Osilodrostat

{{Short description|Chemical compound}} {{Use dmy dates|date=March 2020}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = | Watchedfields = | verifiedrevid = | image = Osilodrostat.svg | image_class = skin-invert-image | width = 225 | alt = | caption =

| pronounce = | tradename = Isturisa | Drugs.com = {{drugs.com|monograph|osilodrostat-phosphate}} | MedlinePlus = a625069 | DailyMedID = Osilodrostat | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Isturisa APMDS">{{cite web | title=Isturisa | website=Therapeutic Goods Administration (TGA) | date=29 August 2022 | url=https://www.tga.gov.au/resources/auspmd/isturisa | access-date=29 April 2023}}</ref><ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=21 December 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=2 January 2023 | archive-date=3 April 2022 | archive-url=https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database | url-status=live }}</ref> | pregnancy_category= | routes_of_administration = By mouth | class = Steroidogenesis inhibitor | ATC_prefix = H02 | ATC_suffix = CA02 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment = <ref name="Isturisa APMDS" /> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Isturisa Product information | website=Health Canada | date=3 July 2025 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=106212 | access-date=12 October 2025}}</ref><ref>{{cite web | title=Summary Basis of Decision for Isturisa | website=Drug and Health Products Portal | date=1 September 2012 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1755537964152 | access-date=12 October 2025}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Isturisa FDA label">{{cite web | title=Isturisa- osilodrostat tablet, coated; Isturisa- osilodrostat tablet, coated; Isturisa- osilodrostat tablet, coated | website=DailyMed | date=24 July 2025 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3a5ec24-63c3-4d83-b1c0-6c550fbe7ae2 | access-date=24 August 2025}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Isturisa EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| IUPAC_name = 4-[(5''R'')-6,7-Dihydro-5''H''-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile | C=13 | H=10 | F=1 | N=3 | SMILES = C1CC2=CN=CN2C1C3=C(C=C(C=C3)C#N)F | StdInChI_Ref = | StdInChI = 1S/C13H10FN3/c14-12-5-9(6-15)1-3-11(12)13-4-2-10-7-16-8-17(10)13/h1,3,5,7-8,13H,2,4H2/t13-/m1/s1 | StdInChI_comment = | StdInChIKey_Ref = | StdInChIKey = USUZGMWDZDXMDG-CYBMUJFWSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Osilodrostat''', sold under the brand name '''Isturisa''', is a medication used for the treatment of adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease.<ref name="FDA PR">{{cite press release | title=FDA Approves New Treatment for Adults with Cushing's Disease | website=U.S. Food and Drug Administration (FDA) | date=6 March 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease | access-date=6 March 2020 | archive-date=26 July 2020 | archive-url=https://web.archive.org/web/20200726184317/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-cushings-disease | url-status=dead }} {{PD-notice}}</ref> Osilodrostat is an orally active (taken by mouth), nonsteroidal corticosteroid biosynthesis inhibitor which was developed by Novartis for the treatment of Cushing's syndrome and pituitary ACTH hypersecretion (a specific subtype of Cushing's syndrome).<ref name="pmid27600150">{{cite journal | vauthors = Fleseriu M, Castinetti F | title = Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies | journal = Pituitary | volume = 19 | issue = 6 | pages = 643–653 | year = 2016 | pmid = 27600150 | pmc = 5080363 | doi = 10.1007/s11102-016-0742-1 }}</ref> It specifically acts as a potent and selective inhibitor of 11β-hydroxylase (CYP11B1).<ref name="Isturisa FDA label" />

The most common side effects are adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema (swelling caused by fluid retention).<ref name="FDA PR" /><ref name="Isturisa EPAR" />

Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking osilodrostat.<ref name="FDA PR" />

Osilodrostat was approved for medical use in the European Union in January 2020,<ref name="Isturisa EPAR">{{cite web | title=Isturisa EPAR | website=European Medicines Agency (EMA) | date=18 February 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/isturisa | access-date=6 March 2020 | archive-date=7 March 2020 | archive-url=https://web.archive.org/web/20200307071939/https://www.ema.europa.eu/en/medicines/human/EPAR/isturisa | url-status=live }}</ref> and for medical use in the United States in March 2020.<ref name="FDA PR" /><ref name="FDA snapshot">{{cite web | title=Drug Trial Snapshot: Isturisa | website=U.S. Food and Drug Administration (FDA) | date=6 March 2020 | url=http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-isturisa | access-date=27 March 2020 | archive-date=21 September 2020 | archive-url=https://web.archive.org/web/20200921140154/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-isturisa | url-status=dead }} {{PD-notice}}</ref><ref name="FDA Drug Approval Package">{{cite web | title=Drug Approval Package: Isturisa | website=U.S. Food and Drug Administration (FDA) | date=6 April 2020 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000TOC.cfm | access-date=17 January 2021 | archive-date=21 January 2021 | archive-url=https://web.archive.org/web/20210121063222/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212801Orig1s000TOC.cfm | url-status=dead }}</ref> The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.<ref>{{cite web | title=New Drug Therapy Approvals 2020 | website=U.S. Food and Drug Administration (FDA) | date=31 December 2020 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020 | access-date=17 January 2021 | archive-date=18 January 2021 | archive-url=https://web.archive.org/web/20210118011953/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020 | url-status=dead }}</ref>

==History== In October 2014, an orphan designation was granted by the European Commission for osilodrostat for the treatment of Cushing's syndrome.<ref>{{cite web | title=EU/3/14/1345 | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3141345 | access-date=23 July 2020 | archive-date=24 July 2020 | archive-url=https://web.archive.org/web/20200724060644/https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3141345 | url-status=live }}</ref>

Osilodrostat's safety and effectiveness for treating Cushing's disease among adults was evaluated in a study of 137 adult subjects (about three-quarters women) with a mean age of 41 years.<ref name="FDA PR" /> The majority of subjects either had undergone pituitary surgery that did not cure Cushing's disease or were not surgical candidates.<ref name="FDA PR" /> In the 24-week, single-arm, open-label period, all subjects received a starting dose of 2 milligrams (mg) of osilodrostat twice a day that could be increased every two weeks up to 30 mg twice a day.<ref name="FDA PR" /> At the end of this 24-week period, about half of subjects had cortisol levels within normal limits.<ref name="FDA PR" /> After this point, 71 subjects who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received osilodrostat or a placebo (inactive treatment).<ref name="FDA PR" /> At the end of this withdrawal period, 86% of subjects receiving osilodrostat maintained cortisol levels within normal limits compared to 30% of subjects taking the placebo.<ref name="FDA PR" />

The US Food and Drug Administration (FDA) approved osilodrostat based on the evidence from one clinical trial (NCT02180217) of 137 subjects with Cushing's disease.<ref name="FDA snapshot" /> The trial was conducted at 66 sites across 19 countries (United States, Argentina, Austria, Bulgaria, Canada, China, Columbia, Germany, Spain, France, Great Britain, India, Italy, Japan, Korea, Netherlands, Russia, Thailand, and Turkey).<ref name="FDA snapshot" />

There was one trial of 48 weeks duration that assessed the benefits and side effects of osilodrostat.<ref name="FDA snapshot" /> The trial enrolled subjects with Cushing's disease for whom pituitary gland surgery was not an option or did not work.<ref name="FDA snapshot" /> The trial was divided in four periods.<ref name="FDA snapshot" /> Subjects received osilodrostat two times a day in all four periods.<ref name="FDA snapshot" /> After the first two periods (24 weeks), the benefit of osilodrostat was assessed by the percentage of subjects who had 24-hour urinary free cortisol levels within normal limits.<ref name="FDA snapshot" />

In the third period (which lasted eight weeks), half of the subjects who had normal urinary free cortisol levels after 24 weeks of treatment continued taking osilodrostat and the other half was switched to placebo.<ref name="FDA snapshot" /> Neither the subjects nor the healthcare providers know which treatment was given during this period.<ref name="FDA snapshot" /> The benefit of osilodrostat was assessed on the percentage of subjects who had normal cortisol levels at the end of this period versus the subjects who received placebo.<ref name="FDA snapshot" />

The FDA granted osilodrostat an orphan drug designation and granted the approval of Isturisa to Novartis.<ref name="FDA PR" /><ref name="FDA Drug Approval Package" />

==Society and culture== === Legal status === Osilodrostat was authorized for medical use in the European Union in January 2020,<ref name="Isturisa EPAR" /> and approved for medical use in the United States in March 2020.<ref name="FDA PR" /><ref name="FDA snapshot" />

=== Economics === At the recommended starting dose of 2 mg, a year's supply would cost {{US$|172,800}} at 2021 prices in the United States.<ref>{{cite journal |last1=Yuen |first1=Kevin C.J. |title=Osilodrostat: A Review of Recent Clinical Studies and Practical Recommendations for its Use in the Treatment of Cushing Disease |journal=Endocrine Practice |date=September 2021 |volume=27 |issue=9 |pages=956–965 |doi=10.1016/j.eprac.2021.06.012|pmid=34389514 |s2cid=237009673 }}</ref>

== Research == A systematic review and meta-analysis of osilodrostat, published in 2024, found it to have efficacy and safety in normalizing serum cortisol levels in people with Cushing's Syndrome.<ref>{{cite journal | vauthors = Nagendra L, Dutta D, Raizada N, Surana V, Selvan C, Bhattacharya S | title = Efficacy and Safety of Osilodrostat in Managing Cushing's Syndrome: A Systematic Review and Meta-Analysis | journal = Indian Journal of Endocrinology and Metabolism | volume = 28 | issue = 3 | pages = 232–238 | date = 2024 | pmid = 39086571 | pmc = 11288521 | doi = 10.4103/ijem.ijem_260_23 | doi-access = free }}</ref>

==References== {{Reflist}}

==Further reading== * {{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |display-authors=3 |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |isbn=9780470650714 |id=NIHMSID: NIHMS689229 }}

==External links== * {{ClinicalTrialsGov|NCT02697734|Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease (LINC-4)}}

Category:11β-Hydroxylase inhibitors Category:Aldosterone synthase inhibitors Category:Antiglucocorticoids Category:Fluoroarenes Category:Imidazoles Category:Nitriles Category:Drugs developed by Novartis Category:Orphan drugs Category:Pyrroles