Summary Basis of Decision for Isturisa

Clinical Pharmacology

The clinical pharmacology data support the use of Isturisa (osilodrostat) for the specified indication.

Oilodrostat inhibits 11β-hydroxylase (cytochrome P450 [CYP] 11β1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. The inhibition of 11 β-hydroxylase increases the levels of plasma 11-deoxycortisol (a cortisol precursor with limited biological activity) and adrenocorticotropic hormone (ACTH). Treatment with Isturisa was shown to result in a more pronounced increase in plasma 11-deoxycortisol and ACTH in Japanese subjects compared to Caucasian subjects.

The pharmacokinetics of osilodrostat is comparable between healthy subjects and patients with Cushing’s disease. A more than dose-proportional increase in osilodrostat exposure (as measured by the area under the concentration-time curve [AUC] extrapolated to infinity [AUC_inf] and the maximum observed drug concentration [C_max]) was seen within the therapeutic dose range of 2 to 30 mg twice daily.

Pharmacokinetic data showed that following oral administration, osilodrostat was rapidly absorbed, with a time to reach maximum observed concentration (t_max) of approximately 1 hour. Steady state was reached by Day 2. The elimination half-life of osilodrostat was approximately 4 hours. The blood-to-plasma concentration ratio for osilodrostat in humans was 0.85. Osilodrostat showed low plasma protein binding (36.7%) in humans. Coadministration with food did not affect the absorption of osilodrostat to a clinically significant extent.

The major clearance pathway for osilodrostat in humans is metabolism, mediated by multiple CYP enzymes (CYP3A4, CYP2D6, and CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferases (UGT) (UGT1A4, UGT2B7, and UGT2B10). The major metabolite, M34.5, is not expected to contribute to the pharmacological effect of osilodrostat.

The data indicate no clinically significant impact of sex, age, or degree of renal impairment on osilodrostat exposure. However, the AUC and the C_max values were found to be 32% to 58% higher, and 18.5% to 42% higher, respectively, in Asian patients compared to the values observed in patients of other ethnicities at therapeutic doses (1 mg to 30 mg twice daily). The C_max at steady state for the Asian study population at a dose of 30 mg twice daily was predicted to be 248 ng/mL, which is above the cut-off of 232 ng/mL that is associated with a prolongation of the QT interval. An increased frequency of adverse events, serious adverse events, and higher discontinuation rates were noted in Asians compared to non-Asians. There was also a trend of increasing AUC_inf of osilodrostat in subjects with moderate hepatic impairment and those with severe hepatic impairment (1.44-fold and 2.66-fold, respectively) compared to subjects with normal hepatic function. Based on these data, the Product Monograph for Isturisa includes recommendations for reduced initial starting doses of Isturisa in patients of Asian ancestry, patients with moderate hepatic impairment, and patients with severe hepatic impairment.

Osilodrostat caused a concentration-dependent prolongation of the corrected QT (QTc) interval in a randomized, double-blind, placebo- and positive-controlled, crossover electrocardiogram (ECG) assessment study. The study assessed the effect of single doses of osilodrostat (10 mg and 150 mg) on cardiac repolarization in 86 healthy subjects. The maximum placebo-corrected mean increase from baseline in the QTc interval calculated using the Fridericia formula (QTcF interval) was 1.7 ms (90% confidence interval [CI]: 0.2, 3.3) for the 10 mg dose at 3 hours post dosing and 25.4 ms (90% CI: 23.5, 27.2) for the supratherapeutic 150 mg dose at 1 hour post dosing. The predicted mean placebo-corrected QTcF increase from baseline at the highest recommended dose in clinical practice (30 mg twice daily) was estimated to be 5.3 ms (90% CI: 4.2, 6.5), based on an interpolation of the data from the thorough QT study and a population pharmacokinetic analysis. Osilodrostat had no consistent effect on the QRS duration, the PR interval, or heart rate after single doses of 10 mg and 150 mg in these healthy subjects. Relevant recommendations for ECG monitoring have been included in the Product Monograph for Isturisa.

The potential of osilodrostat for drug-drug interactions was evaluated in vitro and in clinical studies.

In vitro, osilodrostat was found to be a substrate of diverse CYP enzymes (CYP3A4, CYP2D6, and CYP2B6) and UGTs (UGT1A4, UGT2B7, and UGT2B10). The compound showed a potential for induction of CYP1A2, CYP2B6, and CYP3A4, a potential for inhibition of CYP1A2, CYP2C19, CYP2D6, and CYP2E1, and weak inhibition of CYP3A4/5, CYP2B6, and CYP2C9. In addition, osilodrostat and its major metabolite M34.5 exhibited an inhibitory potential towards organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, multidrug and toxin extrusion protein 1 (MATE1) and MATE2-K.

A clinical drug-drug interaction study showed that a single dose of 50 mg osilodrostat was a moderate inhibitor of CYP1A2, a weak to moderate inhibitor of CYP2C19, and a weak inhibitor of CYP2D6 and CYP3A4/5. In another clinical study, no clinically significant drug-drug interactions were observed when oral contraceptives were coadministered with osilodrostat (30 mg twice daily for 12 days).

A list of established or potential drug-drug interactions, along with appropriate precautionary measures, has been included in the approved Isturisa Product Monograph. Recommendations include reducing the dose of Isturisa by half when it is coadministered with strong CYP3A4 inhibitors, a possible increase in Isturisa dose when it is coadministered with strong CYP3A4 or CYP2B6 inducers, and a possible reduction in Isturisa dose when strong CYP3A4 and CYP2B6 inducers are discontinued. The Isturisa Product Monograph also includes recommendations regarding the need for caution, and close monitoring of cortisol levels and patient safety when medicinal products that strongly inhibit or induce specific enzymes are introduced or discontinued during Isturisa treatment.

Furthermore, given that Isturisa can prolong the QTc interval, the Isturisa Product Monograph contains a recommendation to avoid concomitant administration of Isturisa with other drugs known to prolong the QT interval and to exercise caution during the concomitant use of drugs that can decrease serum electrolyte levels, since electrolyte disturbances can also increase the risk of QT interval prolongation.

For further details, please refer to the Product Monograph for Isturisa, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Isturisa in adult patients with Cushing’s disease (CD) was primarily evaluated in two global, multicentre, prospective, pivotal Phase III studies (Study C2301 and Study C2302). In addition, supportive efficacy data were provided from a Phase II, open-label, multicentre, proof-of-concept study (Study C2201).

Both pivotal studies were conducted in adult patients with CD who had persistent or recurrent hypercortisolism after primary pituitary surgery and/or irradiation, or who had de novo CD and were not surgical candidates for medical reasons, refused to undergo surgery, or (in Study C2302) did not have access to a specialized center with experience in pituitary surgery (137 patients in Study C2301 and 73 patients in Study C2302). The evaluation of a novel drug treatment in this specific patient population was considered consistent with current treatment guidelines for CD, which recommend surgery (transsphenoidal selective tumour resection) as the first-line treatment, radiotherapy in non-surgical candidates with CD or as second-line treatment for patients with persistent or recurrent disease after transsphenoidal selective tumour resection, and medical treatment in patients with hypercortisolism after unsuccessful surgery and in those with unresectable or metastatic tumours.

Study C2301 included a 26-week, single-arm, open-label treatment period, followed by an 8-week, double-blind, placebo-controlled, randomized withdrawal period. In the randomized withdrawal period, only patients who were considered responders to Isturisa treatment at Week 24 and who were receiving a stable dose were randomized (1:1), in a double-blind manner, to continue receiving Isturisa or to switch to placebo starting at Week 26. At the end of the randomized withdrawal period (Week 34), the randomized patients entered a 14-week, open-label period of Isturisa treatment.

Study C2302 included a 12-week, double-blind, placebo-controlled period followed by a 36-week, open-label period during which all patients received Isturisa.

In both pivotal studies, the starting dose of Isturisa was 2 mg twice a day with gradual titration every 2 weeks (Study C2301) or every 3 weeks (Study C2302) up to a maximum of 30 mg twice a day until the mean urinary free cortisol (mUFC) was less than or equal to the upper limit of normal (ULN). Doses of Isturisa could be reduced to less than 2 mg twice a day if the mUFC was below the lower limit of normal or in the lower part of the normal range for patients with signs and/or symptoms of adrenal insufficiency. A patient was considered to have reached a stable efficacious dose when mUFC remained less than or equal to the ULN and the patient had no signs or symptoms of adrenal insufficiency. In the pivotal studies, the mean and median doses varied between 2 mg and 5 mg twice a day. The highest daily dose received in both studies was 60 mg (i.e., 30 mg twice a day).

Baseline characteristics of the patient population were similar in the two pivotal studies. The majority of patients were female (77% in Study C2301 and 84% in Study C2302) and the mean age of the patients was approximately 41 years, consistent with the known epidemiology of CD. The studies included nine patients 65 years of age or older; no patients were 75 years of age or older. The majority of patients were Caucasian (65.0% in Study C2301 and 67.1% in Study C2302). In both studies, the majority of patients (approximately 88%) had persistent/recurrent CD after pituitary surgery; 12% to 16% of patients had previous pituitary irradiation. The median baseline mUFC was approximately 3.5 times the ULN in Study C2301 and 2.5 times the ULN in Study C2302.

In Study 2301, the primary efficacy endpoint was the proportion of complete responders at the end of the 8-week randomized withdrawal period (at Week 34). A complete response for the primary endpoint was defined as mUFC less than or equal to the ULN based on central laboratory results at the end of the 8-week randomized withdrawal period (Week 34), and no drug discontinuation or dose increase above the Week 26 dose level during the randomized withdrawal period of the study. Patients who discontinued the randomized treatment or discontinued the study during the randomized withdrawal period were considered non-responders. The study demonstrated a statistically significantly higher proportion of complete responders at the end of the 8-week randomized withdrawal period among patients treated with Isturisa (31/36 or 86.1%, 95% CI: 70.5%, 95.3%) than among the placebo-treated patients (10/34 or 29.4%, 95% CI: 15.1%, 47.5%), with an odds ratio of 13.7 (95% CI: 3.7, 53.4; two-sided p < 0.001) for Isturisa versus placebo.

The key secondary endpoint in Study 2301 was the proportion of complete responders at Week 24 during the open-label period. A complete response for the key secondary endpoint was defined as mUFC less than or equal to the ULN at Week 24 and no Isturisa dose increase during Study Period 2 (Week 13 to Week 24) above the level established at the end of Study Period 1 (Week 12). Patients who were missing their mUFC assessment at Week 24 were counted as non-responders for the key secondary endpoint. The proportion of complete responders after 24 weeks of treatment with Isturisa in the initial open-label single-arm phase was 72/137 (52.6%) with a 95% two-sided CI: 43.9%, 61.1%. The lower bound of this 95% confidence interval exceeded 30%, which was the prespecified threshold for statistical significance and the minimum threshold for clinical benefit.

In Study 2302, the primary efficacy endpoint was the proportion of complete responders at the end of the 12-week placebo-controlled period. A complete response for the primary endpoint was defined as mUFC less than or equal to the ULN based on central laboratory results at the end of the 12-week placebo-controlled period (Week 12). Patients who discontinued the randomized treatment or discontinued the study during the placebo-controlled period were considered non-responders. At the end of the 12-week placebo-controlled period, there was a statistically significantly higher proportion of complete responders among patients treated with Isturisa (37/48 or 77.1%, 95% CI: 62.7%, 88.0%) compared to the placebo arm (2/25 or 8.0%, 95% CI: 1.0%, 26.0%) (odds ratio for Isturisa versus placebo: 43.4, 95% CI: 7.1, 343.2, two-sided p < 0.001).

The key secondary endpoint in Study 2302 was the proportion of complete responders to Isturisa in both arms combined at Week 36 (open-label phase). A complete response was defined as mUFC less than or equal to the ULN at Week 36. Dose reductions and temporary dose interruptions for safety reasons did not preclude patients from being counted as a complete responder for the key secondary endpoint. The proportion of complete responders after 36 weeks of treatment with Isturisa in both arms combined was 59/73 (80.8%) with a 95% two-sided CI: 69.9%, 89.1%. The lower bound of this 95% confidence interval was above the prespecified threshold (30%) for statistical significance and clinical benefit.

Prespecified, post hoc, supportive and sensitivity analyses were consistent with the primary analyses, confirming robustness of the efficacy results.

There were no consistent trends observed in either of the pivotal studies regarding endpoints that evaluated physical features of CS or patient-reported outcomes (as measured by the Cushing’s Disease Health-Related Quality-of-Life Questionnaire and the EQ-5D-5L instrument).

Indication

The New Drug Submission for Isturisa was filed by the sponsor with the following proposed indication:

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

While the sponsor submitted results from a Phase II open-label study in 9 Japanese patients diagnosed with endogenous Cushing’s syndrome due to causes other than Cushing’s disease, the data were not considered adequate to establish a safe and efficacious dosing regimen or an overall benefit-harm-uncertainty profile of Isturisa for the Canadian population of patients with causes of Cushing’s syndrome other than Cushing’s disease. Therefore, Health Canada revised the proposed indication to reflect solely the study populations in the two pivotal studies. Accordingly, Health Canada approved the following indication:

Isturisa (osilodrostat) is indicated for the treatment of adult patients with Cushing’s disease who have persistent or recurrent hypercortisolism after primary pituitary surgery and/or irradiation, or for whom pituitary surgery is not an option.

For more information, refer to the Product Monograph for Isturisa, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Isturisa was primarily evaluated in the two pivotal Phase III studies (Study C2301 and Study C2302, described in the Clinical Efficacy section).

The most commonly reported adverse reactions (that occurred in at least 20% of Isturisa-treated patients in at least one study) were fatigue (47% and 45% in Study C2301 and Study C2302, respectively), hypocortisolism-related events (54% and 29%), arthralgia (21% and 47%), decreased appetite (16% and 47%), nausea (45% and 37%), headache (37% and 34%), dizziness (19% and 30%), hypotension (12% and 27%), vomiting (25% and 12%), edema (23% and 16%), increased blood testosterone (12% and 25%), myalgia (15% and 25%), diarrhea (20% and 23%), back pain (21% and 14%), and increased blood corticotrophin (20% and 3%).

The most commonly reported serious adverse reactions in patients treated with Isturisa in both Phase III studies were hypocortisolism related (10% and 4% in Study C2301 and Study C2302, respectively). Two deaths occurred in patients treated with Isturisa during Study C2301. One death was due to suicide and one death was due to cardiopulmonary failure following viral gastroenteritis. Neither of the deaths were considered by the study investigator to be related to study drug. No deaths were reported in Study C2302. The Product Monograph for Isturisa includes a recommendation that patients be educated on the signs and symptoms suggestive of hypocortisolism (nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness, myopathy, severe headache, hypotension, hypoglycemia), especially in the context of a stress such as acute infection, and be advised to inform their health care professional if they experience such symptoms. The Product Monograph also includes a recommendation that patients receiving Isturisa should be warned about the potential for dizziness, fatigue, and hypotension, and should be advised not to drive if these signs and/or symptoms occur.

Elevations in liver transaminases were occasionally observed but were typically mild and reversed spontaneously or following dose adjustment. No patients discontinued Isturisa due to abnormal liver chemistry parameters and there were no cases of concurrent alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal (ULN) and total bilirubin levels greater than or equal to 1.5 times the ULN.

In Study C2301, five (4%) patients treated with Isturisa experienced adverse reactions of QT prolongation (including syncope), all of which were non-serious. One of the adverse reactions occurred in a patient receiving a medication that was prohibited in the protocol due to its known effect on QT (trazodone). In Study C2302, two (3%) patients treated with Isturisa had adverse reactions related to QT prolongation, including one serious reaction leading to hospitalization and one non-serious reaction that occurred concurrently with hypokalemia. The sponsor confirmed that no cases of torsades de pointes have been reported in clinical studies with Isturisa or in the post-market period in other jurisdictions.

Clinical practice guidelines for treatment of CD point out that for agents targeting adrenal steroidogenesis, there is concern regarding pituitary tumour growth due to ACTH-cortisol feedback interruption and that it can be difficult to determine whether such tumour progression is due to this loss of feedback or reflects the underlying behaviour of aggressive, recurrent disease. In the Phase III studies, a progressive increase in ACTH levels compared to baseline was observed in patients treated with Isturisa, but there was no clear relationship identified between ACTH changes from baseline and increases in pituitary tumour volume.

There were isolated adverse reactions of depression and anxiety, including one death due to suicide in Study C2301. The patient had a long-standing history of depression, and the death was considered unrelated to the study drug. Review of the safety data from the Phase III studies did not indicate a clear association between the use of Isturisa and an increased risk of depression or suicidal ideation. Depression is listed as an adverse reaction in the approved Product Monograph for Isturisa. Furthermore, at Health Canada’s request, based on post-market information, “psychiatric events (including depression and suicidal ideation)” were added as an important potential risk in the Canadian addendum to the risk management plan approved in European Union, to be further monitored in the post-market period.

In the clinical study protocols, decreases in neutrophil counts were identified as a known effect related to the decrease of cortisol in patients with CD. In the two Phase III studies, decreased neutrophil counts were common but were not clearly correlated with increased rates of clinical outcomes such as sepsis or other serious concomitant infections. Decreases in hemoglobin were common but were considered to be possibly due to the mechanistic effect of osilodrostat leading to fluid retention and some degree of hemodilution. Decreases in high-density lipoprotein cholesterol, increases in serum triglycerides, and increases in pancreatic lipase were common but were not clearly correlated with increased rates of clinically relevant outcomes. The underlying cause and the clinical relevance of these findings are unknown.

Overall, the safety profile of Isturisa is considered acceptable for the intended patient population. Appropriate warnings and precautions are in place in the approved Product Monograph for Isturisa to address the identified safety concerns.

For more information, refer to the Product Monograph for Isturisa, approved by Health Canada and available through the Drug Product Database.

The non-clinical data package submitted for Isturisa (osilodrostat) included pharmacology, pharmacokinetics, and toxicology studies.

In primary pharmacology studies, osilodrostat inhibited the activity of recombinant human 11β-hydroxylase (cytochrome P450 [CYP] 11β1, the last enzyme in the glucocorticoid synthesis pathway) in vitro with half-maximal inhibitory concentration (IC₅₀) values of 2.5 nM to 3.2 nM, thereby inhibiting the cortisol production in cultured cells. Osilodrostat also inhibited CYP11β2 (aldosterone synthase) and aromatase with IC₅₀ values of 0.7 nM and 1.7 μM, respectively. Neither osilodrostat, nor its major metabolite, M34.5, showed any relevant off-target activity. However, the exposure of M34.5 metabolite after repeating dosing in humans is unknown.

Safety pharmacology studies suggest that osilodrostat could have effects on the cardiovascular system. In vitro, osilodrostat inhibited human ether-à-go-go-related gene (hERG) tail currents in transfected HEK293 cells with an IC₅₀ of 54 µM. In addition, prolongation of the corrected QT (QTc) interval was observed in a rabbit ventricular wedge assay at osilodrostat concentrations greater than 0.4 μM. In vivo, QTc interval prolongation was observed in telemetry studies in cynomolgus monkeys after a single oral osilodrostat dose greater than or equal to 30 mg/kg, or upon a 2-week oral administration of osilodrostat doses greater than or equal to 10 mg/kg. Changes in blood pressure were also observed in some animals. Adverse central nervous system (CNS)-related reactions were reported in a telemetry study in cynomolgus monkeys dosed at 100 mg/kg (a dose resulting in a maximum plasma concentration [C_max] that was more than 130-fold higher than the C_max at the maximum recommended human dose of 30 mg twice daily). No adverse effects on respiratory functions were noted after administration of a single oral dose of osilodrostat (1.5 mg/kg or 5 mg/kg) to male rats.

The toxicology program for osilodrostat was carried out in accordance with relevant guidelines. It included repeat-dose toxicology studies conducted in mice (up to 13 weeks’ duration), rats (up to 26 weeks’ duration) and dogs (up to 39 weeks’ duration), fertility, embryo-fetal, prenatal and postnatal development toxicology studies conducted in rats and rabbits, and juvenile studies conducted in rats. Carcinogenicity was evaluated in 2-year studies in mice and rats. Primary targets of osilodrostat-related toxicity were considered to be the CNS, liver, adrenal glands, and female reproductive system. The no-observed-adverse-effect level was determined to be 2 mg/kg/day in rats (based on a 26-week study) and 10 mg/kg/day in dogs (based on a 39-week study), which produced exposures corresponding to 2.2 times and 8 times, respectively, the anticipated exposure (based on the area under the concentration-time curve) at the maximum recommended human dose of 30 mg twice daily.

The results of the submitted carcinogenicity and genotoxicity studies did not indicate concerns regarding use of osilodrostat in humans.

In embryo-fetal development studies in rats and rabbits, osilodrostat exhibited maternal toxicity, embryo-fetal toxicity, and teratogenicity.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Isturisa. In view of the intended use of Isturisa, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Isturisa, approved by Health Canada and available through the Drug Product Database.

Based on the review of the initially provided quality data in the New Drug Submission for Isturisa, Health Canada determined that the sponsor’s control strategies for several impurities (including nitrosamines) in the drug substance were not adequate to substantiate a conclusion with respect to the safety of Isturisa. This determination led to the issuance of a Notice of Non-Compliance (NON). Upon review of the sponsor’s response to the NON, Health Canada concluded that all issues of concern were addressed satisfactorily.

Overall, the quality (chemistry and manufacturing) information submitted for Isturisa has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at 20 ºC to 25 ºC and protected from moisture.

The proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies). The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in Isturisa are prohibited for use in drug products by the Food and Drug Regulations. The excipients are not of animal or human origin.