ISTURISA 1mg tablets medication leaflet

Isturisa 1 mg film-coated tablets

Isturisa 5 mg film-coated tablets

Isturisa 10 mg film-coated tablets

Isturisa 1 mg film-coated tablets

Each film-coated tablet contains osilodrostat phosphate corresponding to 1 mg osilodrostat.

Isturisa 5 mg film-coated tablets

Each film-coated tablet contains osilodrostat phosphate corresponding to 5 mg osilodrostat.

Isturisa 10 mg film-coated tablets

Each film-coated tablet contains osilodrostat phosphate corresponding to 10 mg osilodrostat.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Isturisa 1 mg film-coated tablets

Pale yellow, round, biconvex with beveled-edge tablets, unscored, debossed with ‘1’ on one side.

Approximate diameter 6.1 mm.

Isturisa 5 mg film-coated tablets

Yellow, round, biconvex with beveled-edge tablets, unscored, debossed with ‘5’ on one side.

Approximate diameter 7.1 mm.

Isturisa 10 mg film-coated tablets

Pale orange brown, round, biconvex with beveled-edge tablets, unscored, debossed with ‘10’ on oneside. Approximate diameter 9.1 mm.

Isturisa is indicated for the treatment of endogenous Cushing’s syndrome in adults.

Treatment should be initiated and supervised by physicians experienced in endocrinology or internalmedicine and with access to the appropriate facilities for monitoring of biochemical responses sincethe dose must be adjusted to meet the patient’s therapeutic needs, based on the normalisation ofcortisol levels.

The recommended starting dose is 2 mg osilodrostat twice daily. For patients of Asian ancestry, areduced starting dose of 1 mg twice daily is recommended (see section 5.2).

The dose can be gradually titrated (initially by dose increments of 1 or 2 mg) based on individualresponse and tolerability, with the aim to achieve normal cortisol levels. It is recommended thatcortisol levels (e.g. 24-hour urinary free cortisol, serum/plasma cortisol) be monitored every 1-2 weeksuntil adequate clinical response is maintained. Thereafter, less frequent monitoring may be consideredas clinically indicated, unless there are reasons for additional monitoring (see sections 4.4 and 4.5).

Increases in dose should not occur more frequently than once every 1-2 weeks and should be guidedby the results of cortisol assessments and by the individual clinical response.

The dose of osilodrostat should be decreased or treatment temporarily interrupted if cortisol levels arebelow the lower limit of normal, or if there is a rapid decrease in cortisol levels to the lower part of thenormal range, or if the patient has signs or symptoms suggestive of hypocortisolism (see section 4.4).

Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels areabove the lower limit of normal in the absence of glucocorticoid substitution. Management of othersuspected adverse reactions at any time during treatment may also require a temporary dose reductionor temporary interruption of treatment.

The usual maintenance dose in clinical studies varied between 2 and 7 mg twice daily.

The maximum recommended dose of Isturisa is 30 mg twice daily.

If a dose is missed, the patient should take the prescribed dose at the next scheduled time; the nextdose should not be doubled.

There is no evidence to suggest that dose adjustment is required in patients aged 65 years or above.

However, data on the use of osilodrostat in this population are limited and Isturisa should therefore beused with caution in this age group.

No dose adjustment is required for patients with renal impairment (see section 5.2). Urinary freecortisol (UFC) levels should be interpreted with caution in patients with moderate to severe renalimpairment, due to reduced UFC excretion. Alternative methods for cortisol monitoring should beconsidered in these patients.

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A). For patientswith moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 1 mg twicedaily. For patients with severe hepatic impairment (Child-Pugh C), the recommended starting dose is1 mg once daily in the evening, with initial up-titration to 1 mg twice daily (see section 5.2).

Data on use in patients with hepatic impairment is limited. More frequent monitoring of adrenalfunction may be required in patients with hepatic impairment during dose titration.

The safety and efficacy of Isturisa in patients less than 18 years of age have not yet been established.

No data is available.

Oral use.

Isturisa can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocortisolism

Inhibition of cortisol synthesis by osilodrostat has led to hypocortisolism-related events such ascortisol withdrawal syndrome (symptomatic decrease of cortisol levels, but still above the lower limitof the normal range) and adrenal insufficiency (cortisol levels below the normal range).

Cortisol levels should be monitored at regular intervals (see section 4.2), since hypocortisolism-relatedevents can occur at any time during treatment and after treatment discontinuation. Additionalmonitoring is recommended especially during conditions of increased cortisol demand, such asphysical or psychological stress, or during changes in concomitant medications that may affectosilodrostat exposure (see section 4.5). It is recommended to use laboratory methods that do notexhibit significant cross-reactivity with cortisol precursors such as 11-deoxycortisol that may increaseduring osilodrostat treatment.

Patients should be alerted to the signs and symptoms associated with hypocortisolism (e.g. nausea,vomiting, fatigue, abdominal pain, loss of appetite and dizziness).

Symptomatic patients should be monitored for hypotension, hyponatraemia, hyperkalaemia and/orhypoglycaemia. If hypocortisolism is suspected, cortisol levels should be measured and temporarydose reduction or interruption of osilodrostat considered. After osilodrostat discontinuation, cortisolsuppression may persist for months, irrespective of osilodrostat administered dose, and might requireadditional monitoring. If necessary, corticosteroid substitution should be initiated. Isturisa may beresumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lowerlimit of normal in the absence of glucocorticoid substitution.

QTc prolongation

In a thorough QT study, osilodrostat was associated with a dose-dependent QT interval prolongation(mean maximum estimated QTcF increase by +5.3 ms at the highest recommended dose of 30 mg)which may cause cardiac arrhythmias (see section 5.1). Adverse reactions of QT prolongation andclinically relevant ECG findings have been reported in clinical studies.

An electrocardiogram (ECG) should be performed prior to the start of Isturisa treatment, within oneweek after treatment initiation, and as clinically indicated thereafter. If the QTc interval exceeds480 ms prior to or during treatment, cardiology consultation is recommended. Temporary dosereduction or interruption may be required.

Any hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to Isturisaadministration and electrolyte levels should be monitored periodically during therapy.

Isturisa should be used with caution and the benefit-risk carefully weighed in patients with risk factorsfor QT prolongation such as:

- congenital long QT syndrome,

- significant cardiovascular disease (including congestive heart failure, recent myocardialinfarction, unstable angina, sustained ventricular tachycardia, advanced heart block andclinically significant bradyarrhythmias), and

- concomitant medicinal products known to prolong the QT interval (see section 4.5).

If Isturisa is used in patients with these risk factors, more frequent ECG monitoring is recommended.

Corticotroph tumour growth

Discontinuation of osilodrostat treatment should be considered in patients who develop MRI-verifiedcorticotroph tumour invasiveness during treatment.

Concomitant use with strong enzyme inhibitors and inducers

Caution and closer monitoring are advised when co-administered medicinal products that stronglyinhibit or induce multiple enzymes are introduced or discontinued during osilodrostat treatment (seesection 4.5), as they may affect osilodrostat exposure and may result in a risk of adverse events (due toa potential increase in exposure) or of decreased efficacy (due to a potential decrease in exposure).

Isturisa may cause foetal harm. Pregnancy status should be verified in women of childbearingpotential prior to the initiation of Isturisa, and these patients should be advised of a potential risk to thefoetus and of the need to use effective contraception during treatment and for at least one week afterstopping treatment (see section 4.6).

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Potential pharmacodynamic interactions

Co-administration of osilodrostat with other therapies known to affect the QT interval can lead to QTprolongation in patients with known cardiac rhythm disorders (see sections 4.4 and 5.1). A washoutperiod should be considered when switching from other products known to affect the QT interval suchas pasireotide or ketoconazole.

Effects of other medicinal products on the pharmacokinetics of osilodrostat

The potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinalproducts that inhibit transporters or a single CYP or UGT enzyme is low (see section 5.2).

Strong enzyme inhibitors

Caution is advised when co-administered medicinal products that strongly inhibit multiple enzymesare introduced or discontinued during osilodrostat treatment (see section 4.4).

Strong enzyme inducers

Caution is advised when co-administered medicinal products that strongly induce multiple enzymes(e.g. rifampin) are introduced or discontinued during osilodrostat treatment (see section 4.4).

Effects of osilodrostat on the pharmacokinetics of other medicinal products

Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes andtransporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme ortransporter substrates with a narrow therapeutic index. Available interaction data is summarised below(see also section 5.2).

Clinical studies

In a healthy volunteer study (n=20) using a single dose of 50 mg osilodrostat and a probe drugcocktail, osilodrostat was found to be a mild inhibitor of CYP2D6 and CYP3A4/5, a mild to moderateinhibitor of CYP2C19, and a moderate inhibitor of CYP1A2.

- CYP2D6 - area under the curve (AUC) geometric mean ratio of 1.5 for dextromethorphan(CYP2D6 substrate) when dosed with osilodrostat compared to when dosed alone.

- CYP3A4 - AUC geometric mean ratio of 1.5 for midazolam (CYP3A4 substrate) when dosedwith osilodrostat compared to when dosed alone.

- CYP2C19 -AUC geometric mean ratio of 1.9 for omeprazole (CYP2C19 substrate) when dosedwith osilodrostat compared to when dosed alone. However, an in vitro signal of time-dependentinhibition has been observed, thus the consequence following repeated dosing is unclear.

Osilodrostat should be used with caution when co-administered with sensitive CYP2C19substrates with a narrow therapeutic index.

- CYP1A2 -AUC geometric mean ratio of 2.5 for caffeine (CYP1A2 substrate) when dosed withosilodrostat compared to when dosed alone. However, an in vitro signal of CYP1A2 inductionhas been observed, thus the consequence following repeated dosing is unclear. Osilodrostatshould be used with caution when co-administered with sensitive CYP1A2 substrates with anarrow therapeutic index such as theophylline and tizanidine.

In a healthy volunteer study (n=24), osilodrostat (30 mg twice daily for 7 days before concomitantadministration with a combined oral contraceptive containing 0.03 mg ethinyl oestradiol and 0.15 mglevonorgestrel and continued for another 5 days) did not have a clinically meaningful effect on the

AUC and maximum serum concentration (Cmax) of ethinyl estradiol (geometric mean ratio: 1.03 and0.88, respectively) and AUC of levonorgestrel (geometric mean ratio: 1.02). The Cmax oflevonorgestrel fell slightly outside the bioequivalence acceptance range (geometric mean ratio: 0.86;90% confidence interval : 0.737-1.00). The effects of a longer induction period and an interaction withother hormonal contraceptives have not been studied (see also sections 4.4 and 4.6).

In vitro data

In vitro data for osilodrostat and its major metabolite M34.5 suggest a potential for both inhibition andinduction for CYP1A2, CYP2B6 and CYP3A4/5, a potential for time-dependent inhibition of

CYP2C19, and an inhibitory potential for CYP2E1 and UGT1A1. It cannot be excluded thatosilodrostat may affect the exposure of sensitive substrates for these enzymes.

In vitro data for osilodrostat and its major metabolite M34.5 suggest an inhibitory potential for

OATP1B1, OCT1, OCT2, OAT1, OAT3 and MATE1. It cannot be excluded that osilodrostat mayaffect the exposure of sensitive substrates for these transporters.

Based on preclinical data, osilodrostat may cause foetal harm when administered to a pregnantwoman. A pregnancy test before initiating treatment is recommended in women of childbearingpotential. Women of childbearing potential have to use effective contraception during and for at leastone week after treatment. If hormonal contraceptives other than the oral combination ofethinylestradiol and levonorgestrel are used, an additional barrier method of contraception isrecommended (see section 4.5). Isturisa should not be used in women of childbearing potential notusing contraception.

There are no or limited amount of data from the use of osilodrostat in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Isturisa should not be used duringpregnancy.

It is unknown whether osilodrostat/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with

Isturisa and for at least one week after treatment.

There is no information on the effect of osilodrostat on human fertility. Animal studies have showneffects on the menstrual cycle and reduced female fertility in rats (see section 5.3).

Isturisa has minor influence on the ability to drive and use machines. Patients should be warned aboutthe potential for dizziness and fatigue (see section 4.8) and should be advised not to drive or usemachines if these symptoms occur.

A total of 210 patients with Cushing´s disease has been treated with osilodrostat in the pivotal Phase

III studies.

The most frequent (incidence ≥ 10%) adverse reactions reported in the pivotal Phase III studies(C2301 and C2302) with Isturisa were adrenal insufficiency (see section 4.4 Warnings andprecaution), fatigue, oedema, vomiting, nausea, decreased appetite headache, dizziness, hypotension,arthralgia, myalgia, tachycardia and blood testosterone increased.

The safety profile of Isturisa was generally consistent across all types of Cushing’s syndrome studiedin clinical trials.

Adverse reactions (Table 1) are listed by MedDRA system organ class. Within each system organclass, the adverse reactions are ranked by frequency, with the most frequent reactions first. Withineach frequency grouping, adverse reactions are presented in order of decreasing seriousness. Inaddition, the corresponding frequency category for each adverse reaction is based on the followingconvention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100);rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 1 Adverse reactions

System organ class Frequency Preferred term*category

Endocrine disorders Very common Adrenal insufficiency

Metabolism and nutrition disorders Very common Hypokalaemia, decreased appetite

Nervous system disorders Very common Dizziness, headache

Common Syncope

Cardiac disorders Very common Tachycardia

Vascular disorders Very common Hypotension

Gastrointestinal disorders Very common Vomiting, nausea, diarrhoea, abdominalpain

Skin and subcutaneous tissuedisorders Very common Rash , hirsutism**, acne**

Musculoskeletal and connective tissue Very common Myalgia, arthralgiadisorders

General disorders and administration Very common Fatigue, oedemasite conditions Common Malaise

Investigations Very common Blood testosterone increased**, bloodcorticotrophin increased

Common Electrocardiogram QT prolonged,transaminases increased

* Some terms denote grouped term of two or more MedDRA preferred terms that wereconsidered clinically similar. The term “adrenal insufficiency” includes the terms“glucocorticoid deficiency”, “adrenocortical insufficiency acute”, “steroid withdrawalsyndrome”, “urine free cortisol decreased”, “cortisol decreased”.

** Observed in female patients.

CYP11B1 inhibition by osilodrostat is associated with adrenal steroid precursor accumulation andtestosterone increases. In a clinical study with osilodrostat, mean testosterone levels in female patientsincreased from high normal at baseline to above the upper limit of the normal range. The increasesreversed when treatment was interrupted. The testosterone increase was associated with mild tomoderate cases of hirsutism or acne in a subset of patients.

Adrenocorticotropic Hormone (ACTH) values above 10-fold upper limit of normal were observed insome Cushing’s disease patients treated with osilodrostat in the clinical studies (see section 5.1) andmay be associated with cortisol values below the lower limit of normal.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolismmay include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizzinessand syncope.

In case of suspected overdosage, Isturisa should be interrupted, cortisol levels checked, and ifnecessary corticosteroid supplementation initiated. Close surveillance may be necessary includingmonitoring of the QT interval, blood pressure, glucose, fluid and electrolyte balance until the patient’scondition is stable.

Pharmacotherapeutic group: Anticorticosteroids, ATC code: H02CA02

Osilodrostat is a cortisol synthesis inhibitor. It potently inhibits 11β-hydroxylase (CYP11B1), theenzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

CYP11B1 inhibition is associated with the accumulation of precursors such as 11-deoxycortisol andacceleration of adrenal biosynthesis including androgens. In Cushing’s disease, the fall in plasmacortisol concentration also stimulates ACTH secretion, via the feedback mechanism which acceleratessteroid biosynthesis (see section 4.8).

In a thorough QT study (n=86 male and female healthy volunteers) with osilodrostat, the maximum

QTcF interval duration differences to placebo were 1.73 ms (90% CI: 0.15, 3.31) at the 10 mg doseand 25.38 ms (90% CI: 23.53, 27.22) at a supratherapeutic dose of 150 mg. Based on an interpolationof these results, the mean maximum prolongation at the highest recommended dose of 30 mg isestimated to be +5.3 ms.

The efficacy and safety of osilodrostat in patients with endogenous Cushing’s syndrome in adults wereevaluated in two phase III multicenter studies (study C2301 and C2302).

Study C2301 is a randomised withdrawal (RW) study, and Study C2302 is, a double-blind,randomised study of osilodrostat vs placebo.

Study C2301

The study C2301 consisted of a 26-week open-label period of single-arm osilodrostat treatment period,followed by an 8-week double-blind randomised withdrawal period in which patients were randomisedin 1:1 ratio to either osilodrostat or placebo and a subsequent osilodrostat 14-week open-label period.

Patients who maintained clinical benefit on osilodrostat could continue in a long-term extension perioduntil last patient achieved week 72, in order to collect further efficacy and safety data.

The eligibility criteria included Cushing’s disease (with confirmation of the pituitary source of excessadrenocorticotrophic hormone), and a mean urinary free cortisol (mUFC, derived from three 24-hoururine collections) value greater than 1.5 times the upper limit of normal (ULN) at screening.

A total of 137 adult patients were enrolled. The mean age of the patients was 41.2 years, and themajority were female (77%). Seven patients were aged 65 years or older. Prior therapy includedpituitary surgery in 88% of patients and prior medical therapy in 75% of patients. The mean andmedian baseline mUFC levels were 1006.0 nmol/24 h (7 x ULN) and 476.4 nmol/24 h (3 x ULN),respectively (ULN: 138 nmol/24 h). Co-morbidities at baseline included hypertension (67.9% ofpatients), obesity (29.9%), diabetes mellitus (21.9%) and osteoporosis (27.7%).

Patients received a starting dose of 2 mg osilodrostat twice daily and the dose could be up-titratedbased on individual response and tolerability during an initial 12-week period. Patients with no furtherdose increases during the following 12 weeks and with a mUFC ≤ ULN at week 24 were randomisedin a 1:1 ratio at week 26 to receive either osilodrostat or matching placebo for 8 weeks (double-blindrandomised withdrawal period), followed by open-label osilodrostat for the remainder of the study. Atweek 26, 71 patients were randomised in a 1:1 ratio to continue receiving osilodrostat (n=36) or toswitch to placebo (n=35). Patients who were not eligible for randomisation at week 24 (n=47)continued on open-label osilodrostat treatment. Nineteen patients discontinued prior to week 26. 113patients completed week 48 and 106 patients entered the extension phase. An additional 8 patientsdiscontinued between week 48 and week 72.

The primary objective was to compare the proportion of complete responders at week 34 (the end ofthe 8-week randomised withdrawal period) between patients randomised to continued active treatmentand placebo. For the primary endpoint, a complete response was defined as a mUFC value ≤ULN atweek 34. Patients whose dose was increased during the randomised withdrawal period or whodiscontinued randomised treatment were considered non-responders. The key secondary endpoint wasto assess the complete response rate at week 24. Patients with dose increases between weeks 12 and 24and patients with no valid mUFC assessment at week 24 were counted as non-responders for the keysecondary endpoint.

The study C2301 met its primary and key secondary endpoints (Table 2).

Median mUFC levels decreased to 62.5 nmol/24 h (-84.1% change from baseline, n=125) at week 12,to 75.5 nmol/24 h (-82.3%, n=125) at week 24 and to 63.3 nmol/24 h (-87.9%, n=108) at week 48 andto 64 nmol/24h ( -86.6%, n=96) at week 72.

Median time to first normal mUFC, with the dose escalation used in the study was 41 days.

Table 2 Key results: Phase III study in Cushing’s disease patients (study C2301)

Osilodrostat Placebon=36 n=34

Primary endpoint: Proportion of 31 (86.1) 10 (29.4)responders at the end of the (70.5, 95.3) (15.1, 47.5)randomised withdrawal period(week 34) n (%) (95% CI)

Response rate difference (odds 13.7 (3.7, 53.4)ratio): osilodrostat vs. placebo 2-sided p value < 0.001

All patients

Secondary endpoints N=137

Key secondary endpoint: Proportion of patients with mUFC ≤ ULN at 72 (52.6%)week 24 and no dose increase after week 12 (95% CI) (43.9, 61.1)

Complete mUFC response rate (mUFC ≤ ULN) at week 48 (95% CI) 91 (66.4%)(57.9, 74.3)

Complete mUFC response rate (mUFC ≤ ULN) at week 72 86 (62.8%)(54.1, 70.9)(95% CI)mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval; response:mUFC ≤ ULN.

Improvements were observed in cardiovascular and metabolic parameters (Table 3) and 85.6% ofpatients with available assessments showed an improvement in at least one physical feature of

Cushing’s disease at week 48. With the longer follow up, improvements in cardiovascular andmetabolic parameters and physical features of Cushing’s disease were maintained.

Table 3 Cardiovascular and metabolic parameters

Baseline Week 24 Week 48

Systolic blood pressure 132.2 124.9 (-4.1%) 121.7 (-6.8%)(mmHg)

Diastolic blood pressure 85.3 81.0 (-3.8%) 78.9 (-6.6%)(mmHg)

Body weight (kg) 80.8 77.3 (-3.0%) 75.5 (-4.6%)

Waist circumference (cm) 103.4 99.1 (-2.6%) 97.4 (-4.2%)

HbA1c (%) 6.0 5.6 (-4.6%) 5.6 (-5.4%)

Osilodrostat treatment also resulted in an improvement in patient-reported outcomes. Improvementsfrom baseline above the established minimal important difference (MID) were observed for Cushing’s

QoL (total score, Physical Problems subscale and Psychosocial Issues subscale), EQ-5D Utility indexand BDI-II (depression) scores. The mean Cushing QoL total score improved from 42.2 at baseline to58.2 (+14.0; +52.3% change from baseline) at week 48. The improvements observed during the corephase were maintained during the extension phase.

Study C2302

Study C2302 used a double-blind, placebo-controlled design in 74 adult patients (of whom 73 weretreated) with Cushing’s disease. The study was comprised of a core phase of 12 weeks of a double-blind, placebo-controlled period, followed by a 36-week open-label treatment period with osilodrostat.

The eligibility criteria included a mean urinary free cortisol value ((mUFC), derived from three 24-hour urine collections) greater than 1.3 times the upper limit of normal (ULN=138 nmol/24h) atscreening, and a confirmation of the pituitary source of excess ACTH.

The mean age of the enrolled patients was 41.2 years, and 84% of them were female. Overall, 87.7%had undergone surgery prior to study entry and 12.3% of patients had received radiotherapy prior tostudy start. The following relevant comorbidities were reported in the medical history of enrolledpatients: hypertension (61.6%), obesity (13.7%), diabetes mellitus (16.4%), and osteoporosis (26.0%).

The median and mean baseline mUFC levels were 340.3 nmol/24h (2.5 x ULN) and 431.7 nmol/24h(3 x ULN), respectively.

At Baseline patients were randomly allocated in a 2:1 fashion to receive either osilodrostat 2 mg bid ormatching-placebo; the dose could be gradually increased at 3-week intervals up to 20 mg bid. At theend of the 12-week double-blind randomised period, all patients were treated with open-labelosilodrostat. The starting dose was 2 mg bid. Patients receiving daily dose < 2mg bid during the 12-week double-blind randomised, placebo-controlled phase, were continued with their last dose fromperiod 1 regardless of treatment.

The primary objective of the study was to compare the proportion of complete responders(mUFC ≤ ULN) at the end of the 12-week placebo-controlled period between patients randomised toosilodrostat and the ones randomised to placebo. Patients who discontinued the randomised treatmentor discontinued the study during the placebo-controlled period were considered non-responders. Thekey secondary objective was to assess the proportion of complete responders in both arms combined atweek 36 (mUFC ≤ ULN) in patients receiving osilodrostat. Dose reductions and temporary doseinterruptions for safety reasons do not preclude patients from being counted as a complete responderfor the key secondary endpoint.

In study C2302 the primary efficacy endpoint (proportion of complete responders at the end of the 12-weeks placebo-controlled period) was met.

Table 4 Results of the primary endpoint - Phase III study (C2302)

Osilodrostat Placebon=48 n=25

Primary endpoint: 37 (77.1) 2 (8.0)

Complete response rate at the end of12-weeks placebo-controlled period(95% CI*) (6 2 .7, 88.0) (1.0, 26.0)

Response rate difference (odds 43.4 (7.1, 343.2)ratio): osilodrostat vs. placebo 2-sided p-value < 0.0001

All patients

Secondary endpoints N = 73

Key secondary endpoint: Proportion of complete responder after 36-week 59/73 (80.8%)treatment with osilodrostat in both arms combined (95% CI) (69.9, 89.1)mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval; response:mUFC ≤ ULN.

Overall, mUFC consistently decreased during treatment with osilodrostat. Median mUFC was reducedfrom 342.2 nmol/24h (2.5 x ULN) at baseline to 49.2 nmol/24h (0.4xULN; change from baseline -83.6%) at week 12 in patients treated with osilodrostat while placebo patients median mUFC wentfrom 297.6 nmol/24h (2.2 x ULN) at baseline to 305.5 nmol/24h (2.2 x ULN; change from baseline+4.5%).

Median time to first normal mUFC, with the dose escalation used in the study was 35 days in patientstreated with osilodrostat.

Osilodrostat treatment showed an improvement in cardiovascular-related clinical and metabolicparameters (e.g. fasting glucose, systolic blood pressure (SBP), diastolic blood pressure (DBP),weight, and waist circumference) associated with Cushing’s disease. The improvement in theseparameters was already observed at the end of the placebo-controlled period (week 12) and maintainedduring the open-label treatment period (week 12 to 48).

During the placebo-controlled period, there was a trend for more patients in the osilodrostat armexperiencing improvement in their physical features of Cushing’s disease, relative to the placebo arm.

The exceptions were in the domains of facial rubor, striae, and proximal muscle atrophy.

Other causes of Cushing’s syndrome

The efficacy of osilodrostat was also assessed in 9 adult Japanese patients with other causes of

Cushing’s syndrome (adrenal adenoma, ectopic corticotropin syndrome and ACTH independentmacronodular adrenal hyperplasia; study C1201). At week 12 (primary endpoint), a complete response(mUFC ≤ ULN) was observed in 6 patients (66.7%) and a partial response (mUFC decrease by at least50%) in one additional patient (11.1%). The median average dose used in the study was 2.6 mg/day(range 1.3-7.5 mg/day). The mean duration of treatment in this study was 24 weeks, and long-termexposure was limited.

The European Medicines Agency has deferred the obligation to submit the results of studies withosilodrostat in one or more subsets of the paediatric population in adrenal cortical hyperfunction (seesection 4.2 for information on paediatric use).

Osilodrostat is a highly soluble, highly permeable compound (BCS class 1). It is rapidly absorbed (tmax~1 h) and oral absorption in humans is assumed to be nearly complete. Steady state is reached byday 2.

Co-administration with food did not affect absorption to a clinically significant extent. In a healthyvolunteer study (n=20), the administration of a single dose of 30 mg osilodrostat with a high-fat mealresulted in a modest reduction of AUC and Cmax by 11% and 21%, respectively, and the median tmaxwas delayed from 1 to 2.5 hours.

No clinically relevant accumulation was observed in clinical studies. An accumulation ratio of 1.3 wasestimated for the 2 to 30 mg dose range.

The median apparent volume of distribution (Vz/F) of osilodrostat is approximately 100 litres. Proteinbinding of osilodrostat and of its major metabolite M34.5 is low (less than 40%) andconcentration-independent. The osilodrostat blood-to-plasma concentration ratio is 0.85.

Osilodrostat is not a substrate for OATP1B1 or OATP1B3 transporters.

In a human ADME study in healthy subjects following the administration of a single dose of 50 mg[14C]-osilodrostat, metabolism was deemed the most important clearance pathway for osilodrostatsince ~80% of the dose was excreted as metabolites. The three main metabolites in plasma (M34.5,

M16.5 and M24.9) represented 51%, 9% and 7% of the dose, respectively. Both M34.5 and M24.9have longer half-lives than osilodrostat and some accumulation is expected with twice-daily dosing.

The decrease in the contribution of osilodrostat to the radioactivity AUC with time post-dose wasfound to coincide closely with a corresponding increase in the contribution of M34.5.

Thirteen metabolites were characterised in the urine, with the three main metabolites being M16.5,

M22 (an M34.5 glucuronide) and M24.9, with 17, 13 and 11% of the dose, respectively. Theformation of the major urinary metabolite M16.5 (direct N-glucuronide) was catalysed by UGT1A4,2B7 and 2B10. Less than 1% of the dose was excreted as M34.5 (di-oxygenated osilodrostat) in theurine but 13% of the dose was identified as M22 (M34.5-glucuronide). The formation of M34.5 wasnon-CYP-mediated.

Multiple CYP enzymes and UDP glucuronosyltransferases contribute to osilodrostat metabolism andno single enzyme contributes more than 25% to the total clearance. The main CYP enzymes involvedin osilodrostat metabolism are CYP3A4, 2B6 and 2D6. Total CYP contribution is 26%, total UGTcontribution is 19% and non-CYP non-UGT mediated metabolism was shown to contribute to ~50%of total clearance. In addition, osilodrostat showed a high intrinsic permeability, low efflux ratio andmodest impact of inhibitors on the efflux ratio in vitro. This suggests that the potential for clinicaldrug-drug interactions (DDI) with concomitantly administered medicinal products that inhibittransporters or a single CYP or UGT enzyme is low.

In vitro data indicate that the metabolites do not contribute to the pharmacological effect ofosilodrostat.

The elimination half-life of osilodrostat is approximately 4 hours.

In an ADME study, the majority (91%) of the radioactive dose of osilodrostat was eliminated in theurine, with only a minor amount eliminated in the faeces (1.6% of dose). The low percentage of thedose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the majorclearance pathway in humans.

Exposure (AUCinf and Cmax) increased more than dose-proportionally over the therapeutic dose range.

Drug-drug interactions (see also section 4.5)

In vitro data indicate that neither osilodrostat nor its major metabolite M34.5 inhibits the followingenzymes and transporters at clinically relevant concentrations: CYP2A6, CYP2C8, CYP2C9,

UGT2B7, P-gp, BCRP, BSEP, MRP2, OATP1B3 and MATE2-K. Since the exposure of M34.5 hasnot yet been determined after repeated dosing, the clinical relevance of the in vitro drug-druginteraction results for M34.5 is unknown.

In a phase I study in 33 subjects with varying degrees of hepatic function using a single dose of 30 mgosilodrostat, AUCinf was 1.4- and 2.7-fold higher in the moderate (Child-Pugh B) and severe(Child-Pugh C) hepatic impairment cohorts, respectively. Cmax was 15 and 20% lower in the moderateand severe cohorts. The terminal half-life increased to 9.3 hours and 19.5 hours in the moderate andsevere cohorts. Mild hepatic impairment (Child-Pugh A) did not influence exposure to any significantextent. The absorption rate was not affected by the degree of hepatic impairment.

In a phase I study in 15 subjects with varying degrees of renal function using a single dose of 30 mgosilodrostat, comparable systemic exposure was seen in subjects with severe renal impairment,end-stage renal disease and normal renal function.

Race/ethnicity and bodyweight

The relative bioavailability was approximately 20% higher in Asian patients compared to otherethnicities. Body weight was not shown to be a major determinant of this difference.

Age and gender

Age and gender had no significant impact on osilodrostat exposure in adults. The number of elderlypatients in clinical studies was limited (see section 4.2).

In repeat dose toxicity studies conducted in mice, rats and dogs, the central nervous system, liver,female reproductive organs, and the adrenal gland were the primary target organs. The NOAEL forhepatic, reproductive organ and adrenal effects in long-term (26- and 39-week) studies was at leastfour-fold human clinical exposure based on AUC. CNS findings (aggression, hypersensitivity to touchand increased or decreased activity) were noted in the rat, mouse and dog. The NOAEL for the CNSeffects was approximately 2-fold human free Cmax based on the most sensitive species.

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammaliansystems with and without metabolic activation do not indicate a relevant risk in humans. In rat andmice carcinogenicity studies, an increased incidence of hepatocellular adenoma/carcinoma (at lowerdoses in males than females), and neoplastic changes of thyroid follicular adenoma/carcinoma (in malerats only) were observed. The findings are likely rodent specific and considered not relevant tohumans.

Fertility and reproductive toxicity

Reproductive studies in rabbits and rats demonstrated embryotoxicity, foetotoxicity (increasedresorptions and decreased foetal viability, decreased foetal weights, external malformations, andvisceral and skeletal variations) and teratogenicity at maternally toxic doses. The NOAEL was 10-foldhuman exposure (AUC) in a pre- and postnatal developmental study, and 8- to 73-fold humanexposure (AUC) in a rat fertility and early embryonic development study. The maternal and foetal

NOAEL in the rabbit embryofoetal development study was 0.6-fold human exposure (AUC).

Juvenile toxicity

The findings in juvenile rat toxicity studies were largely consistent with those observed in adult ratstudies. Delayed sexual maturation was noted at high doses with no effects on overall reproductiveperformance or parameters after a 6-week recovery period. There were no effects on long bone growthor behavioural performance.

Cellulose, microcrystalline

Mannitol

Croscarmellose sodium

Magnesium stearate

Silica, colloidal anhydrous

Hypromellose

Titanium dioxide (E171)

Macrogol

Talc1 mg tablet

Iron oxide yellow (E172)

Iron oxide red (E172)5 mg tablet

Iron oxide yellow (E172)10 mg tablet

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

3 years

Do not store above 25 °C. Store in the original package in order to protect from moisture.

Alu/Alu blister of 10 tablets.

Packs containing 60 tablets (6 blisters of 10 tablets).

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Rare Diseases

Tour Hekla52 avenue du Général de Gaulle92800 Puteaux

France

Isturisa 1 mg film-coated tablets

EU/1/19/1407/001

Isturisa 5 mg film-coated tablets

EU/1/19/1407/002

Isturisa 10 mg film-coated tablets

EU/1/19/1407/003

Date of first authorisation: 09 January 2020

Date of latest renewal: 07 October 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.