebo groups. The key secondary efficacy endpoint was the proportion of complete responders in the 24 week open label
`period. To be considered successful, the lower bound of the 95% CI for the proportion of patients who had normalization of mUFC at week 24
`
`was to exclude 30%, representing the minimum threshold demonstrating a clinically significant response to therapy in all treatment-naïve patients
`
`without any insight as to whether the patient will be a responder to osilodrostat or not (i.e. how the drug will be used in clinical practice). The
`primary analysis demonstrated that osilodrostat was superior to placebo at Week 34, the end of the RW period: 86.1% (95% CI: 70.5, 95.3) of
`patients in the osilodrostat group maintained normal mUFC without dose change compared to 29.4% (95% CI: 15.1, 47.48) of patients in the
`placebo group. The response rate was not affected by the dose or history of pituitary radiation and ranged from 83.9% to 100%, based on the
`randomization stratification factor (dose at week 24 -> 5 mg bid and ≤5 mg bid and history of pituitary radiation). Therefore, the primary analysis
`confirmed that the UFC lowering effect was attributable to the drug itself and not to the other factors such as inactive disease, cyclic CS, etc. (as
`demonstrated by significant difference in the proportion of responders in active drug versus placebo groups). The key secondary efficacy
`endpoint achieved the pre-specified goal: 72 of 137 (52.6%; 95% CI: 43.9, 61.1) of patients met the definition for complete responder at week 24;
`lower bound excludes 30%.
`
`The most common adverse events (AE) in the 48-week Core Phase of the pivotal study C2301 were hypocortisolism related AEs (51%), nausea
`
`(37%), headache (30%), insomnia (26.3%) fatigue (24%), vomiting (19.7%), nasopharyngitis (19.7%). The high rate of hypocortisolism related
`
`AEs was most likely overestimated due to poor definition of the term of ‘adrenal insufficiency (AI)’ in the protocol that was based on non­
`specific signs and symptoms (nausea, fatigue, etc.) of the condition without concurrent serum cortisol levels. As such, some patients who poorly
`tolerated rapidly decreasing cortisol levels were defined as having adrenal insufficiency; however, their cortisol levels remained within normal
`range. There was no death due to AI in the study, and all events improved/resolved with osilodrostat dose adjustment and/or treatment with
`glucocorticoids. Overall, hypocortisolism-related AEs are expected events based on the mechanism of action of osilodrostat. Monitoring and
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`3
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`Reference ID: 4568946
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`

`

`Cross Discipline Team Leader Review
`dose adjustment/interruption and treatment with glucocorticoids will be recommended in the WARNING and PRECAUTION section of the
`USPI to mitigate this risk. In addition, the pre-specified titration schedule used in the clinical study may also account for this risk, and I
`recommend a more conservative approach to titration in the postmarketing setting. Thus, the risk will be further mitigated by the labeled dosing
`recommendations which will advise not to increase the dose more frequently than every 2 weeks, to consider using smaller dose increments and
`to base the decision of whether to increase the dose not only on absolute cortisol values, but also on the rate of cortisol change and individual
`patient signs and symptoms.
`
` Other potential safety issues associated with the use of osilodrostat include the risk of QT prolongation and adrenal hormone precursor
`
`
`
`
` accumulation-related adverse reactions (hypertension, hypokalemia, hirsutism, acne). All these risks will be mitigated through product labeling
` which will include recommendations on appropriate patient selection, on monitoring for occurrence of these reactions and on interventions to
`
`
`
`
`
` address these reactions including but not limited to osilodrostat dose adjustment and/or temporary interruption. A WARNING and PRECUATION
` section discussing these safety concern will be included in labeling to ensure prescribers recognize that osilodrostat may be associated with these
`
`
`
`
`risks and can take appropriate precautions in patients at risk.
`
`In conclusion, safety and efficacy data from the single, double blind randomized withdrawal phase 3 study conducted to support the approval of
`osilodrostat for the treatment of recurrent or non-surgical Cushing’s disease have demonstrated that the benefits outweigh the risks in this
`population. Thus, I recommend approval of osilodrostat for the treatment of adult patients with CD. However, I recommend restricting the
`indication to adult patients with CD for whom pituitary surgery is not an option or has not been curative reflecting the patient population
`evaluated in the clinical program.
`All identified safety issues can be mitigated by communicating risks in the product label and recommending appropriate patient selection,
`monitoring and dose adjustment if required.
`
`The following postmarketing requirements should be issued to further characterize the safety profile of osilodrostat.
`- To complete the ongoing Phase 3 multi-center, randomized, double-blind, 48-week study with an initial 12-week placebo-controlled
`period (study C2302). This study will evaluate the safety profile of osilodrostat, including rate of hypocortisolism-related AEs using a
`dosing regimen that dose titration every 3 weeks)
`
`These safety issues may be assessed postmarketing because they do not adversely impact the overall benefit risk assessment at this time.
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`Reference ID: 4568946
`
`4
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`

`

`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Benefit-Risk Dimensions
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`
`
`  CD is a rare disease, caused by an ACTH secreting-pituitary adenoma, which
`results in excess cortisol secretion.
` CD is a serious and life-threatening disease. Hypercortisolemia leads to
`decreased quality of life and increased morbidity and mortality,
`primarily due to cardiovascular complications.
` The 2015 Endocrine Society Guideline on treatment of Cushing’s
`Syndrome recommends normalizing UFC levels in subjects with
`Cushing’s Syndrome as a means of preventing hypercortisolemia­
`related complications (hypertension, hyperglycemia, obesity,
`psychiatric abnormalities, bone loss, etc.), and thus improving
`morbidity and mortality in this population.
`
` Prolonged hypercortisolemia is associated
`with increased morbidity and mortality in
`
`patients with CD, including decreased overall
`quality of life (QOL) and increased death due
`to cardiovascular complications.
` Normalization of UFC is the goal of
`treatment and is associated with improvement
`
`
`in the signs and symptoms of the disease and
`
`amelioration of complications such as
`diabetes and obesity.
`
` Transsphenoidal surgery is a first-line treatment for CD.
` Medical therapy is a second-line treatment option in patients not suitable for
`surgery and in patients with persistent or recurrent disease after TSS.
` Two drugs are approved in the US for treatment of CS; pasireotide and
`mifepristone. Injectable formulations of pasireotide are approved for the
`treatment of CD and effective in 40% of patients. Oral formulation of
`mifepristone (Korlym) is approved for the subgroup of patients with CS-
`patients who have cortisol-induced hyperglycemia.
`  Therapies used ‘off-label’ to treat hypercortisolemia include steroidogenesis
`inhibitors (ketoconazole, metyrapone, mitotane, etomidate) and dopamine
`agonists (cabergoline, bromocriptine) are effective in 70-80 % and
`recommended for the treatment of patients with CS by current guidelines
`from professional societies.
`
`
`
` There are a limited number of alternative
`therapies available for the treatment of CS and
`
`CD, some of which are approved (pasireotide
`and mifepristone) and some of which are used
`off-label
` Therapeutic options for treatment of CS
`remain limited and many patients with CS
`remain undertreated.
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`Reference ID: 4568946
`
`5
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`

`

`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Benefit
`
`
`
`
`
`
`
` Osilodrostat is effective in reducing mUFC levels from baseline in patients
`with CD as demonstrated in a single pivotal, multi-center, double blind,
`randomized withdrawal (RW) study of osilodrostat following a 24-week,
`single arm, open-label dose titration period (study C2301).
` Osilodrostat was superior to placebo at the end of the randomized
`withdrawal period: 86.1% (95% CI: 70.5, 95.3) of patients in the
`osilodrostat group maintained normal mUFC without dose change
`compared to 29.4% (95% CI: 15.1, 47.48) of patients in placebo group.
` The primary analysis (in the RW period) confirmed that the UFC
`lowering effect was attributable to the drug itself and not to other
`factors such as inactive disease, cyclic CS, etc. (as demonstrated by a
`significant difference in the proportion of responders in the active
`drug and placebo groups).
`
` Osilodrostat normalized UFCs in approximately 52% of all
`treatment-naïve patients after 24 weeks of treatment in the open
`label, single arm period of the study (key secondary endpoint).
` By the end of the study, week 48, 66.4% of all patients had normal
`mUFC.
`Improvements in other secondary efficacy endpoints (e.g., decrease
`in mUFC and serum cortisol levels) in all patients are supportive of
`the efficacy of osilodrostat in treating of hypercortisolemia in
`patients with CD.
`  The safety profile of osilodrostat in patients with CD was well
`characterized in the overall clinical program.
`
`  The most frequent AEs were hypocortisolism related AEs, nausea,
`vomiting, headache, insomnia and fatigue.
` Hypocortisolism-related AEs, including AI, are expected adverse events
`
`based on osilodrostat’s mechanism of action. There was a high rate of such
`events observed in study C2301 (50%). However, only approximately 1/2
`of these events were associated with low UFC levels or required
`glucocorticoid treatment, indicating that the reported rate was
`overestimated. No deaths were reported, and all cases of AEs resolved with
`osilodrostat dose decrease/interruption and/or treatment with
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
` Risk and Risk
`
`
`Management
`
`Reference ID: 4568946
`
` Treatment with osilodrostat should normalize
`UFC and reduce morbidity and mortality and
`improve quality of life in treatment-naïve
`patients with hypercortisolemia secondary to
`Cushing’s disease.
` Osilodrostat is effective in approximately
`52% of all treatment-naïve patients after 6
`months of treatment (key secondary
`endpoint)
` The response can be maintained in
`approximately 80% of patients who
`responded to the drug and tolerated the drug
`during the first 6 months of treatment
` The magnitude of the effect observed in the
`open-label, single arm periods of the study
`and in the RW period may not reflect the
`magnitude of the effect that will be seen in
`clinical practice in all treatment-naïve
`patients.
`
` Treatment with osilodrostat is associated
`with nausea, vomiting, fatigue,
`hypocortisolism related AEs, AEs
`associated with accumulation of adrenal
`precursors and androgens.
` The high rate of hypocortisolism-related
`AEs was overestimated in the pivotal study
`and/or was due to aggressive dose titration.
`The risk of hypocortisolemia will be
`communicated through labeling and
`mitigated through proper monitoring and
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`Cross Discipline Team Leader Review
`
`Dimension
`
`Evidence and Uncertainties
`glucocorticoids. The clinical data also raised a possibility that these events
`
`may be due to fast dose titration, as evident by the fact that the majority of
`these events occurred during first 12 weeks of drug titration.
` Osilodrostat blocks cortisol synthesis; an increase in levels of steroid
`hormone precursors (11-DOC and DOC) and androgen precursors was
`observed during treatment with osilodrostat. AEs associated with
`accumulation of these precursors (hypertension, hypokalemia, edema,
`hirsutism acne) were observed in up to 12% of patients. Hypertension and
`hypokalemia resolved in all patients without or with dose adjustments
`
`and/or treatment with potassium supplements and antihypertensive drugs.
` Osilodrostat is associated with QT interval prolongation at supratherapeutic
`doses.
` No clinically meaningful changes in tumor volume were identified in the
`study to date.
` Changes in hemoglobin, absolute neutrophil count, LFTs were small and of
`unknown clinical significance.
` Labeling will be used to mitigate against the serious risks of
`hypocortisolemia, QTc interval prolongation, and adrenal hormone
`precursor accumulation-related AEs.
` A post-marketing requirement to complete the ongoing Phase 3 study
`C2302 to further evaluate the safety profile of osilodrostat with slower
`titration schedule will be issued.
`
` No risks identified require risk management beyond labeling to warrant
`consideration of a Risk Evaluation and Mitigation Strategy (REMS).
`
`Conclusions and Reasons
`dose adjustment. To further mitigate this
`risk, titration not more frequently than
`every 2 weeks using small increments of 1­
`2 mg will be recommended.
` The risks of AEs associated with
`accumulation of adrenal precursors
`including hypokalemia, hypertension,
`hirsutism acne, etc. are expected AEs based
`on the drug’s mechanism of action,
`monitorable AEs and will be mitigated
`through appropriate labeling.
`
` The risk of QTc prolongation will be
`mitigated by proper patient selection,
`monitoring and dose adjustment if required.
` The potential improvement in the safety
`profile of osilodrostat with slower titration
`regimen (i.e. every 3 weeks) will be further
`evaluated in study C2302 (postmarketing
`requirement).
` The potential safety risk of change in
`osilodrostat exposure when co-administered
`
`with strong CYP3A4 inhibitors will be
`further characterized in a post-marketing
`requirement (i.e., drug-drug interaction
`study).
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`Reference ID: 4568946
`
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`

`

`Cross Discipline Team Leader Review
`
`2. Background
`On March 7, 2019 Novartis submitted a New Drug Application (NDA) for osilodrostat under
`
`Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for the following indication:
`Treatment of patients with Cushing’s disease.
`
`Osilodrostat is a novel inhibitor of cortisol (via inhibition of 11-β-hydroxylase) and of
`aldosterone (via inhibitions of aldosterone synthase) synthesis formulated for oral
`
`administration.
`
`Endogenous Cushing’s syndrome (CS) is a serious, multisystem disorder that results from the
`overproduction of cortisol by the adrenal glands. CS is a rare disease, with an incidence of 0.7
`to 2.4 per million per year4. Most cases of Cushing’s syndrome (80%) are ACTH-dependent
`and due to oversecretion of adrenocorticotropic hormone (ACTH): the source of ACTH may
`be pituitary (Cushing’s Disease) or ectopic. Cushing’s Disease (CD) is the most common
`cause of endogenous CS, and accounts for approximately 70% of all cases of endogenous CS.
`
`The clinical manifestations of CD are variable, often times severe and are related to the local
`growth of the tumor (headache, loss of vision) and to systemic symptoms of hypercortisolism.
`
`Systemic symptoms include impaired glucose tolerance or diabetes, hypertension, myopathy,
`
`bone loss which can lead to fracture, compromised immune function, and psychiatric
`disturbances, among others. CS (and CD) is associated with decreased quality of life and an
`
`increased mortality rate. The mortality rate in patients with CS is 5-fold higher than that of that
`of the general population 5. Cardiovascular complications are the main cause of death in CS,
`and the risk of death is independently increased by co-existing diabetes mellitus and/or
`
`hypertension6.
`
`Because of the significant morbidity associated with CS, early therapy is fundamental. In
`general, surgery is first-line therapy and the treatment of choice for all causes of CS. Surgery is
`successful in 60-80% patients with CD caused by pituitary microadenoma7. However, even in
`patients who respond to surgery, up to 25 % will experience recurrence within 10 years.
`
`Second-line therapy of CS includes radiation, medical therapy, and bilateral adrenalectomy.
`
`Although not curative, medical therapy plays an important role in the management of CS.
`Medical therapy is employed pre-operatively for control of severe hypercortisolemia, in
`patients with persistence or recurrence of CS despite having undergone surgery, in patients
`
` 4 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet. 2006 May
`
`13;367(9522):1605-17.
`5 Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin
`Endocrinol (Oxf). 1994 Apr;40(4):479-84.
`6Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing's disease over 50 years
`
`
`in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab. 2011 Mar;96(3):632-42
`7 Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. .Endocrinol Metab Clin North Am. 2008
`Mar;37(1):135-49
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`8
`
`Reference ID: 4568946
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`

`

`Cross Discipline Team Leader Review
`
`with CD who undergo radiotherapy to control hypercortisolemia until the results of
`radiotherapy become effective, and in patients who are not candidates for radiation or surgery
`due to poor health. Lifelong medical treatment to suppress cortisol levels may be required if
`the primary cause of CS cannot be treated successfully with surgery and/or radiation.
`
`
`Availability of medical therapies for the treatment of CS and CD
`
` Approved therapies
`FDA approved two drugs for treatment of CS/CD: Korlym (mifepristone) and Signifor
`(pasireotide):
`
` Mifepristone, a glucocorticoid receptor antagonist, was approved on February 17, 2012 for
`the treatment of cortisol-induced hyperglycemia in patients with CS. Mifepristone does not
`reduce cortisol levels but, by blocking the glucocorticoid receptor in peripheral tissues, it
`also blocks the action of cortisol.
`
` Pasireotide is a somatostatin analog that binds to somatostatin receptors on the surface of
`ACTH-secreting pituitary tumors and reduces ACTH output with subsequent decline in
`cortisol levels. Two injectable pasireotide formulations (Signifor and Signifor LAR) were
`approved in 2012 and 2018, respectively, for the treatment of adult patients with Cushing’s
`disease for whom pituitary surgery is not an option or has not been curative.
`
`Both drugs are associated with adverse reactions including vaginal bleeding and risk of
`pregnancy termination (mifepristone), hyperglycemia, diabetes, QT interval prolongation,
`cholestasis, gastrointestinal AEs (pasireotide) and adrenal insufficiency (associated with both
`drugs). For pasireotide, the need of injections can affect compliance or acceptability of the
`treatment. In addition, neither mifepristone nor pasireotide is expected to be effective in all
`
`patients. Registration trials have shown that pasireotide normalized or decreased urine cortisol
`
`by 50% in ⁓ 40% of patients. As already mentioned, mifepristone is approved only for a
`subgroup of Cushing’s syndrome patients - patients who have abnormalities in glucose
`metabolism - which include about 50-60% of all Cushing’s syndrome patients.
`
` Off label therapies
`Current guidelines from professional societies list several unapproved drugs as part of the
`medical management of patients with Cushing syndrome or Cushing disease8 9. According to
`
`these guidelines, steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane and
`etomidate) are recommended and the most widely used agents in the treatment of CS of any
`etiology: these drugs are effective in 75- 80% of patients 80%10. Treatment with these drugs is
`
`
`
`8 Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus
`AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla
`GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushing's
`syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62.
`
` 9 Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Endocrine Society
`Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab.
`2015 Aug;100(8):2807-31.
`
` 10 Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing's syndrome: adrenal-blocking drugs
`and ketaconazole. Neuroendocrinology. 2010;92 Suppl 1:111-5
`
`
`
`CDER Cross Discipline Team Leader Review Template
`
` Version date: October 10, 2017 for all NDAs and BLAs
`
`9
`
`Reference ID: 4568946
`
`

`

`Cross Discipline Team Leader Review
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`associated with such adverse events as gastrointestinal adverse effects, adrenal insufficiency,
`liver toxicity (ketoconazole), edema, hypertension and hirsutism (metyrapone), etc. Thus,
`extensive clinical monitoring is required which may limit their use in patients with CS.
`
`
`Overall, there are several alternative therapies available for the treatment of CS and CD, some of
`which are approved and some of which are used off-label, however, therapeutic options for
`treatment of CS remain limited and many patients with CS remain undertreated.
`
`Regulatory History
`
`Osilodrostat has been in clinical development under
` DMEP.
`
`
`
`However, because osilodrostat inhibits cortisol synthesis, the Sponsor decided to
`continue development of this drug for treatment of CD. This review is focused on use of
`osilodrostat for the treatment of patients with CD; the
`not be discussed further in details in this review, unless otherwise specified.
`
`will
`
`The major regulatory interactions between the Sponsor (Novartis) and DMEP for the CD
`indication are summarized below.
`
`1) IND 117489 in DMEP was opened on 6/18/2013 with a protocol for a thorough QT study
`(TQT) in healthy volunteers (CLCI699C2105, referred to as study C2105 hereafter).
`
`2) Osilodrostat was granted Orphan Drug designation for “the treatment of Cushing’s disease”
`on 9/13/2013 by the Office of Orphan Products Development.
`
`3) End-of-Phase 2 meeting (EOP2), 10/09/2013
` Several issues and uncertainties regarding the proposed Phase 3 clinical program were
`
`raised during this meeting.
`The Division stated disagreement with the Sponsor’s design of the pivotal Phase 3 study
`(LCI699C2301), i.e. double-blind,
`, randomized withdrawal study. The
`Division recommended the conduct of a randomized, double-blind, placebo-controlled study to
`establish efficacy (8-12 weeks) followed by an extension phase to establish durability of effect
`
`and obtain long-term comparative safety data. The Division indicated that such a trial would
`be ethical provided adequate safeguard are in place in the protocol. The Sponsor disagreed
`with the proposed trial design and indicated that randomized withdrawal allows for assessment
`
`
`of rebound and withdrawal effect in responders and that such information is important for
`adrenolytic therapy and that the efficacy information collected at a later time of the trial (i.e.
`after the drug titration is completed) is likely to be more relevant. Additionally, the Sponsor
`also expressed the concern that use of placebo may lead to difficulty in recruitment. The
`
`Division was also concerned that the randomized withdrawal study would provide information
`for the responders only. Lastly, the Division also indicated that the study with the up-front
`randomized design will require smaller sample size based on various power calculations to
`CDER Cross Discipline Team Leader Review Template
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` Version date: October 10, 2017 for all NDAs and BLAs
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`10
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`Reference ID: 4568946
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`Cross Discipline Team Leader Review
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`detect a significant difference based on UFC (43-108 patients) compared to the sample size
`proposed in the randomized withdrawal study.
`The Division also expressed the concern that the proposed study is lacking a comparator for
`safety assessment. The Sponsor indicated that comparison of a placebo versus efficacious dose
`(as in proposed randomized withdrawal study) will be more informative than comparison of
` placebo versus patients in a titration phase (as in the Division’s proposed study). However, the
`
`
` Sponsor proposed to submit controlled data from
` to
`relieve the Division’s concern. The Division disagreed with the proposed
`.
`No agreement on the design of the pivotal study was reached during the meeting.
` The Division and the Sponsor reached an agreement on other points of the discussion
`including study population (patients with CD and elevated UFC> 1.5XULN), proposed doses
`and proposed primary endpoint (i.e. the proportion of patients with UFC < ULN).
`In addition, the Division asked the Sponsor to stratify by the post-radiation interval, to include
`evaluation of changes to antidiabe