Regulatory Decision Summary for Isturisa

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drug Regulations, for Isturisa, filed by Recordati Rare Diseases Canada, Inc.

This submission was filed for Isturisa (osilodrostat) 1 mg, 5 mg, and 10 mg tablets for oral administration for the treatment of endogenous Cushing’s syndrome in adults. Upon review of the submitted data package, Health Canada authorized Isturisa 1 mg, 5 mg, and 10 mg tablets for oral administration for the following indication: 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.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Isturisa (osilodrostat) is a new active substance and a first-in-class steroidogenesis inhibitor. The proposed indication was for the treatment of endogenous Cushing’s syndrome in adults.

Cushing’s syndrome occurs when an individual is exposed to high cortisol levels for a prolonged period. Endogenous causes of Cushing’s syndrome are rare and include pituitary tumours that produce excess adrenocorticotropic hormone (ACTH), a condition known as Cushing’s disease, as well as neuroendocrine tumours and adrenal pathologies.

The efficacy and safety of Isturisa at the proposed dosing regimen were evaluated in two global, multi-centre Phase III studies, C2301 and C2302, which enrolled a total of 210 adult patients with Cushing’s disease who had persistent or recurrent hypercortisolism after primary pituitary surgery and/or irradiation, and patients with de novo Cushing’s disease who were not surgical candidates. Both studies included optional open-label extension phases.

Study C2301 enrolled 137 patients and included a 26-week open-label treatment period followed by an 8-week double-blind randomized withdrawal period. The primary endpoint, the proportion of randomized patients with mean urinary free cortisol less than or equal to the upper limit of normal at Week 34 without dose increase, was met, and the difference between osilodrostat and placebo was clinically significant (86.1% versus 29.4%; odds ratio 13.7; 95% confidence interval [CI] 3.7, 53.4; p<0.001). The complete response rate after 24 weeks of open-label treatment without dose increase between Weeks 13 and 24 was 52.6% (95% confidence interval 43.9, 61.1), and the lower bound of the confidence interval exceeded the pre-specified threshold for statistical significance and clinical benefit.

Study C2302 enrolled 73 patients and included a 12-week double-blind placebo-controlled period followed by a 36-week open-label period. The primary endpoint, the proportion of complete responders at Week 12, was met, and the difference between osilodrostat and placebo was clinically significant (77.1% versus 8.0%; odds ratio 43.4; 95% confidence interval 7.1, 343.2; p<0.001). The proportion of complete responders after 36 weeks of treatment was 80.8% (95% confidence interval 69.9, 89.1), and the lower bound of the confidence interval exceeded the pre-specified threshold for statistical significance and clinical benefit.

Serious safety concerns identified in the clinical studies included hypocortisolism and adrenal insufficiency, hypotension, and QT interval prolongation. Other adverse effects included gastrointestinal symptoms, dizziness, fatigue, and signs of adrenal hormone precursor and androgen accumulation. Non-clinical studies identified a risk of teratogenicity, requiring verification of pregnancy status prior to initiating treatment and the use of effective contraception by women of childbearing potential.

Pharmacokinetic analyses showed that osilodrostat exposure is increased in Asian individuals and in individuals with moderate or severe hepatic impairment; therefore, a lower initial starting dose is recommended for these subgroups.

A Phase II supportive study in patients with causes of Cushing’s syndrome other than Cushing’s disease was insufficient to support an indication beyond Cushing’s disease.

The submitted data were considered adequate to support the use of Isturisa 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. The revised indication reflects the population studied in the pivotal trials.

An updated Canadian addendum to the European Union Risk Management Plan was reviewed and considered acceptable. Risks are communicated in the approved Product Monograph and will be monitored post-market through routine and non-routine pharmacovigilance activities, including two pharmacovigilance studies.

Chemistry and manufacturing data demonstrated that the drug substance and drug product can be consistently manufactured to meet specifications.

The final labeling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favorable for Isturisa 1 mg, 5 mg, and 10 mg tablets for oral administration for the approved indication when used under recommended conditions. A Notice of Compliance was issued.

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